Recent-onset Disease Research Articles

The longitudinal relation between chronic diseases and depression in older persons in the community: the Longitudinal Aging Study Amsterdam

Objective The purposes of this study were to examine the differences in influence of various chronic diseases on depressive symptomatology over time and to determine whether there were differences in such influence depending on physical limitations and time of onset of disease. Study design and setting Data for this study were obtained from the Longitudinal Aging Study Amsterdam. Two thousand two hundred eighty-eight respondents (age 55–85) were included and followed for a maximum of 6 years. Depressive symptoms (using the CES-D scale), the presence of seven frequently occurring chronic diseases, physical limitations, and sociodemographic variables were assessed by structured interviews. Generalized estimating equation models were estimated for each disease and compared with each other. Results Lung disease, arthritis, cardiac disease, and cancer were all positively associated with increased depressive symptoms over time. Stroke was associated with depressive symptoms, but these associations were not found when adjusted for physical limitations. For atherosclerosis and diabetes mellitus only weak or no associations with depressive symptoms were found. Recent onset of disease resulted in less strong associations for in cancer, lung disease, and arthritis. Conclusion The results demonstrate that the level of depressive symptoms varies across type of chronic disease. In cardiac disease, arthritis, cancer, and lung disease increased depressive symptoms could not be attributed to physical limitations, but in stroke the association found with depressive symptoms was to a large extent attributable to physical limitations.

Evaluating inflammatory joint disease: how and when can autoantibodies help?

The diagnosis of inflammatory joint disease rests on a constellation of symptoms, signs, laboratory test results and, occasionally, histological findings. Classification criteria have been developed by national learned societies, international panels of experts or, more rarely, an expert working alone. These criteria are intended to provide a common language for therapeutic trials and international publications. Yet, they are often inappropriately used as diagnostic tools for the individual patient. Identification of an early seroimmunologic marker with high sensitivity and specificity for classifying patients with recent-onset joint disease is a daunting challenge. Test performance characteristics such as sensitivity, specificity, positive and negative predictive values, and the positive or negative likelihood ratio help to assess the diagnostic usefulness of a laboratory test in a specific situation. The difference between the pretest and posttest likelihoods of obtaining a positive or negative result measures the usefulness, or performance, of a laboratory test in a specific situation according to the prevalence of the disease. A higher positive likelihood ratio indicates a more useful test. In a patient with inflammatory joint disease, the diagnosis can be sought by assaying a limited number of autoantibodies according to a decision tree. Thus, IgM rheumatoid factors (latex test or ELISA) and antibodies to filaggrin or other citrullinated proteins (antikeratin antibodies by indirect immunofluorescent assay or anticyclic citrullinated peptides by ELISA) identify more than 70% of cases of early rheumatoid arthritis with greater than 98% specificity. If these markers are negative, testing for antinuclear antibodies by indirect immunofluorescent assay on HEp-2 cells identifies 99% of cases of lupus and progressive systemic sclerosis. Confirmation of the diagnosis can be obtained by characterizing the autoantibodies: thus, presence of antidouble-stranded DNA (dsDNA, by the Farr radioimmunoassay, indirect immunofluorescent assay on Crithidia luciliae, or ELISA (IgG)) or of antinucleosome antibodies (ELISA) indicates lupus, whereas anticentromere, antitopoisomerase I (Scl 70), and antinucleolar antibodies point to progressive systemic sclerosis. A positive test for antibodies to soluble nuclear antigens of the U1 RNP type suggests mixed connective tissue disease or lupus but may indicate scleroderma. Anti-Sm antibodies are found in fewer than 10% of lupus patients but are highly specific. Anti-SSA (Ro) and anti-SSB (La) suggest lupus or primary Sjögren’s syndrome. When tests are negative for ANA, several antibodies to cytoplasmic organelles are valuable diagnostic tools, such as anti-J01 for polymyositis syndromes and antiribosome antibodies for lupus, although their sensitivity is modest (20–25%). Finally antineutrophil cytoplasmic antibodies (ANCAs) ensure the diagnosis of small-vessel vasculitides, which often involve the lungs and kidneys. Thus, in diffuse Wegener’s granulomatosis, ANCAs exhibiting the classic cytoplasmic pattern and corresponding by ELISA to anti-PR3 are found. In microscopic polyangiitis the ANCAs are peripheral and correspond by ELISA to antimyeloperoxidase antibodies. Tests for other antibodies are less often needed to evaluate inflammatory joint disease.

