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Biomedical subjects

J Ginsberg

Publications and source records attributed to J Ginsberg.

At least 19 recordsLinked to original sources
PubMed1992

Human leukocyte antigen-DRB1*1104 in the chronic iridocyclitis of pauciarticular juvenile rheumatoid arthritis.

To determine whether genetic markers for chronic iridocyclitis could be identified, we used both serologic and oligonucleotide dot blot techniques to characterize immunogenetically 164 children with early-onset pauciarticular juvenile rheumatoid arthritis. Seventy-eight children (47.6%) had chronic iridocyclitis and 86 (52.4%) had not had evidence of eye disease during a mean follow-up period after the onset of arthritis of 15.8 years (minimum of 5.5 years). Control subjects were 218 healthy, unrelated individuals. The analysis was limited to alleles known to be associated with an increased or decreased risk of early-onset pauciarticular juvenile rheumatoid arthritis or of chronic iridocyclitis in this form of juvenile rheumatoid arthritis. Only one split of human leukocyte antigen (HLA)-DR5, HLA-DRB1* 1104, showed a statistically significant association with a risk of chronic iridocyclitis (chi-square value = 7.52; p = 0.036 adjusted; odds ratio 3.45); HLA-DQA1* 0501 and HLA-DQB1* 0301, both in linkage disequilibrium with HLA-DRB1* 1104, also were significantly associated with eye disease. Patients with both the DRB1* 1104 and DPB1* 0201 genes had a 7.7-fold increased risk for chronic iridocyclitis compared with that for other patients. The presence of HLA-DRB1* 1104 was about four times as specific, but only about one third as sensitive, as antinuclear antibodies in identifying patients at risk for eye disease. Although all children with early-onset pauciarticular juvenile rheumatoid arthritis should undergo periodic slit-lamp examinations, those with the HLA class II gene DRB1* 1104 are at particularly high risk for eye disease, and we recommend that they be monitored carefully for its evolution.

Adult↗
PubMed1992

Protein kinase C as a mediator of TSH and thyroid autoantibody action.

Although it is well-established that TSH activates a cAMP-dependent pathway in the thyroid follicular cell leading to thyroid hormone synthesis and release, the present review provides new evidence that TSH also activates a non-cAMP-dependent signal transduction system. This cascade involves phosphoinositide (PI) turnover, diacylglycerol accumulation and protein kinase C (PKC) activation. Activation of this pathway leads to an inhibition of differentiated thyroid function in vitro. Recent evidence suggests that TSH can activate both pathways via a single transcription unit. Unlike TSH, TSH-receptor antibodies may selectively activate cAMP with no effects on PI turnover. In contrast, preliminary studies suggest TSH-blocking antibodies may activate PKC. PKC may be an important mediator of TSH and, possibly, thyroid autoantibody action.

Autoantibodies↗
PubMed1992

The iridocyclitis of early onset pauciarticular juvenile rheumatoid arthritis: outcome in immunogenetically characterized patients.

In a cohort of 72 patients with iridocyclitis (iritis) and early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) the course of the eye disease was matched with ocular outcome. Chronicity of inflammation (greater than 6 months/episode) was correlated with complications of eye disease that caused impairment of vision. HLA antigens in these patients were compared with the HLA antigens in a cohort of 77 patients with EOPA-JRA in whom iridocyclitis had failed to develop over a followup of 5 years or longer. HLA-DR5 (11) was correlated with the presence of eye disease, and HLA-DR1 with its absence; HLA-DRw8, which strongly predisposes to EOPA-JRA, was neutral with respect to eye disease.

Arthritis, Juvenile↗
PubMed1991

Painless thyrotoxic thyroiditis in association with ovarian and adrenal failure.

Polyglandular autoimmune syndrome (PGAS) type II is a disorder characterized by Addison's disease, autoimmune thyroid disease, and diabetes mellitus. In this report, a 19-year-old woman having Addison's disease, ovarian failure, painless thyroiditis, and an HLA type characteristic of PGAS II is described. Painless thyroiditis has been considered recently to have an autoimmune basis and has been reported previously in another patient with Addison's disease. The otherwise characteristic features of the patient in this case allow her to be classified as having PGAS II, thereby expanding the scope of reported autoimmune thyroid disorders in PGAS II.

Adrenal Gland Diseases↗
PubMed1991

Phorbol ester and phospholipase C-mediated differentiated thyroid function in vitro: the effects of protein kinase C inhibition and downregulation.

