Calcinosis, Raynaud's Phenomenon, Esophageal Dysmotility, Sclerodactyly Research Articles

Imaging studies of kleptomania in a middle-aged woman with obsessive-compulsive disorder: a case report

A 57-year-old woman who had been arrested for shoplifting visited our hospital. She was diagnosed with kleptomania. She had previously been diagnosed with CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and obsessive-compulsive disorder. Cranial magnetic resonance imaging showed mild atrophy of the bilateral dorsolateral prefrontal cortices, left hippocampus, and occipital cortex, as well as diffuse mild T2 hyperintensity in the deep and subcortical white matter, including the frontal region. During a single-photon emission computed tomography scan, significant hyperperfusion was observed in the right ventral striatum, including the nucleus accumbens, ventral thalamus, and right ventrolateral prefrontal areas. Patchy hypoperfusion was found in the bilateral posterior cingulate, parietal, and occipital regions. The patient's neurocognitive function was normal, except for slight impairment of her executive function. Her symptoms and neuroimaging findings were not suggestive of a specific neurocognitive disorder. Hyperactivity of the right ventral striatum may contribute to both obsessive-compulsive disorder and kleptomania. Although frontotemporal lobar degeneration is a major neurocognitive disorder related to illegal behaviours, CREST syndrome-induced white matter microstructural damage in the orbitofrontal lobe could have caused our patient's kleptomania.

Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database.

Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.

Transplantation of somatic nuclei into oocyte cytoplasm reveals that the chromosome properties determine the chromosome separation fate in rabbit

G2/M somatic nuclei were introduced into enucleated meiotically competent oocytes and subsequently cultured in TCM199 plus 10% fetal calf serum (FCS). Pseudo-first polar bodies could be extruded, but the chromosomes failed to arrange normally. Kinetochores were traced with immunofluorescent microscopy using autoimmune sera from patients with CREST (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia) scleroderma. In vitro matured oocytes arrested at second meiotic metaphase and kinetochores were detectable as paired structures aligned at the spindle equator. At meiotic anaphase, present or past the kinetochores separated and remained aligned at the distal sides of the chromosomes until telophase, when their alignment perpendicular to the spindle axis was lost. Kinetochores failed to arrange normally after transferring somatic nuclei into oocytes. Our results suggest that somatic cell nuclei are unable to proceed normally through meiosis when introduced into oocyte meiotic cytoplasm.

Esophageal investigations in connective tissue disease: which tests are most appropriate?

Our aim was to review the use of esophageal investigations in patients with suspected connective tissue disease (CTD). Forty-seven patients (39 women and 8 men) with suspected CTD were referred for esophageal manometry at the gastrointestinal physiology unit in the Royal Victoria Hospital, Belfast, U.K., over a 10-year period (1987-1997). The mean age was 51.7 years (range = 21-79 years). Chart review was conducted 1 to 10 years after manometry to confirm the final diagnoses: scleroderma was found in 11; CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia), 8; mixed connective tissue disease, 14; Raynaud's alone, 5; and other CTDs, 9. All 47 successfully underwent esophageal manometry. In addition to manometry, 24 underwent gastroscopy; 27, barium meal; and 3, esophageal pH studies. Clinically significant esophageal abnormalities were noted in 8 (33%) on gastroscopy, in 15 (56%) on barium meal, and in 31 (66%) on manometry. Gastroscopy had a significantly lower positivity rate than the others (p < 0.05). Only three patients had pH testing, yet all three pH tests were abnormal. During manometry, abnormal findings were significantly more common in scleroderma-CREST when compared with other diagnoses (89% vs. 50%; p < 0.02). Thirty-three patients reported dysphagia. Abnormal manometry was more likely in these cases (82% vs. 33%; p < 0.02). A high percentage of patients with CTD have significant esophageal motility disorders. Investigations were more likely to be positive with scleroderma-CREST than other CTDs, even if dysphagia was present. Barium meal and manometry are more useful than OGD. pH studies were under-used. There is need for a standardized approach to esophageal investigations in patients with CTDs.