Only limited support for a role of psychosomatic factors in psoriasis: Results from a case-control study

Objective: To investigate the role of stressful events, social support, attachment security and alexithymia in triggering or exacerbating psoriasis. Methods: Outpatients experiencing a recent onset or exacerbation of psoriasis ( n=40) were compared with outpatients with skin conditions in which psychosomatic factors are regarded as negligible ( n=116). Stressful events during the last year were assessed with Paykel's Interview for Recent Life Events. Attachment style, alexithymia and perceived social support were assessed with the ECR questionnaire, the TAS-20 and the MSPSS, respectively. Results: The mean number of recently experienced life events, or of undesirable, uncontrollable or major events was not different between psoriatic patients and controls. The only stress measure that showed a slight trend towards an association with psoriasis was having experienced four or more stressful events in the preceding year. There was a statistical trend towards an association between alexithymia and psoriasis, whereas there were no significant differences between patients with psoriasis and controls with respect to perceived social support and attachment security. Subgroup analysis suggested that the role of all psychosomatic factors studied might be more important in certain clinical types, such as guttate and diffuse plaque psoriasis. Conclusions: Our findings provide only limited support for a role of psychosomatic factors in psoriasis. Future studies should investigate chronic and daily stressors in addition to major life events, include measures of stress appraisal and include specifically patients with a recent onset of disease.

Infections in children with nephrotic syndrome.

To determine the different types of infections in nephrotic children and their association with the activity of disease. A descriptive study. It was carried out at National Institute of Child Health (NICH), Karachi from August 1995-July 1996. All children with nephrotic syndrome who had various infections during the study period were evaluated for the activity of disease and type of infections. Out of 62 children with nephrotic syndrome having infections, 45 (72.58%) were boys and 17 (27.42%) girls in a ratio of 2.5:1. Out of them 53 (85.45%) were known nephrotics and 36 (58%) of them were on steroid therapy. Nine were new cases and had not received steroids. A total of 74 episodes of infections were observed in 62 children. Acute respiratory infections (ARI) and skin infections were the most common (29.27% and 27.02% respectively) followed by diarrhoea (13.51%), UTI (12.5%) and peritonitis (10.81%). Two patients had pulmonary tuberculosis and 3 patients had more than one infection (cellulitis, peritonitis and pneumonia). All children with cellulitis and peritonitis were in active disease, whereas more than 80% of patients with ARI, diarrhoea and UTI were having either relapse or had recent onset of disease. The study showed that ARI, cellulitis and diarrhoea were most common infections followed by UTI and peritonitis. Majority of the infections (>78%) were associated with active disease

Valeur diagnostique de la sérologie de Lyme systématique chez les patients présentant un rhumatisme inflammatoire débutant vivant dans une région non endémique

Objective. – To evaluate the diagnosis value of systematic serological testing for Lyme borreliosis in patients with recent-onset inflammatory joint disease, in a non-endemic area. Methods. – Inclusion of patients hospitalised in a French rheumatology department for recent-oncet (disease duration < 1 year) inflammatory joint disease, and living in a non-endemic area. For all patients, a careful medical history, including tick bite and erythema migrans, physical examination, electrocardiogram, and detection of serum antibodies to Borrelia burgdorferi (ELISA) were obtained. Results. – Ninety patients (39 men, 51 women, mean age = 48.1 years ± 17.9, mean disease duration = 4.3 months ± 4.3) were included. A tick bite was reported in one patient (1.1%), and erythema migrans in none. ELISA serological testing for Bb was negative in all cases. Conclusion. – These results suggest that screening for Lyme disease cannot be recommended in patients with early-onset inflammatory joint disease, living in a non-endemic area and with no clinical history suggestive of Lyme arthritis. Similar studies on larger populations are needed to confirm this conclusion.

IgG1 subclass dominates autoimmune response to tyrosine phosphatase-like molecule IA-2 in Chinese type 1 diabetes patients.

