Pulmonary renal syndromes--a review.

Several systemic diseases share clinical, pathologic and radiologic characteristics. This article emphasizes similarities and differences in the clinical and chest radiographic manifestations of six diseases with both pulmonary and renal abnormalities-Goodpasture''s syndrome, Wegener''s granulomatosis, lymphomatoid granulomatosis, Churg-Strauss syndrome, systemic lupus erythematosus, and scleroderma.     

Ocular and systemic manifestations of connective tissue disease: Part II,the seronegative spondyloarthropathies and vasculitides

The connective tissue diseases are musculoskeletal disorders which have multisystemic involvement, frequently have associated ocular manifestations, and although the specific etiologies are unknown, they all demonstrate abnormalities of the immune system. In the second of this two part series, the systemic and ocular findings of a number of the seronegative spondyloarthropathies and vasculitides will be discussed. These include ankylosing spondylitis, Reiter's syndrome, polyarteritis nodosa, Wegener's granulomatosis, and giant cell arteritis.     

Relapses in Wegener's granulomatosis: the role of infection.

Out of 20 relapses that occurred in patients with Wegener''s granulomatosis, nine were provoked by bacterial or viral infection. Seven of these occurred during maintenance treatment in response to infection with common pathogens, and treatment of the infection alone was insufficient to produce remission. Circulating immune complexes were seen only in relapses due to infection and rarely in infections that occurred without relapse. A possible mechanism for infection-provoked relapses is that infection-derived complexes reactivate disease; alternatively, the acute-phase or cellular response to infection may enhance quiescent disease. Infection may exacerbate Wegener''s granulomatosis and other autoallergic diseases, but whether it does so by a common mechanism is not known and further study is required.     

Towards a more rapid diagnosis of rapidly progressive glomerulonephritis.

An attempt was made to provide simple practical guidelines to alert general practitioners to the diagnosis of rapidly progressive glomerulonephritis and lead to early referral to hospital. The duration of illness before referral to this hospital and its effect on outcome in patients with crescentic nephritis were assessed retrospectively from the case notes of 24 patients referred over two years. Four patients had Goodpasture''s syndrome, 11 Wegener''s granulomatosis, seven microscopic polyarteritis, and two idiopathic progressive glomerulonephritis. The duration of symptoms before referral to the local hospital was similar in the four groups of patients and varied from one week to 28 months (mean 10 months). The duration of stay in the local hospital was two, nine, 11, and 180 days in the patients with Goodpasture''s syndrome and a mean of four days (range one to eight) in those with Wegener''s granulomatosis and 10 days (one to 18 days) in those with microscopic polyarteritis. In the local hospital the diagnosis was based on the results of renal biopsy and detection of antibodies to glomerular basement membrane in two patients with Goodpasture''s syndrome and on the results of renal biopsy in seven of the other patients aided by the detection of antibodies to the cytoplasm of neutrophils (ANCA) in 10. Three of the 24 patients died and four required maintenance haemodialysis. Patients who present to their general practitioners with persistent non-specific symptoms should have a urine dipstick test and then blood tests and emergency referral to hospital if necessary. Hospital physicians should be aware of the speed and accuracy with which current assays can confirm a diagnosis of rapidly progressive glomerulonephritis.     

Immunopathologic differences of Sjögren's syndrome versus sicca syndrome in HCV and HIV infection

A clinical picture of dry eye and dry mouth with the histological counterpart of focal lymphocytic sialoadenitis, usually detected in minor salivary glands, is considered the hallmark of Sjögren's syndrome. The association of sicca complaints and focal sialoadenitis can be also found in a number of other diseases, including some systemic viral infections. Among these conditions, chronic hepatitis C virus infection, associated with mixed cryoglobulinaemia and extra-hepatic manifestations, and HIV infection, particularly in the phase of diffuse interstitial lymphocytic infiltration, may mimic the clinical and histological aspects of Sjögren's syndrome. However, each disorder is characterised by specific, disease-related immunopathological aspects. Besides sicca complaints, the various disorders may also share a number of systemic extra-glandular features and the possible development of mucosa-associated lymphoid tissue lymphomas. This latter event represents in all of these diseases the final result of an antigen-driven chronic stimulation of B lymphocytes.     

Diseases associated with specific HL-A antigens.