The concurrence of rheumatoid arthritis and limited systemic sclerosis: Clinical and serologic characteristics of an overlap syndrome

Objective The characteristics of 3 patients with longstanding rheumatoid arthritis (RA) and consecutive evolution of limited cutaneous systemic sclerosis (lcSSc) were evaluated and compared with those of patients with lcSSc alone (n = 20) or with RA alone (n = 120). Methods Clinical features of the different patient populations were compared. Serologic analyses included tests for antinuclear antibodies (ANA) and ANA subsets, in particular anticentromere antibodies (ACA) and anti-heterogeneous nuclear RNP (hnRNP)-A2/RA33 (anti-A2/RA33). Results The 3 patients with RA developed lcSSc 11, 29, or 50 years after the onset of RA. Features of lcSSc were Raynaud's phenomenon, sclerodactyly, and telangiactasias in all 3 patients, and esophageal dysmotility in 1 patient. Rheumatoid factor (RF) and anti-A2/RA33 were each found in 2 patients, and 1 of these patients was seropositive for both RF and anti-A2/RA33. ACA titers were positive in all cases. However, similar to the development of RA prior to lcSSc, the occurrence of autoantibodies typical of RA preceded the occurrence of ACA, at least in 2 of the patients. Using affinity-purified antibodies, cross-reactivities between anti-centromere protein A (CENP-A) and anti-CENP-B antibodies with anti-A2/RA33 antigens were seen in the 2 anti-A2/RA33-positive patients. Such cross-reactivities were not found in lcSSc patients without concomitant RA. Epitope mapping revealed that both autoantibody specificities recognized the known major epitopes: anti-CENP-B reacted with the C-terminal region and anti-A2/RA33 with the second RNA binding domain in the N-terminal region of hnRNP-A2. Conclusion The RA-lcSSc overlap syndrome in these 3 patients with longstanding RA was characterized by an incomplete CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias) syndrome. The study demonstrated the presence of autoantibodies typical of both diseases and cross-reactivity of ACA with hnRNP-A2/RA33 in the sera of these patients.

Serial nailfold capillary microscopy in primary Raynaud's phenomenon and scleroderma

Eighty-four patients with long-standing Raynaud's phenomenon (RP) were evaluated by nailfold capillary microscopy (NCM) in a cross-sectional and longitudinal study. The patients were classified in five diagnostic groups: primary familial RP (n = 16), primary nonfamilial RP (n = 20), possible scleroderma (n = 27), scleroderma (n = 16), and the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome (n = 8). In the cross-sectional study, NCM showed gradually decreasing numbers of capillary loops and increasing numbers of widened and giant loops in the following order: primary RP, possible scleroderma, and scleroderma/ CREST, suggesting that these diseases are part of a continuing spectrum of RP. In the longitudinal study there was a decrease in the total number of nailfold capillary loops in scleroderma/CREST but not in primary RP and possible scleroderma.

Anticentromere Autoantibodies

To evaluate an enzyme-linked immunosorbent assay (ELISA) for anticentromere autoantibodies (ACA). Sera from 611 patients with scleroderma, CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), Raynaud's disease, and connective tissue disease control patients were studied by ELISA using the fusion protein CENP-B, by immunofluorescence on dividing HEp-2 cells, and by immunoblotting on chromosomes and CENP-B. Compared with immunofluorescence, the CENP-B ELISA sensitivity was 94% and the specificity was 93%. In 19.7% of the cases, there was a probability of a false-positive result and in 1.9%, a probability of a false-negative result, yielding positive and negative predictive values of 0.80 and 0.98, respectively. The CENP-B ELISA is a sensitive and specific assay for ACA.

Anti-Scl-70 antibodies detected by immunoblotting in progressive systemic sclerosis: specificity and clinical correlations.

One hundred and forty five serum samples from patients with a connective tissue disease and 30 serum samples from healthy blood donors were analysed by immunoblotting. The presence of anti-Scl-70, which seems to discriminate between progressive systemic sclerosis (PSS) and the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome, was found in 31/64 (48%) patients with PSS, in 6/55 (11%) patients with systemic lupus erythematosus, in 2/26 (8%) patients with mixed connective tissue disease, and in none of 30 healthy blood donors. These data resulted in a specificity of 93% for this antibody in systemic sclerosis. For patients with PSS the duration of disease was significantly shorter in those with anti-Scl-70 antibodies than in those without, whereas the presence of anti-Scl-70 did not correlate with severity of disease. An 82% prevalence of anticentromere antibodies in patients with the CREST variant compared with a 4% prevalence in patients with PSS or with overlap syndrome confirms the high diagnostic value of this autoantibody for the CREST variant of PSS.