Islet autoantibodies are known markers for type 1 diabetes with an immune-mediated basis; their isotype or subclass profiles may also provide clues to changes in immune response during disease or after intervention. For ICAs and GADab, the IgG1 subclass consistently dominates in recent-onset disease. The aims of our study were to determine the isotype patterns for IA-2ab in Asian Chinese patients with autoimmune diabetes. From an initial screening of over 400 diabetes patients, 40 subjects (mean age 22.2 +/- 15.8 years) with IA-2ab were enrolled for this study. IA-2ab was detected by radioimmunoassay of [35S]-labelled recombinant human IA-2 ic(605 - 979). Of them, 31 (median age 15 years, range 2 - 57 years; 16 children) had clinical type 1 diabetes (that is, they required insulin at onset or within 1 year) with the majority having been recently diagnosed (< 1 year). The other 9 patients had clinical type 2 diabetes phenotype. IA-2ab IgG subclasses determined with monospecific secondary antibodies showed that both type 1 diabetic adults and children had similarly non-restricted isotype patterns with a strong presence of IgG1-IA-2ab. The rank order was IgG1 > 3 > 2 > 4; 15 subjects had detectable IgG4-IA-2ab. Clonality of immune response determined with kappa/lambda chain-specific antibodies also showed a non-restricted pattern. Patients aged 38.2 +/- 15.2 years with type 2 diabetes had broad patterns of isotypes - IgG1/3 was detected more frequently (n = 8) than IgG2/4 (n = 5). Of three patients on insulin treatment, one was also positive for GADab. The remaining 6 patients were on oral hypoglycaemic treatment. IA-2ab in type 2 diabetes showed a low titre compared to type 1 diabetes. Isotype responses to IA-2 had a strong IgG1 presence, similar to ICAs and GADab. With IgG3 subclass representation, a predominant Th1 milieu in the systemic environment is likely. There is no suggestion of differences in immune response to IA-2 between adults and children with type 1 diabetes.

Prevention of vascular damage in scleroderma with angiotensin-converting enzyme (ACE) inhibition.

Great strides have been made in identifying and managing the organ-based complications of systemic sclerosis (SSc). There is no room for the nihilism towards treating this disease that used to be so prevalent. However, there is still relatively little hard evidence on which to base treatment decisions. Previous trials have been constrained by the low disease prevalence and the difficulty in recruiting sufficient patients especially with disease of recent onset. The results of past trials have often been confounded by the failure to recognize the marked heterogeneity of SSc and the inclusion of patient subsets with widely varying disease expression, course and outcome. It is recognized that progress will only be made in this area with coordinated multicentre studies. As a result, national and international networks of clinicians with expertise in the management of SSc have been formed. In the UK, the Systemic Sclerosis Study Group has established a national scleroderma register and, together with the Scleroderma Special Interest Group of the British Society for Rheumatology (BSR), a multicentre base for therapeutic studies. As a result of developments in our understanding of the pathogenesis of scleroderma and our ability to subset patients more effectively, a number of rather more rational approaches to treating the disease and its complications are being tested. In parallel with this, considerable progress is being made in developing universally agreed measures of disease activity and severity and in identifying surrogate laboratory markers of disease activity that are relevant to therapeutic studies. These multicentre trials need substantial funding and often do not attract support from the pharmaceutical industry. It was because of the difficulty in financing long-term, multicentre studies in uncommon conditions that the ARC/BSR Clinical Trials Programme was established. The QUINS trial, which is funded by this Programme, is described here as an example of one of several therapeutic protocols being developed by the UK Systemic Sclerosis Study Group that are currently being tested in multicentre trials. Contact details are provided in the appendix for clinicians who are interested in registering patients on the UK Scleroderma Register or participating in this or in the other therapeutic studies.

Expression of IP-10/CXCL10 and MIG/CXCL9 in the Thyroid and Increased Levels of IP-10/CXCL10 in the Serum of Patients with Recent-Onset Graves' Disease

Both mRNA and protein expression of the chemokines IP-10/CXCL10 and Mig/CXCL9, as well as of their receptor, CXCR3, were assessed in the thyroid glands of 16 patients suffering from Graves' disease (GD). In addition, IP-10/CXCL10 levels were measured in the serum of 50 GD patients. Expression of IP-10/CXCL10, Mig/CXCL9, and CXCR3 was poor or absent in normal thyroid tissue from patients undergoing thyroidectomy because of primary localized thyroid tumors, while both the chemokines and their receptor were present in most thyroid glands of patients affected by GD. IP-10/CXCL10 and Mig/CXCL9 localized to infiltrating lymphocytes and macrophages, as well as to resident epithelial follicular cells, whereas CXCR3 was mainly found at the level of infiltrating inflammatory cells and endothelial cells from large and small vessels. Of note, maximal expression of IP-10/CXCL10 and Mig/CXCL9 was found in the thyroid gland of patients with recent-onset GD and was correlated with interferon (IFN)-gamma. Accordingly, high levels of IP-10/CXCL10 could be measured in the serum of patients with short-duration GD. Taken together, the results of this study demonstrate that the CXCR3-binding chemokines IP-10/CXCL10 and Mig/CXCL9 play an important role in the recruitment of cells and in the amplification of inflammation in GD. They also suggest that the production of these chemokines by resident follicular epithelial cells may contribute to the recruitment of CXCR3-expressing type 1 T-helper cells in the initial phases of GD.