Significantly increased prevalences of particular HL-A antigens have been reported for many human diseases. The correlation is particularly striking in ankylosing spondylitis, Reiter''s syndrome, psoriasis and some immunopathic disorders, so that HL-A typing may be of great value in diagnosis. The possible mechanisms whereby these associations may occur suggest the cause of certain disorders, and further investiatation will likely help in the understanding of the pathogenesis of many diseases.     

Hypersensitivity pneumonitis.

Although the cause and development of most inflammatory and fibrotic interstitial lung diseases are unknown, both the antigenic stimuli and the immunopathogenic mechanisms that produce the syndrome of hypersensitivity pneumonitis have been well described. Hypersensitivity pneumonitis is a group of related inflammatory and fibrotic interstitial lung diseases that result from hypersensitivity immune reactions to the repeated inhalation of antigens derived from fungal, bacterial, animal protein, and reactive chemical sources. Immune complex-induced inflammatory reactions initiate acute lung injury; T cell-mediated hypersensitivity reactions perpetuate it and induce chronic inflammatory, granulomatous, and fibrotic responses in the interstitium of the lungs. Because the natural history of many interstitial lung diseases of unknown causes involves the progressive evolution through these same phases, knowledge about immune pathogenesis gained from studies of hypersensitivity pneumonitis may provide a way to understand the causes and development of other interstitial lung diseases.     

Molecular mimicry--hypothesis or reality?

A number of observations support molecular mimicry as a possible pathogenetic mechanism in diseases such as acute rheumatic fever, reactive arthritis after enteric infection or associated with Reiter''s syndrome, myasthenia gravis, or even in rheumatoid arthritis. Molecular mimicry can be defined as a sharing of epitopes in linear or 3-dimensional presentation on disparate proteins from entirely different sources--for instance, group A streptococcal membranes and human cardiac myosin. How exposure to or infection with organisms sharing molecular similarity with antigens of the human host can evade tolerance and actually induce a self-reacting humoral or cellular immune response is still not clear; however, a large body of evidence has now been accumulated that documents apparent molecular mimicry mechanisms in these disorders. In some diseases, the molecular mimicry appears to involve human target organs and specific components of the infectious organism, whereas in others the host HLA cell surface molecules appear to share antigens with presumed bacterial or viral initiators of disease.     

General anesthesia in Eisenmenger's syndrome.

The anesthetic management of a woman with Eisenmenger''s syndrome undergoing abdominal hysterectomy with general anesthesia is described. Proper anesthetic management of patients with this syndrome depends on a knowledge of the pathophysiologic process and associated complications. The potential problems of systemic hypotension, pulmonary embolism and infective endocarditis are outlined. Sudden death is a common and pregnancy is a major hazard.     

“Sicca Complex” in Liver Disease

Sixty-three patients with liver disease were studied for the presence of the components of Sjögren''s syndrome. The “sicca complex” (that is, patients without arthritis) was detected in 42% of patients with active chronic hepatitis, 72% with primary biliary cirrhosis, and 38% with cryptogenic cirrhosis. One patient with active chronic hepatitis and one with primary biliary cirrhosis had rheumatoid arthritis. No evidence of Sjögren''s syndrome was detected in seven patients with alcoholic cirrhosis. It is suggested that the sicca complex and autoimmune liver disease may be part of a systemic disorder in which immunological mechanisms are concerned in the pathogenesis.     

Fibrosing Alveolitis Associated with Renal Tubular Acidosis

The discovery of a case of renal tubular acidosis and fibrosing alveolitis led to the investigation of 19 further patients. Abnormal pulmonary function tests were found in a further four patients with overt renal tubular acidosis and in four out of eight patients with “incomplete” renal tubular acidosis. The response to an ammonium chloride test in seven patients with cryptogenic fibrosing alveolitis was normal. Those patients with a defect of both renal acidification and pulmonary gas transfer had concurrent autoimmune diseases such as Sjögren''s syndrome and primary biliary cirrhosis. It is suggested that the renal and pulmonary abnormalities may be part of a systemic disorder capable of affecting many organs. Moreover, hyperglobulinaemia and autoantibodies in these patients further suggests that immunological mechanisms are concerned in the pathogenesis of these abnormalities.     

Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant.

