Clinical aspects and immune reactions in sarcoidosis*

Introduction: Sarcoidosis is a granulomatous disorder of unknown aetiology, affecting young adults and frequently involving the lungs. Objective: The aim of the present review was to give an overview of the clinical aspects in sarcoidosis. Results: The majority of patients recover, but some develop a chronic disease that may result in fibrosis and respiratory failure. Besides the lungs, peripheral lymph nodes, the skin, the liver and the eyes are commonly affected as well. The genetic background, as well as environmental factors, is of importance for developing sarcoidosis. The incidence varies in different populations, in the Nordic countries approximately with 20/100 000 new patients yearly. Sarcoidosis is diagnosed when clinical and radiological findings are supported by histological evidence in the form of non‐caseating epithelioid cell granulomas, and when other causes of these features are excluded. Patients in need of treatment are usually treated with corticosteroids, topically or as oral steroids. A clinical effect of immunomodulatory drugs blocking tumour necrosis factor (TNF)α has been suggested from several case reports, while two controlled studies showed only minor effects; however, with a tendency to a more pronounced effect on patients with a more severe disease. The immune response in sarcoidosis, with a typical accumulation of CD4+ T‐cells to the lungs, indicate the existence of specific antigens in this disease. Recently, antigens derived from infectious agents such as Mycobacteria and Proprionibacterium acnes have come into focus. Lymphocyte populations with immunoregulatory functions have recently been investigated and seem to be dysfunctional in sarcoidosis, opening the possibility of developing new treatment strategies in this disease. Conclusion: Recent technical developments have provided better tools, enabling detailed and more thorough analyses of the inflammatory process in sarcoidosis. Please cite this paper as: Grunewald J. Clinical aspects and immune reactions in sarcoidosis. The Clinical Respiratory Journal 2007; 1:64–73.     

Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT.

We developed a questionnaire to assess autonomic symptoms in patients with Parkinson's disease (PD) and evaluated its reliability and validity. Based on the results of a postal survey in 46 PD patients, 21 multiple system atrophy patients, and 8 movement disorders specialists, items were included according to their frequency, burden, and clinical relevance. The questionnaire was evaluated in 140 PD patients and 100 controls, and test-retest reliability was established in a sample of 55 PD patients. The SCOPA-AUT consists of 25 items assessing the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction. Test-retest reliability was good. Autonomic problems increased significantly with increasing disease severity for all autonomic regions, except sexual dysfunction. We conclude that SCOPA-AUT is a reliable and valid questionnaire that evaluates autonomic dysfunction in PD.     

Serological investigation of canine encephalitozoonosis in Norway

Encephalitozoon cuniculi, a microsporidian parasite of vertebrates, is considered a health risk to AIDS patients and other immunocompromised human beings. In most hosts, infection with the parasite runs a subclinical course. In some carnivore species, however, clinical disease affecting whole litters arises from intrauterine transmission of the parasite. In both blue foxes (Alopex lagpus) and dogs (Canis familiaris), outbreaks of encephalitozoonosis can be severe. Canine encephalitooonosis has been reported from various parts of the world, including South Africa and the United States. In Norway, there have been large outbreaks of the disease in blue fox farms, affecting also mink, but there have been no reports of encephalitozoonosis in dogs. Infection in dogs would represent a zoonotic problem, due to the close social relationship between dog and man. The purpose of the present study was to investigate the possible occurrence of E. cuniculi infection in Norwegian dogs by serological methods. In the study, 1,104 canine serum samples, originally submitted for biochemical analysis by veterinary practitioners throughout Norway, were screened by enzyme-linked immunosorbent assay for antibodies to E. cuniculi. Samples from 237 of the dogs were tested also by the indirect fluorescent antibody test. All samples were concluded as negative. The results indicate that the likelihood of occurrence of E. cuniculi infection in Norwegian dogs is small.     

Raised intracranial pressure,the syndrome of inappropriate antidiuretic hormone secretion,and arginine vasopressin in tuberculous meningitis

Intracranial pressure (ICP) monitored shortly after admission over a period of 1 h in 31 children with tuberculous meningitis (TBM) was significantly higher (median 22.5 mm Hg, range 8.4–50.9 mmHg) in 19 children with laboratory evidence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) than in 12 children without such evidence (median 16.2 mmHg, range 5.8–42.5 mmHg; P = 0.027). Neither plasma nor cerebrospinal fluid arginine vasopressin (AVP) was related to ICP (r = 0.33 and 0.13 respectively). Mean arterial pressure (MAP) was measured in 23 children and a moderate correlation was found with plasma AVP (r = 0.62; P = 0.0019). In TBM, plasma AVP may be secreted as a response to raised ICP in an effort to raise MAP and maintain cerebral perfusion pressure. In this setting excess fluid may be inappropriately retained, leading to hyponatremia and hypo-osmolemia.     