Autoantibodies to mitochondria in systemic sclerosis. Frequency and characterization using recombinant cloned autoantigen.

Mitochondrial autoantibodies, a hallmark of primary biliary cirrhosis (PBC), have been widely described for many years in patients with systemic sclerosis, and there have been several reports of the concurrence of systemic sclerosis and PBC. However, there is very little information with respect to the significance of these autoantibodies or any definitive evidence that the antigens involved represent the mitochondrial autoantigens (M2 complex) described in PBC. We have cloned and sequenced a rat complementary DNA which encodes for all the epitopes recognized by autoantibodies to the major, or 70-kd, mitochondrial autoantigen in patients with PBC. Using this recombinant fused autoantigen, as well as by immunoblotting with human placental mitochondria, we tested for antimitochondrial antibody specificity in sera from 250 patients with systemic sclerosis. Nineteen sera (7.6%), including those from patients with CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) and diffuse scleroderma, had reactivity with human placental mitochondria proteins by immunoblot testing. All 19 sera reacted with the M2 complex. All sera that reacted with the 70-kd protein likewise reacted with the recombinant cloned autoantigen. The predominant autoantibody isotype to the 70-kd protein was IgG3. Interestingly, the 70-kd protein is 11% proline, an amino acid which is frequently preceded by hydrophobic amino acids.

Tubulin interaction with kinetochore proteins: analysis by in vitro assembly and chemical cross-linking.

The sera from patients with the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) variation of the autoimmune disease scleroderma contain autoantibodies that specifically recognize the kinetochore by immunofluorescence. Two major antigens of molecular masses 18 and 80 kD are consistently identified by Western blotting of proteins of isolated chromosomes using CREST sera. In this paper, the possible roles that these two proteins play in the interaction of metaphase chromosomes with tubulin and microtubules are examined using two different procedures. In one set of experiments. Chinese hamster ovary (CHO) chromosomes were extracted with 1-2 M NaCl before incubating with phosphocellulose-purified tubulin under in vitro microtubule assembly conditions. After this treatment, the kinetochores of the residual chromosome scaffolds can still initiate the in vitro assembly of microtubules. Immunoblots of the chromosome scaffold proteins demonstrate that the 18-kD protein has been solubilized by the 1-2 M NaCl extraction, suggesting that this protein is not essential for microtubule assembly at the kinetochore. In a second approach, tubulin was covalently cross-linked to kinetochores of CHO chromosomes using the reversible cross-linking reagent dithiobis (succinimidyl propionate). After DNase I digestion, the chromosomes were solubilized and subjected to anti-tubulin affinity chromatography. Tubulin-kinetochore protein complexes were specifically eluted and analyzed by PAGE and immunoblotting with scleroderma CREST serum. Only a small number of proteins were eluted from the antitubulin affinity column as shown by Coomassie Blue-stained gels. In addition to tubulin, an 80-kD polypeptide, bands at 110 and 24 kD, as well as a faint band at 54 kD, can be resolved. Several minor bands can also be seen in silver-stained gels. The 80-kD protein band from whole metaphase chromosomes reacted with scleroderma CREST serum by immunoblotting and therefore probably represents the major centromere antigen CENP-B. This report provides evidence for a specific protein complex on metaphase chromosomes that is contiguous with kinetochore-bound tubulin and may be involved in microtubule-kinetochore interactions during mitosis.

Synaptonemal complex antigen location and conservation.

