Circulating microparticles and plasma levels of soluble E- and P-selectins in patients with systemic sclerosis.

OBJECTIVES: Microparticles (MPs) may be involved in the pathogenesis of systemic sclerosis (SSc), which includes vasculopathy, endothelial cell activation, and coagulation activation. Circulating MPs from SSc patients were characterized and their relationship with soluble markers of vascular activation investigated. METHOD: This study included 121 SSc patients [79 with limited (lcSSc) and 42 with diffuse cutaneous SSc (dcSSc)] and 49 sex- and age-matched healthy controls (HCs). The MPs were characterized by flow cytometry for annexin V (AnxV)-binding capacity and their expression of surface markers of platelets (PMPs), leucocytes (LMPs), or endothelial cells (EMPs). Plasma levels of soluble (s) E- and P-selectins were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The total concentrations of MPs and of PMPs, LMPs, and EMPs were 22-42% lower in SSc patients than in HCs (p < 0.001). However, within the cell-derived MP pool, a 47% higher fraction of AnxV non-binding MPs (F-AnxV(-) MPs) was found in the SSc patients compared to the HCs (p < 0.05). The plasma levels of sE- and sP-selectins were increased by 47-64% in the SSc patients compared to HCs (p < 0.001). Multiple regression analysis showed that the raised plasma levels of sE- and sP-selectin were associated with F-AnxV(-) EMPs in dcSSc patients (p = 0.008 and p = 0.001, respectively) but not in lcSSc patients (p = 0.33 and p = 0.82, respectively). CONCLUSIONS: While the total number of MPs was decreased, the number of F-AnxV(-) MPs increased in SSc patients. The F-AnxV(-) EMPs were associated with plasma levels of markers of vascular activation in patients with dcSSc.

Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres.

OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.

Skin signs in Ehlers-Danlos syndrome: clinical tests and para-clinical methods.

OBJECTIVE: The criteria for Ehlers-Danlos syndrome (EDS) and the hypermobility syndrome (HMS) should be reliable. Examination for general joint hypermobility has high reliability but there is only sparse information on the reliability of skin tests, and no information on the level of normal skin extensibility. The present study aimed to assess skin signs by means of clinical and para-clinical methods. METHODS: A total of 31 EDS patients and 28 healthy controls were examined blinded and in random order. Inter-examiner analysis of clinical tests for skin extensibility, consistency, scarring, and bruising was performed, followed by analyses of extensibility with the suction cup (SC), consistency with a soft tissue stiffness meter (STSM), and thickness with ultrasonography (US). Semi-quantitative assessment of skin extensibility in healthy controls was incorporated in the tests. RESULTS: The clinical analyses demonstrated kappa values of: 0.72 for extensibility, 0.23 for consistency, 0.53 for scarring, and 0.63 for bruising. Skin extensibility measurements in healthy controls (n = 28) were 2.79 and 2.93 cm (mean + 2 SD), respectively, by the two examiners. There were significant differences between patients with classical-type EDS and controls with respect to skin extensibility by SC (4.91 vs. 12.52 kPa/mm) and skin consistency by STSM (0.59 vs. 0.76 N). We found no difference in skin thickness. CONCLUSION: The reproducibility of the clinical skin tests was substantial to good, apart from the consistency measurements. We suggest that skin consistency is withdrawn as a diagnostic criterion. The upper level for normal skin extensibility should be 3 cm. SC and STSM are promising para-clinical methods, but their diagnostic sensitivity and specificity need to be determined.

Factors affecting survival in juvenile systemic sclerosis.