B lymphocytopenia in rheumatoid arthritis is associated with the DRB1 shared epitope and increased acute phase response

The influence of HLA DRB1 alleles on B-cell homeostasis was analyzed in 164 patients with rheumatoid arthritis (RA). The percentages of CD19+ B lymphocytes determined in the peripheral circulation of 94 retrospectively recruited RA patients followed a bimodal distribution. Two frequency peaks (B-celllow patients and B-cellhigh patients) were separated by the population median of a B-cell frequency of 8.5% of all lymphocytes. Human leucocyte antigen genotyping revealed that the B-celllow patients were more frequently positive for the RA-associated HLA DRB1 shared epitope (SE) than were B-cellhigh patients. Accordingly, SE-positive patients had lower CD19 percentages in the rank-sum analysis when compared with SE-negative patients, and were markedly B lymphocytopenic when compared with a healthy control group. To confirm the differential frequencies of CD19+ B cells, absolute numbers in peripheral blood were determined prospectively in a cohort of 70 RA patients with recent onset disease. SE-positive patients were found to have lower absolute numbers of circulating CD19+ B cells. B-cell counts below the mean of the study population were associated with higher acute phase response and with increased levels of rheumatoid factor IgA. No correlation between absolute numbers of circulating B cells and radiographic progression of joint destruction was seen. The influence of immunogenetic parameters on B-cell homeostasis in RA reported here has not been described previously. The clinical relevance of B lymphocytopenia in SE-positive RA will be further investigated in longitudinal studies.

Second-line drugs used in recent-onset rheumatoid arthritis in Brittany (France)

Objective. The management of recent-onset rheumatoid arthritis (RA) is not well standardized. We conducted a survey of drugs prescribed to RA patients in Brittany at presentation and during the first 1 to 3 years of follow-up. Methods. A cohort of 270 patients with recent-onset inflammatory joint disease was recruited between 1995 and 1997. The evaluation at presentation included a medical history, a thorough physical examination, and a standard battery of investigations. Follow-up at 6-month intervals was offered. At the last visit, between June and December 1999, a panel of five rheumatologists established that 98 patients had RA. Results. At presentation, hydroxychloroquine and injectable gold were the most widely used second-line drugs, and only two patients were offered a combination of second-line drugs. At the last visit, the most commonly used drugs were methotrexate, injectable gold, and hydroxychloroquine (23, 23, and 21 patients, respectively); only three patients were on more than one second-line drug and 38 (38/98, 39%) patients were on glucocorticoid therapy. Conclusion. Rheumatologists in Brittany prefer monotherapy with hydroxychloroquine or injectable gold as the initial treatment. Later, they rely mainly on methotrexate, injectable gold, and hydroxychloroquine, often in combination with glucocorticoid therapy.

Sensitivity of the polymerase chain reaction for the diagnosis of cutaneous leishmaniasis due to Leishmania ( Viannia) guyanensis

The sensitivity of the polymerase chain reaction (PCR) in 35 consecutive outpatients with cutaneous leishmaniasis caused by Leishmania ( Viannia) guyanensis was evaluated using, as gold standard, the in vitro isolation of the parasite through culture of aspirates of the cutaneous ulcers. All isolates were identified using electrophoretic enzyme analysis. Patients were mainly young males with recent onset disease without prior specific treatment. PCR was performed using DNA extracted from fresh frozen biopsies of cutaneous ulcers. The reaction used a pair of oligonucleotides that amplify the conserved region of the minicircle molecule. PCR showed 100% sensitivity (95% CI from 90.0 to 100.0). These results were similar to the visualization of amastigotes in imprint preparations of cutaneous biopsy tissue and the inoculation of biopsy material in golden hamsters. Despite the high sensitivity of the PCR, in this particular clinical setting of cutaneous leishmaniasis caused by L. ( V.) guyanensis in the Brazilian Amazon, it appears that the method of choice for diagnosis should be the direct visualization of amastigotes using imprint preparations and the PCR reserved for those patients with negative imprint results.