The lupus anticoagulant was found in the plasma of 31 of 60 patients with systemic lupus erythematosus and other connective tissue disorders (mixed connective tissue disease, systemic vasculitis, polyarteritis nodosa, primary sicca syndrome, discoid lupus, Behcet''s syndrome, and systemic sclerosis). Strong associations were found with biological false positive seroreaction for syphilis and thrombocytopenia. The most striking association, however, was with the high prevalence of thrombosis. This tendency to thrombosis was independent of disease activity of systemic lupus erythematosus. The lupus anticoagulant appears to be a useful marker for a subset of patients with systemic lupus erythematosus at risk for the development of thromboembolic complications.     

Length of survival of patients with acquired immune deficiency syndrome in the United Kingdom.

An analysis of the lengths of survival of patients with the acquired immune deficiency syndrome presenting with different opportunistic diseases was performed using epidemiological data routinely collected at the PHLS Communicable Disease Surveillance Centre. The overall crude case fatality rate was 55.4% (93/168). The median survival times were: 21.2 months for Kaposi''s sarcoma, 12.5 months for Pneumocystis carinii pneumonia, and 13.3 months for other opportunistic infections. The shortest median survival time (6.6 months) was found for those with both Kaposi''s sarcoma and P carinii pneumonia. There were significant differences between durations of survival of patients with Kaposi''s sarcoma and those with all other diseases, which indicated impaired cellular immunity apart from opportunistic infections. This analysis shows that those with Kaposi''s sarcoma alone have the most favourable prognosis.     

Clinical value of whole-body PET/CT in patients with active rheumatic diseases

Advanced imaging techniques may enable early diagnosis and monitoring of therapy in various rheumatic diseases. To prevent irreversible tissue damage, inflammatory rheumatic disease must be diagnosed and treated in pre-clinical stages, requiring highly sensitive detection techniques. Positron emission tomography (PET) provides highly sensitive, quantitative imaging at a molecular level, revealing the important pathophysiological processes underlying inflammation. This review provides an overview of the current utility of ¹⁸?F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) in patients with active rheumatic diseases such as rheumatoid arthritis, spondyloarthritis, polymyalgia rheumatica, adult-onset Still’s disease, relapsing polychondritis, immunoglobulin G4-related disease, large-vessel vasculitis, Wegener’s granulomatosis, polymyositis, and dermatomyositis. We also discuss the role of FDG-PET/CT in the diagnosis and monitoring of these diseases.     

Prenatal and postnatal prevalence of Turner's syndrome: a registry study.

OBJECTIVE--To study prevalence of Turner''s syndrome in Denmark and to assess validity of prenatal diagnosis. DESIGN--Study of data on prenatal and postnatal Turner''s syndrome in Danish Cytogenetic Central Register. SUBJECTS--All registered Turner''s syndrome karyotypes (100 prenatal cases and 215 postnatal cases) during 1970-93. MAIN OUTCOME MEASURES--Prevalence of Turner''s syndrome karyotypes among prenatally tested fetuses and Turner''s syndrome among liveborn infants. RESULTS--Among infant girls, prevalence of Turner''s syndrome was 32/100,000. Among female fetuses tested by amniocentesis, prevalence of Turner''s syndrome karyotypes was 176/100,000 (relative risk of syndrome, 6.74 compared with prevalence among untested pregnancies). Among female fetuses tested by chorion villus sampling, prevalence of syndrome karyotypes was 392/100,000 (relative risk, 16.8). We excluded prenatal tests referred because of results of ultrasound scanning: among fetuses tested by amniocentesis revised relative risk was 5.68, while revised relative risk among fetuses tested by chorion villus sampling was 13.3. For 29 fetuses with prenatal diagnosis of possible Turner''s syndrome, pregnancy was allowed to continue and 24 children were live born. Thirteen of these children were karyotyped postnatally, and diagnosis of Turner''s syndrome had to be revised for eight, seven being normal girls and one boy. This gives tentative predictive value of amniocentesis in diagnosing Turner''s syndrome of between 21% and 67%. There was no significant relation between mother''s age and risk of Turner''s syndrome. CONCLUSIONS--Discrepancy between prenatal and postnatal prevalence of Turner''s syndrome challenges specificity of prenatal examination in diagnosing Turner''s syndrome.     