OBJECTIVES: To determine whether demographic, clinical and immunological features may predict the outcome in juvenile SSc (JSSc). METHODS: Clinical and laboratory characteristics of patients with JSSc collected from paediatric rheumatology centres worldwide were analysed. First, univariate tests identified those features significantly related with fatal outcome, and then multivariate logistic regression analysis was applied to determine the predictors of mortality. RESULTS: One hundred and thirty-four patients from 40 centres were eligible for the analysis. Sixteen patients died and a rapidly fatal course was observed in most of them: 4/16 died within 1 yr after diagnosis and 10/16 within 5 yrs. At the moment of diagnosis, patients with poor outcome showed a significantly higher frequency of internal organ involvement, particularly cardiac, respiratory and gastrointestinal systems. No significant difference emerged for entity of skin, vascular and musculo-skeletal involvement, nor for auto-antibodies profile and laboratory tests. Multivariate analysis showed the following factors to be significant predictors of mortality: fibrosis on chest X-rays [odds ratio (OR) 11.2], raised creatinine levels (OR 22.7) and pericarditis (OR 41.3), while a short disease duration at diagnosis conferred protection (OR 0.3). CONCLUSIONS: All patients with JSSc and fatal outcome were affected by the diffuse form of the disease, and most of them showed a very rapid progression and early signs of internal organ involvement. This suggests that, in children, SSc may have two possible courses: a rapid development of internal organ failure leading to severe disability and eventually to death, or a slow course of the disease with lower mortality.

A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus.

BACKGROUND: In a recent open pilot trial, R-salbutamol sulphate, a well-known molecule with anti-inflammatory effects, was tested successfully on patients with therapy-resistant discoid lupus erythematosus (DLE). OBJECTIVES: To compare the efficacy and safety of R-salbutamol cream 0.5% vs. placebo on DLE lesions in a multicentre, double-blinded, randomized, placebo-controlled phase II trial. METHODS: Thirty-seven patients with at least one newly developed DLE lesion were randomized - 19 to the R-salbutamol cream 0.5% and 18 to placebo - and treated twice daily for 8 weeks. Efficacy was evaluated through scores of erythema, scaling/hypertrophy and induration as well as pain and itching; general improvement scored by the investigator and global improvement scored by patients' assessment were also evaluated. RESULTS: The mean area under the curve of improvement for scaling/hypertrophy, pain, itching and global patient assessment was significantly better for the actively treated patients as compared with placebo (scaling/hypertrophy, P = 0.0262; pain, P = 0.0238; itching, P = 0.0135; global patient assessment, P = 0.045). Moreover, the percentage of patients without induration was significantly higher in the active group compared with the placebo group (P = 0.013), and a statistically significantly greater decrease in the size of the lesional area was also seen in the overall analysis of the R-salbutamol-treated patients (P = 0.0197). No serious adverse events were reported. CONCLUSIONS: Application of R-salbutamol cream 0.5% was safe and well tolerated. Statistically significant effects were seen on scaling/hypertrophy, induration, pain and itching as well as patient global assessment, suggesting that R-salbutamol could be a promising new topical therapy alternative for DLE.

Parallel and serial processes in motion detection.

Apparent motion was used to explore humans' ability to perceive the direction of motion in the visual field. A marked qualitative difference in this ability was found between short- and long-range motion. For short-range motion, the detection of the direction of motion is characterized by parallel operation over a wide visual field (that is, detection performance is independent of the number of objects in an array). When the positional displacement is large relative to an object's size, the direction of motion is detected in a serial manner. The process of detection is limited in this case by the ability to detect other events, such as appearance and disappearance of an object, and the ability to compute their spatio-temporal relations. The results are consistent with a previously suggested division of the motion detection system into short- and long-range processes. The direction of short-range motion can be perceived in parallel (preattentively), whereas long-range motion is attentive and requires more complicated computations. It seems that the detection of long-range motion is a conjunction task, combining the detection of disappearance and appearance.

Skin extensibility and consistency in patients with Ehlers-Danlos syndrome and benign joint hypermobility syndrome.