Isolation of Borna disease virus from human brain tissue.

Serological and molecular epidemiological studies indicate that Borna disease virus (BDV) can infect humans and is possibly associated with certain neuropsychiatric disorders. We examined brain tissue collected at autopsy from four schizophrenic patients and two healthy controls for the presence of BDV markers in 12 different brain regions. BDV RNA and antigen was detected in four brain regions of a BDV-seropositive schizophrenic patient (P2) with a very recent (2 years) onset of disease. BDV markers exhibited a regionally localized distribution. BDV RNA was found in newborn Mongolian gerbils intracranially inoculated with homogenates from BDV-positive brain regions of P2. Human oligodendroglia (OL) cells inoculated with brain homogenates from BDV-positive gerbils allowed propagation and isolation of BDVHuP2br, a human brain-derived BDV. Virus isolation was also possible by transfection of Vero cells with ribonucleoprotein complexes prepared from BDV-positive human and gerbil brain tissues. BDVHuP2br was genetically closely related to but distinct from previously reported human- and animal-derived BDV sequences.

Frequency of islet cell autoantibodies (IA-2 and GAD) in young Brazilian type 1 diabetes patients.

Type 1 diabetes, as an autoimmune disease, presents several islet cell-specific autoantibodies such as islet cell antibody (ICA), anti-insulin, anti-glutamic acid decarboxylase (GAD) and the antibody (Ab) against tyrosine phosphatase (PTP)-like protein known as ICA-512 (IA-2). In order to determine the frequency of the anti-GAD and anti-IA-2 autoantibodies in Brazilian type 1 diabetes patients we studied 35 diabetes mellitus (DM) type 1 patients with recent-onset disease (</=12 months) and 37 type 1 diabetes patients with long-duration diabetes (>12 months) who were compared to 12 children with normal fasting glucose. Anti-GAD65 and anti-IA-2 autoantibodies were detected with commercial immunoprecipitation assays. The frequency of positive results in recent-onset DM type 1 patients was 80.0% for GADAb, 62.9% for IA-2Ab and 82.9% for GADAb and/or IA-2Ab. The long-duration type 1 diabetes subjects presented frequencies of 54.1% for GADAb and IA-2Ab, and 67.5% for GAD and/or IA-2 antibodies. The control group showed no positive cases. Anti-GAD and IA-2 assays showed a high frequency of positivity in these Brazilian type 1 diabetes patients, who presented the same prevalence as a Caucasian population.

Treatment issues in interstitial lung disease in tropical countries

Management of interstitial lung disease, especially idiopathic pulmonary fibrosis, is both difficult and unsatisfactory. In many patients, only supportive therapy can be instituted. Attempts have been made to use anti-inflammatory therapy to reverse inflammation, provide symptomatic relief, stop disease progression, and prolong survival; the results of such treatment have varied from no improvement to significant prolongation of survival. Corticosteroids are the most frequently used anti-inflammatory agents. Cytotoxic drugs, such as oral azathioprine or intermittent intravenous cyclophosphamide, have also been shown to be effective both alone and in combination with low-dose oral corticosteroids. Of the other antifibrotic drugs that have been used, colchicine seems to provide some benefit. It is especially useful in aged persons and those with corticosteroid-induced problems or concomitant illnesses that are likely to be worsened by steroids. Anti-inflammatory therapy is costly to administer and monitor, particularly in the developing world. It is therefore important to consider these issues before instituting treatment. Younger patients and patients with less-severe disease of recent onset are most likely to respond to treatment. Similarly, patients with lymphocytic alveolitis or desquamative interstitial pneumonia respond better. Despite the use of newer strategies for treatment, the overall prognosis for patients with interstitial lung disease has not really changed, and the median population survival remains almost the same as it was about 30 years ago.