Minimal displacement of novel self-anchoring catheters suitable for temporary prostate implants.

Catheters were developed that can be fixed in the prostate gland by self-expanding parts for use in PDR brachytherapy. Daily CT-scans were made to investigate the magnitude of catheter displacement. The mean absolute displacement during the 3 day treatment was 1.2 mm. The resulting minor alterations in dose-volume parameters were of no clinical importance.     

Sequence specificity of mutation induced by the anti-tumor drug cisplatin in the CHO aprt gene

Cis-diammine dichloroplatinum (cisplatin) is an effective anticancerdrug which forms adducts with DNA, in both bacterial and mammaliancells. It is suspected of producing tumors as well. To determinethe molecular nature of geneti alterations induced by cisplatin,we cloned and sequenced cisplatin-induced mutants in the adeninephosphoribosyl-transferase (aprt) gene of Cinese hamster ovary(CHO) cells. Mutation by cisplatin appears to be targeted asthe sites of mutation are consistent with the known bindingspecificity of cisplatin. Many mutations occur at or proximalto the sequence 5'-AGG-3' and 5'-GAG-3' and include transversions,transitions, frameshifts and short deletions and duplications.Several double changes were also observed. No major rearrangementswere recovered in our collection. At several locations, a numberof mutants were found to be clustered within a small targetregion, but unlike traditional hotspots, tese represent diversechanges occurring in a localized region of a few base pairs.     

Effect of morphological abnormalities on blood retinal barrier permeability in diabetic retinopathy

The morphological base for the impaired function of the blood retinal barrier was studied in 50 eyes of 10 insulin dependent and 21 non-insulin dependent patients with various levels of diabetic retinopathy. The permeability of the blood retinal barrier (P_BRB) was determined by vitreous fluorophotometry with correction for autofluorescence, lenstransmission and non-protein bound plasma fluorescein concentration. Morphological abnormalities of diabetic retinopathy assessed by fundus photography and fluorescein angiography were individually scored on a decimal scale and related to the P_BRB by multiple regression analysis. The P_brb was not correlated to morphological abnormalities of non-proliferative retinopathy [(1) microaneurysms, (2) hard exudates, (3) soft exudates, (4) intraretinal hemorrhages, (5) fluorescein leakage, and (6) capillary closure, p > 0.3]. The P_BRB was correlated to morphological abnormalities of (pre)proliferative retinopathy [(1) intraretinal microvascular abnormalities (S_irma) and (2) new vessels (S_neo): p_brb = A – B.S_IRMA – C.S_neo with P_BRB in nm/sec, A = 1.5 ± 0.5, B = 0.9 ± 0.2 and C = 1.7 ± 0.4, R² = 0.65, p < 0.0001]. It can be concluded that the increased blood retinal barrier permeability in diabetic patients is mainly due to (pre)proliferative abnormalities and not to non-proliferative abnormalities.     

Antibody Response Against the Glomerular Basement Membrane Protein Agrin in Patients with Transplant Glomerulopathy

Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have transplant glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested. In 11 of 16 patients with TGP and in 3 of 16 controls with CAN in the absence of TGP we demonstrate circulating antibodies reactive with GBM isolates. The presence of anti-GBM antibodies was associated with the number of rejection episodes prior to diagnosis of TGP. Sera from the TGP patients also reacted with highly purified GBM heparan sulphate proteoglycans (HSPG). Indirect immunofluorescence with patient IgG showed a GBM-like staining pattern and colocalization with the HSPGs perlecan and especially agrin. Using patient IgG, we affinity purified the antigen and identified it as agrin. Reactivity with agrin was found in 7 of 16 (44%) of patients with TGP and in 7 of 11 (64%) patients with anti-GBM reactivity. In conclusion, we have identified a humoral response against the GBM-HSPG agrin in patients with TGP, which may play a role in the pathogenesis of TGP.