OBJECTIVES: The reproducibility of clinical tests for skin extensibility and consistency, essential for differentiating between types of Ehlers-Danlos syndrome (EDS) and benign joint hypermobility syndrome (BJHS), is unknown. Paraclinical methods may provide objective differential diagnostic methods. METHODS: Six EDS, 11 BJHS, and 19 controls completed the trial. We analysed the overall inter-examiner agreement on clinical tests for skin extensibility and consistency, in addition to analyses on suction cup (SC) and soft tissue stiffness meter (STSM) methods. RESULTS: Overall agreement on tests for skin extensibility and consistency varied between 0.44 and 0.72. Extensibility evaluated by SC showed an insignificant difference between EDS patients and controls (p = 0.056). Consistency evaluated by STSM showed significant differences (p = 0.001). CONCLUSIONS: Overall inter-examiner agreement on clinical tests for skin extensibility and consistency was below 0.80, which was required a priori to conduct a reproducibility study. Further refinement of tests and a training phase are necessary. The SC and STSM results are encouraging but must be reproduced in a larger study population.

Autoantibodies to lamins A and C in sera of patients showing peripheral fluorescent antinuclear antibody pattern on HEP-2 cells.

Lamins A, B, and C are the major proteins of a polymeric structure called nuclear lamina, which is intercalated between chromatin and the inner membrane of the nuclear envelope. Using immunofluorescence on HEp-2 cells, specific enzyme-linked immunosorbent assay, and Western blotting performed against nuclear lamina preparation from Ehrlich ascites tumor cells, we characterized three patients, whose sera contained antibodies to nuclear lamins. The reaction pattern observed in two of the patients may result from single or combined occurrence of anti-lamin A and C antibodies. The third patient had antibodies that probably recognized an epitope in the carboxy-terminal region of lamin C. The sera were donated by a heterogeneous group of patients, and no common clinical or laboratory signs seemed to link them together.

Screening for autoantibodies to the nucleolar U3- and Th(7-2) ribonucleoproteins in patients' sera using antisense riboprobes.

In this study we report the detection of autoantibodies to the nucleolar U3- and Th(7-2) ribonucleoprotein (RNP) particles in sera from patients with connective tissue diseases. The method described employs radioactively labelled antisense U3- and Th RNA which are hybridized to immunoprecipitated U3- or Th RNA from a HeLa cell extract. Of the 66 sera that were screened with this method seven sera (11%) precipitated only Th RNP, 16 sera (24%) precipitated only U3 RNP and 4 sera (6%) precipitated both U3- and Th RNP. Both anti-U3 RNP and anti-Th RNP activity appeared to be mostly associated with scleroderma or scleroderma-associated diseases. Using this method we also showed that some of the Th RNP particles in a cell extract are associated with the La autoantigen. We conclude that for the identification of immunoprecipitated RNAs this method is very sensitive and provides unambiguous data.

Aligning pictorial descriptions: an approach to object recognition.

This paper examines the problem of shape-based object recognition, and proposes a new approach, the alignment of pictorial descriptions. The first part of the paper reviews general approaches to visual object recognition, and divides these approaches into three broad classes: invariant properties methods, object decomposition methods, and alignment methods. The second part presents the alignment method. In this approach the recognition process is divided into two stages. The first determines the transformation in space that is necessary to bring the viewed object into alignment with possible object models. This stage can proceed on the basis of minimal information, such as the object's dominant orientation, or a small number of corresponding feature points in the object and model. The second stage determines the model that best matches the viewed object. At this stage, the search is over all the possible object models, but not over their possible views, since the transformation has already been determined uniquely in the alignment stage. The proposed alignment method also uses abstract description, but unlike structural description methods it uses them pictorially, rather than in symbolic structural descriptions.

Three-dimensional object recognition based on the combination of views.