The axial cores of chromosomes in the meiotic prophase nuclei of most sexually reproducing organisms play a pivotal role in the arrangement of chromatin, in the synapsis of homologous chromosomes, in the process of genetic recombination, and in the disjunction of chromosomes. We report an immunogold analysis of the axial cores and the synaptonemal complexes (SC) using two mouse monoclonal antibodies raised against isolated rat SCs. In Western blots of purified SCs, antibody II52F10 recognizes a 30- and a 33-kD peptide (Heyting, C., P. B. Moens, W. van Raamsdonk, A. J. J. Dietrich, A. C. G. Vink, and E. J. W. Redeker, 1987, Eur. J. Cell Biol., 43: 148-154). In spreads of rat spermatocyte nuclei it produces gold grains over the cores of autosomal and sex chromosomes. The cores label lightly during the chromosome pairing stage (zygotene) of early meiotic prophase and they become more intensely labeled when they are parallel aligned as the lateral elements of the SC during pachytene (55 grains/micron SC). Statistical analysis of electronically recorded gold grain positions shows that the two means of the bimodal gold grain distribution coincide with the centers of the lateral elements. At diplotene, when the cores separate, the antigen is still detected along the length of the core and the enlarged ends are heavily labeled. Shadow-cast SC preparations show that recombination nodules are not labeled. The continued presence suggests that the antigens serve a continuing function in the cores, such as chromatin binding, and/or structural integrity. Antibody III15B8, which does not recognize the 30- and 33-kD peptides, produces gold grains predominantly between the lateral elements. The grain distribution is bimodal with the mean of each peak just inside the pairing face of the lateral element. The antigen is present where and while the cores of the homologous chromosomes are paired. From the location and the timing, it is assumed that the antigen recognized by III15B8 functions in chromosome pairing at meiotic prophase. The two anti-rat SC antibodies label rat and mouse SCs but not rabbit or dog SCs. A positive control using human CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) anti-centromere serum gives equivalent labeling of SC centromeres in the rat, mouse, rabbit, and dog. It is concluded that the SC antigens recognized by II52F10 and III15B8 are not widely conserved. The two antibodies do not bind to cellular or nuclear components of somatic cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Fractionation and initial characterization of the kinetochore from mammalian metaphase chromosomes.

We have partially isolated the kinetochore and associated centromeric structures from mammalian metaphase chromosomes. Human autoantibodies from scleroderma CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) patients were used as immunofluorescent probes to monitor fractionation. The procedure includes digestion of total chromosomal DNA with micrococcal nuclease, dehistonization with heparin, and dissociation of the remaining material with detergent and urea. We used a density gradient (metrizamide) to obtain an enriched fraction of stained material (kinetochore). When examined by electron microscopy, the kinetochore fraction is seen to contain numerous small immunoperoxidase-positive masses which are morphologically similar to the centromere/kinetochore region of intact metaphase chromosomes. The particulate fraction that contains kinetochore components represents less than 5% of total chromosomal proteins and contains less than 1% of total DNA. Two polypeptides of 18 and 80 kD were identified as kinetochore antigens by immunoblotting with CREST antiserum. In this paper we discuss the distribution of these kinetochore polypeptides with the associated centromeric chromatin.

Evolution of primary Raynaud's phenomenon (Raynaud's disease) to connective tissue disease.

Eighty-seven patients diagnosed as having primary Raynaud's phenomenon (Raynaud's disease) were reexamined after this symptom had been present for a mean of 8.8 years (range 2.0-34.5). One or more additional clinical feature(s) suggesting an underlying connective tissue disease were found in 12 patients (14%) at first evaluation, and in 23 (26%) by the last evaluation. The most frequent findings were puffy fingers (10 patients), digital tip pitting scars (8 patients), and digital tip ulcerations (6 patients). Distal esophageal hypomotility and/or decreased pulmonary diffusing capacity for carbon monoxide were found in 12 patients. Only 4 individuals (5%) developed clear evidence of a connective tissue disease, and in all cases, the diagnosis was the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) syndrome variant of systemic sclerosis. This condition became obvious 8-17 years after the onset of Raynaud's phenomenon. One or more serologic test values were initially abnormal in 2 of these CREST syndrome patients, as well as in 12 patients who continued to have primary Raynaud's phenomenon at the last evaluation. The combination of puffy fingers, digital pitting scars, and serum anticentromere antibody, all consistent with CREST syndrome, occurred in a small group of patients. None of the 78 patients whose serologic tests were repeated during followup had a change in the serologic profile. These results suggest that only a small proportion of patients with primary Raynaud's phenomenon develop one of the connective tissue diseases during the first decade after onset. When such a disorder does appear, systemic sclerosis with the CREST syndrome variant is the most likely eventual diagnosis.

A long-term longitudinal study of anticentromere antibodies.

A longitudinal retrospective study of 37 patients previously tested for anticentromere antibodies (ACA) in 1982 was carried out. No ACA were found in stored sera from 22 ACA-negative patients including 1 patient with CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia). All ACA-positive patients, with 1 exception, were found to have ACA in their sera over prolonged periods of time. One patient developed ACA for the first time when the third feature of the CREST syndrome (Raynaud's phenomenon) was noted. Anticentromere antibodies were IgG, and no consistent change in titer over time was found.