INTERLEUKIN (IL)-12 RECEPTOR β2 SUBUNIT EXPRESSION IS UP-REGULATED IN CROHN'S DISEASE

81 Background. IL-12 modulates immune response in chronic colitis. IL-12 mediates its functions by binding to a membrane receptor, composed by at least two subunits: β1 and β2. IL-12 responsiveness correlates with IL-12Rβ2 content and studies in experimental models showed that IL-12Rβ2 is preferentially expressed by Th1 cells. Aim. To examine whether IL-12Rβ2 expression is up-regulated in Crohn's disease (CD). Specific aims were: a. to demonstrate transcripts for IL-12Rβ2 in CD tissue; b. to investigate whether transcripts for IL-12Rβ2 are differently expressed in early and late CD; to explore whether corticosteroid (CS) treatment may affect IL-12Rβ2 expression. Materials and methods. Eight paediatric (mean age: 8±3 yrs), with a recent onset of disease (< 1 year), and ten adult (mean age: 36±18 yrs) (disease established for at least 4 years) CD patients were enrolled. Four out of 8 paediatric and 4 of 10 adult CD patients were on corticosteroid treatment. All patients had an active disease at the time of study. Two biopsy specimens were taken from involved colonic areas during endoscopy. Controls included 5 adult and 2 paediatric patients with irritable bowel syndrome. Total RNA was extracted from freshly obtained biopsy specimens and retrotranscripted in cDNA. IL-12Rβ2 was tested by semiquantitative reverse transcription-PCR and level of expression assessed as a ratio of IL-12Rβ2/β-actin signal intensity. Results. Transcripts for IL-12Rβ2 were detected in all tested samples. When IL-12Rβ2 was examined in a semiquantitative manner, a more pronounced (p<0.05) expression was found in CD patients (0.6±0.3) in comparison to controls (0.3±0.1). No difference in IL-12Rβ2 mRNA accumulation was observed between paediatric and adult CD patients. In patients off CS treatment the amount of transcripts for IL-12Rβ2 was higher (p<0.05) than in patients on CS treatment. This was evident in either paediatric and adult patients (0.9±0.25 vs 0.32±0.2 and 0.95±0.3 vs 0.28±0.1, p<0.05, respectively). No difference was observed between CD patients on CS treatment and controls. Conclusion. IL-12Rβ2 is upregulated in CD, further supporting the concept that IL-12 is involved in modulating local immune response in CD.

Immunity to heat shock proteins and neurological disorders of women.

Stress or heat shock proteins are constitutively expressed in normal CNS tissues in a variety of cell types (oligodendrocytes, astrocytes, and neurons). Their presence may protect cells from various stresses, such as hypoxia, anoxia, and excessive excitatory stimulation. Increased amounts of hsp are expressed in various cells of the CNS during acute toxic-metabolic states and in chronic degenerative and inflammatory diseases. Increased expression of hsp may lead to immune responses to these proteins. Antibodies to mycobacterial hsp bind to normal human myelin and to oligodendrocytes in regions of MS demyelination. Cellular immune responses to hsp occur with increased frequency and magnitude in persons with MS, especially those with recent onset of disease. In addition, there are populations of T cells expressing gamma/delta T cells in the brains and spinal fluids of persons with MS, suggesting an in situ immune response to hsps. Humoral immune responses to hsp are found in CSF, but no disease specificity has been documented. Some myelin proteins have sequence homology with particular hsps. One instance is the homology between a peptide of mycobacterial Hsp65 and the myelin protein CNP. Our data on EAE suggest that immune responses to either cross-reactive hsp epitopes or whole hsp can modify the course of both acute and chronic relapsing EAE. In addition, the severity and frequency of environmental exposure to infectious agents can modify the course of EAE, possibly by altering the patterns of immune response to hsp. Finally, tolerance to the small hsp, alpha B-crystallin, a putative autoantigen in persons with MS, alters the course of relapsing EAE, supporting its role in chronic, autoimmune CNS disease. Modifying immune responses to hsp may be a potential new treatment option for persons with MS.

Choroidal abnormalities in birdshot chorioretinopathy: an indocyanine green angiography study.

Birdshot chorioretinopathy is a rare inflammatory disorder with an insidious onset that can slowly progress to severe visual loss. The pathogenesis is unknown. This study used indocyanine green (ICG) angiography to investigate the degree of choroidal vascular involvement with progression of disease and to determine the nature of the birdshot lesions. Seven patients with birdshot chorioretinopathy had ICG angiography performed with a scanning laser ophthalmoscope at various stages of clinical disease. Results were compared with fluorescein fundal angiography (FFA). All large choroidal vessels appeared normal. The birdshot lesions were demonstrated with ICG but not with FFA and were represented by dark areas on ICG angiography. Typically these areas were bordered by large or medium-sized choroidal vessels and their appearance suggested small choroidal vessel hypoperfusion. In disease of recent onset, some lesions masked fluorescence from large underlying choroidal vessels possibly due to inflammatory choroidal infiltrates. In long-standing disease, the choroidal angioarchitecture was relatively normal within the birdshot lesions. This study of birdshot chorioretinopathy demonstrates abnormalities in the small choroidal vessels within the birdshot lesions. ICG angiography detects the birdshot lesions more readily than FFA and may be of benefit in assessing disease activity.