Visual object recognition is complicated by the fact that the same 3D object can give rise to a large variety of projected images that depend on the viewing conditions, such as viewing direction, distance, and illumination. This paper describes a computational approach that uses combinations of a small number of object views to deal with the effects of viewing direction. The first part of the paper is an overview of the approach based on previous work. It is then shown that, in agreement with psychophysical evidence, the view-combination approach can use views of different class members rather than multiple views of a single object, to obtain class-based generalization. A number of extensions to the basic scheme are considered, including the use of non-linear combinations, using 3D versus 2D information, and the role of coarse classification on the way to precise identification. Finally, psychophysical and biological aspects of the view-combination approach are discussed. Compared with approaches that treat object recognition as a symbolic high-level activity, in the view-combination approach the emphasis is on processes that are simpler and pictorial in nature.

Prenatal diagnostic techniques. Chorionic villus sampling.

Chorionic villus sampling (CVS) is a new prenatal diagnostic technique which is performed in the first trimester of pregnancy. Traditional methods of prenatal diagnosis, including amniocentesis and fetoscopy, must be performed in the midtrimester. In concert with the development of DNA methods of fetal cell analysis, first trimester fetal diagnosis utilizing CVS offers many advantages over traditional mid-trimester techniques. In addition, CVS may potentially allow therapeutic intervention to prevent or ameliorate some congenital defects.

Gonococcal keratoconjunctivitis.

Gonococcal keratoconjunctivitis is a potentially devastating infection, because Neisseria gonorrhoeae can cause a rapid, severe, ulcerative keratitis resulting in visual loss. The therapeutic decision making process is complicated by the necessity for prompt, effective parenteral therapy, frequent coinfection with other sexually transmitted diseases, and emergence of antibiotic resistance. Because of the evolving problem of antibiotic resistance and the need for cost containment, the current recommendations of hospitalization for intravenous penicillin may need to be modified. The third generation cephalosporin, ceftriaxone, has properties that suggest it may be the best available antimicrobial agent as a single-dose treatment of gonococcal conjunctivitis. Spectinomycin may be a useful alternative in the penicillin-allergic adult patient.

Necrobiosis lipoidica. An immunofluorescence study.

Biopsy specimens from 12 patients with necrobiosis lipoidica (diabeticorum) were studied by direct immunofluorescent microscopy. The immunoglobulin IgM was present in blood vessel walls of involved skin from six patients, and the third component of complement (C3) was present in the blood vessel walls of involved skin from seven patients. The immunoglobulin IgA was similarly observed in two patients. In addition, IgM, C3, or fibrinogen were observed at the dermal-epidermal junction of involved skin from seven patients. Necrobiotic areas invariably contained fibrinogen. These findings suggest that an immunecomplex vasculitis may be involved in the pathogenesis of necrobiosis lipoidica.

The lupus band test as a measure of disease activity in systemic lupus erythematosus.

One hundred twenty-seven biopsy specimens from clinically normal light-protected skin of 88 patients with active and inactive lupus erythematosus (LE) were examined for deposits of IgG, IgM, IgA, and C3 at the dermal-epidermal junction (DEJ). Deposits were found in 91% of those with active disease and in 33% of those with inactive disease. The finding of such deposits reflected active disease just as did a decrease in serum C3 and C4 levels, elevated anti-double-stranded DNA, the presence of LE cells, lymphopenia, and an elevation of the ESR. The presence or absence of deposits in repeated biopsy specimens indicated changing disease activity, as estimated clinically, just as did changes in the other variables mentioned. Neither immunoreactants in skin nor any other laboratory abnormality reflected renal disease or other type of organ involvement. Deposits of IgG were not more commonly found in patients with renal disease.

Vasculitis in granuloma annulare: histopathology and direct immunofluorescence.

Biopsy specimens from patients with granuloma annulare were studied by conventional light and immunofluorescence microscopy. In six of 20 patients, IgM was present in blood vessels of involved skin, and C3 was present in blood vessels in ten of 20 patients. In addition, IgM, C3, or fibrinogen were observed at the dermal-epidermal junction of eight patients. Necrobiotic areas contained fibrinogen. A retrospective histopathologic study of 38 biopsy specimens from other patients with granuloma annulare showed blood vessels with vessel wall necrosis, fibrinoid change, thickening, or occlusion in most specimens. Nuclear dust and extravasation of RBCs were also noted. These findings suggest that an immunoglobulin-mediated vasculitis may be involved in the pathogenesis of granuloma annulare.