An Effective Method to Identify Shared Pathways and Common Factors among Neurodegenerative Diseases

Groups of distinct but related diseases often share common symptoms, which suggest likely overlaps in underlying pathogenic mechanisms. Identifying the shared pathways and common factors among those disorders can be expected to deepen our understanding for them and help designing new treatment strategies effected on those diseases. Neurodegeneration diseases, including Alzheimer''s disease (AD), Parkinson''s disease (PD) and Huntington''s disease (HD), were taken as a case study in this research. Reported susceptibility genes for AD, PD and HD were collected and human protein-protein interaction network (hPPIN) was used to identify biological pathways related to neurodegeneration. 81 KEGG pathways were found to be correlated with neurodegenerative disorders. 36 out of the 81 are human disease pathways, and the remaining ones are involved in miscellaneous human functional pathways. Cancers and infectious diseases are two major subclasses within the disease group. Apoptosis is one of the most significant functional pathways. Most of those pathways found here are actually consistent with prior knowledge of neurodegenerative diseases except two cell communication pathways: adherens and tight junctions. Gene expression analysis showed a high probability that the two pathways were related to neurodegenerative diseases. A combination of common susceptibility genes and hPPIN is an effective method to study shared pathways involved in a group of closely related disorders. Common modules, which might play a bridging role in linking neurodegenerative disorders and the enriched pathways, were identified by clustering analysis. The identified shared pathways and common modules can be expected to yield clues for effective target discovery efforts on neurodegeneration.     

Antineutrophil cytoplasmic autoantibody in renal disease

ANCA are an important marker for identifying pauci-immune necrotizing and crescentic glomerulonephritis and systemic vasculitis. Patients with ANCA-associated renal disease have a spectrum of illness ranging from renal-limited disease to widespread vasculitis, including the clinicopathologic syndromes of polyarteritis nodosa and Wegener's granulomatosis. ANCA may be directly involved in the pathogenesis of pauci-immune glomerulonephritis and necrotizing systemic vasculitis.     

Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system

Evidence is lacking for direct pathogenicity of human anti-proteinase-3 (PR3) antibodies in development of systemic vasculitis and granulomatosis with polyangiitis (GPA, Wegener''s granulomatosis). Progress in study of these antibodies in rodents has been hampered by lack of PR3 expression on murine neutrophils, and by different Fc-receptor affinities for IgG across species. Therefore, we tested whether human anti-PR3 antibodies can induce acute vasculitis in mice with a human immune system. Chimeric mice were generated by injecting human haematopoietic stem cells into irradiated NOD-scid-IL2Rγ^−/− mice. Matched chimera mice were treated with human IgG from patients with: anti-PR3 positive renal and lung vasculitis; patients with non-vasculitic renal disease; or healthy controls. Six-days later, 39% of anti-PR3 treated mice had haematuria, compared with none of controls. There was punctate bleeding on the surface of lungs of anti-PR3 treated animals, with histological evidence of vasculitis and haemorrhage. Anti-PR3 treated mice had mild pauci-immune proliferative glomerulonephritis, with infiltration of human and mouse leukocytes. In 3 mice (17%) more severe glomerular injury was present. There were no glomerular changes in controls. Human IgG from patients with anti-PR3 autoantibodies is therefore pathogenic. This model of anti-PR3 antibody-mediated vasculitis may be useful in dissecting mechanisms of microvascular injury.     

Five cases of cyclical Cushing's syndrome.

Reported cases of cyclical Cushing''s syndrome are rare. Of 14 successive patients with Cushing''s syndrome nine collected sequential urine samples for the estimation of cortisol:creatinine ratio. Five had cyclical Cushing''s syndrome while two had considerable variation in urinary cortisol excretion without a cyclical pattern being established. Two of the five patients with a cyclical syndrome had paradoxical responses to dexamethasone. In only one patient with a cyclical pattern did the cortisol:creatinine ratio fall after treatment with bromocriptine or cyproheptadine, or both. The high incidence of the cyclical form of Cushing''s syndrome has important clinical implications. A high index of suspicion of the syndrome is required in patients with symptoms or signs of Cushing''s syndrome but with normal cortisol values, in patients with fluctuating cortisol values, and in patients with anomalous responses to dexamethasone. Because of possible variations in steroidogenesis the results of drug studies in Cushing''s syndrome must be interpreted cautiously.