The effect of thymectomy on autoreactive T- and B-lymphocytes in myasthenia gravis

Eleven patients with myasthenia gravis were followed for three years after thymectomy. Acetylcholine receptor-specific T-cell stimulation was found in 8/11 patients before operation as compared to 2/11 three years after thymectomy. Changes of T-cell antireceptor-reactivity were commonly paralleled by changes in disease severity. The numbers of cells secreting IL-2 upon stimulation with human acetylcholine receptor correlated with those secreting IFN-γ. T-cell reactivity against a monoclonal acetylcholine receptor antibody did not decrease after thymectomy. Such reactivity could reflect a beneficial immune response counteracting anti-receptor reactivity. The frequency of autoantibody-secreting cells remained unchanged, while the serum concentration of acetylcholine receptor antibodies started to decrease one year after thymectomy. All examined thymus-cell suspensions contained autoreactive T- and B-lymphocytes. There was a preferential enrichment of autoreactive lymphocytes in the thymus in a few patients with recent onset of disease

CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.

Low doses of the CD3 mAb 145 2C11 restored self tolerance to beta cell Ags in adult overtly diabetic NOD mice. Within 2 to 4 wk after treatment, complete and permanent remission of diabetes was observed. Autoreactive T cells were not deleted in CD3 Ab-protected animals as evidenced first, by the persistence of peripheral insulitis and, second, by the capacity of spleen cells from CD3 Ab-treated mice to transfer diabetes to adult irradiated syngeneic recipients. Moreover, the conferred tolerance was reproducibly reversed by a single injection of cyclophosphamide. For 5 to 7 wk after treatment, IFN-gamma production by stimulated spleen cells was significantly decreased in treated animals. One unique feature was that the CD3 Ab-induced tolerance ensued only from treatment of overtly diabetic NOD mice. Durable protection was exclusively observed when treating mice with recent onset disease (14-20 wk old). At variance with this finding, treatment of 4- and 8-wk-old mice was without effect, and complete but transient protection followed the treatment of 12-wk-old NOD mice. The tolerogenic properties of 145 2C11 did not depend on its mitogenic capacity, since nonmitogenic F(ab')2 fragments also appeared potent at inducing durable remission in overtly diabetic NOD, although nonmitogenic CD3 F(ab')2 fragments could mediate T cell signaling, as evidenced by cytokine gene transcription (IL-2, IFN-gamma, IL-4, and IL-10) assessed by PCR on splenocytes from treated mice. A concomitant cyclosporine treatment abrogated the CD3 mAb-induced protection, further pointing to the crucial role of T cell signaling in the effect observed.

Increased cerebrospinal fluid levels of glial fibrillary acidic protein (GFAp) in Lyme neuroborreliosis.

Glial fibrillary acidic protein (GFAp), the main protein constituent of the intermediate filaments of astrocytes, was analysed in the cerebrospinal fluid (CSF) of 20 patients with Lyme neuroborreliosis as a marker of the astroglial reaction. The mean GFAp level before antibiotic treatment in the study group was significantly elevated (592 pg/ml +/- 596 [SD]) compared to that in 24 healthy controls (121 +/- 87 [SD]) (p < 0.01). The highest CSF-GFAp levels were seen in the patients with the most severe disease, but the levels were also increased in patients with peripheral paresis, such as facial palsy with no or only minor encephalitic symptoms. This implies that the infection was not limited to radix dorsalis or the meningeal tissues, but affected the central nervous system as well. Furthermore, the astroglial reaction seemed to occur early in Lyme neuroborreliosis since CSF-GFAp levels were elevated also in patients with recent (< 3 weeks) onset of disease. After antibiotic treatment, the GFAp levels decreased. It is suggested the CSF-GFAp concentrations might be useful for monitoring CNS involvement in Lyme neuroborreliosis.