Clinical implications of ribonucleoprotein antibody.

Out of 97 patients with circulating ribonucleoprotein antibodies, 44 (45%) satisfied the criteria for systemic sclerosis, systemic lupus erythematosus, polymyositis/dermatomyositis, or rheumatoid arthritis. Forty-two (43%) of the 97 patients whose cases did not fulfill these criteria had at least two of the following three clinical manifestations: arthritis, Raynaud's phenomenon, and swollen or sclerotic fingers. A fifth of the latter group of patients had chronic, restrictive pulmonary disease or myopathy and two thirds had hypergammaglobulinemia, IgM rheumatoid factor, and sensitized epidermal nuclei. Few patients had hypocomplementemia. One patient had nephropathy. Most patients had an unchanged, benign disease course for, on the average, nine years. It is suggested that the term mixed connective tissue disease (MCTD) be reserved for such patients, and that the acronym MCTD be changed to SRA (swollen fingers, Raynaud's phenomenon, and arthritis). Treatment with glucocorticoids is necessary for only a minority of patients.

Immunological and chromosomal studies in a patient with Sézary syndrome.

A patient with the small-cell variant of Sézary syndrome was studied before and during treatment with low-dose chlorambucil. He had depressed responses to phytohemagglutinin (PHA) and concanavalin A that returned to normal with clinical improvement. Spontaneously dividing cells were found in the peripheral blood by culturing lymphocytes without PHA for 24 hours. Seventy-two-hour PHA-stimulated lymphocyte cultures revealed predominantly hypodiploid chromosome numbers. Both abnormalities improved during treatment. Lymphocytes that were studied for sister chromatid exchanges had an increased number of exchanges per metaphase. Immunofluorescence studies revealed immunoglobulins and C at the dermoepidermal junction and in the dermal vessel walls. Our findings demonstrate that the depression of mitogen responsiveness that is sometimes seen in Sézary syndrome can be favorably affected by chemotherapy. Likewise, some chromosomal abnormalities may regress during successful therapy. These findings may provide a way of measuring the response to therapy.

Bilateral angle-closure glaucoma in association with the acquired immune deficiency syndrome.

Two homosexual men, 35 and 42 years old, had bilateral acute angle-closure glaucoma in association with the acquired immune deficiency syndrome. In one patient, the angle-closure attack was the initial manifestation of AIDS. Choroidal effusion with secondary anterior rotation of the ciliary body at the scleral spur appeared to be the pathophysiologic mechanism. Pupillary block, angle crowding, and inflammatory synechial angle closure must be differentiated from anterior rotation of the ciliary body as the mechanism of the angle closure to provide optimal treatment. Whereas primary angle closures are treated with miotics and iridectomy, secondary angle closure may be worsened with this treatment. Cycloplegics and, if necessary, drainage of suprachoroidal fluid may be curative in AIDS-related angle closure associated with a choroidal detachment. Both patients died before the long-term efficacy of this treatment could be assessed.

Fractionated epibulbar I-125 plaque radiotherapy for recurrent mucoepidermoid carcinoma of the bulbar conjunctiva.

PURPOSE/METHODS: A patient with recurrent conjunctival mucoepidermoid carcinoma was treated successfully with surgical excision of the tumor and fractionated epibulbar I-125 plaque radiotherapy. RESULTS/CONCLUSIONS: Local excision with fractionated epibulbar plaque radiotherapy is an effective means of eradication in select cases of recurrent mucoepidermoid carcinomas of the conjunctiva. This treatment may avoid more aggressive surgical treatment and preserve vision.