Tumor-promoting phorbol esters, e.g., 12-O-tetradecanoylphorbol 13-acetate (TPA), inhibit TSH-stimulated iodide organification in vitro implying a role for protein kinase C (PKC) in the regulation of differentiated thyroid function. To further explore the PKC dependence of this action of TPA, we studied the effects of PKC inhibition and downregulation on phorbol-mediated differentiated thyroid function in vitro. In addition, the effects of the nonphorbol PKC activator, phospholipase C (PLC) were studied. TPA (100 nM) inhibited TSH-stimulated iodide organification in cultured porcine thyroid cells by over 95% and caused PKC translocation in vitro. Exogenous PLC (1 U/mL) could mimic these effects of TPA. The PKC inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) inhibited TSH-stimulated iodide organification at concentrations exceeding 10 microM. However, partial recovery of phorbol- and PLC-inhibited iodide organification was seen in the presence of identical concentrations of H7. H7 had no effect on PKC translocation in porcine thyroid cell extracts. After 24 h of TPA treatment to induce PKC downregulation, no recovery of TSH-stimulated iodide organification was observed, suggesting that the effects of TPA were irreversible. These studies indicate that the effects of TPA and PLC on differentiated thyroid function are mediated, at least in part, by PKC. These findings provide further evidence for a role for PKC in the regulation of differentiated thyroid function.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Soluble fibrin degradation products potentiate tissue plasminogen activator-induced fibrinogen proteolysis.

Despite its affinity for fibrin, tissue plasminogen activator (t-PA) administration causes systemic fibrinogenolysis. To investigate the mechanism, t-PA was incubated with plasma in the presence or absence of a fibrin clot, and the extent of fibrinogenolysis was determined by measuring B beta 1-42. In the presence of fibrin, there is a 21-fold increase in B beta 1-42 levels. The potentiation of fibrinogenolysis in the presence of fibrin is mediated by soluble fibrin degradation products because (a) the extent of t-PA induced fibrinogenolysis and clot lysis are directly related, (b) once clot lysis has been initiated, fibrinogenolysis continues even after the clot is removed, and (c) lysates of cross-linked fibrin clots potentiate t-PA-mediated fibrinogenolysis. Fibrin degradation products stimulate fibrinogenolysis by binding t-PA and plasminogen because approximately 70% of the labeled material in the clot lysates binds to both t-PA- and plasminogen-Sepharose, and only the bound fractions have potentiating activity. The binding site for t-PA and plasminogen is on the E domain because characterization of the potentiating fragments using gel filtration followed by PAGE and immunoblotting indicates that the major species is (DD)E complex, whereas minor components include high-molecular weight derivatives containing the (DD)E complex and fragment E. In contrast, D-dimer is the predominant species found in the fractions that do not bind to the adsorbants, and it has no potentiating activity. Thus, soluble products of t-PA-induced lysis of cross-linked fibrin potentiate t-PA-mediated fibrinogenolysis by providing a surface for t-PA and plasminogen binding thereby promoting plasmin generation. The occurrence of this phenomenon after therapeutic thrombolysis may explain the limited clot selectivity of t-PA.

Enzyme Activation↗
PubMed1991

Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis.

The risk of iridocyclitis in children with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) has been shown to be associated with certain HLA haplotypes. Our report contains an actuarial analysis, using one-year intervals, of 161 subjects and estimates haplotype specific risks. Individuals who possess the major susceptibility haplotype HLA-DR5 (11) developed eye disease earlier and with a greater frequency than did those with the protective HLA-DR1 haplotype. Highly significant differences were found between the resulting life-table curves for HLA-DR5 and HLA-DR1 positive subjects (p = 0.00003). These time oriented risk estimates may aid clinicians in determining more precisely the probability of iridocyclitis throughout the course of the disease in children with EOPA-JRA.

Adolescent↗
PubMed1990

Androgen receptor defects in patients with minimal and partial androgen resistance classified according to a model of androgen-receptor complex energy states.

We have characterized intracellularly the androgen-receptor (A-R) complexes formed by genital skin fibroblasts from 2 unrelated males with qualitative defects of the androgen receptor: one has a small nonhypospadic penis as part of a syndrome of mild androgen resistance; the other was born with ambiguous external genitalia. The dissociation rate constants of testosterone, methyltrienolone (MT), dihydrotestosterone (DHT) and mibolerone (MB) from normal androgen receptors were determined at various temperatures: when plotted by the method of Arrhenius, they yielded a linear hierarchy of dissociation states with energies of state IV greater than III greater than II greater than I, respectively. Relative to this hierarchy, patient A-R complexes were displaced to higher, androgen-inappropriate energies in a mutant-distinctive pattern. MB- or MT-R complexes of both patients were thermolabile; however, both up-regulated normally in response to prolonged incubation with either hormone. Apparent equilibrium affinity constants (Kd) of the DHT- and MB-R complexes formed by both patients were normal; however, the binding capacity (Bmax) for MB in 1 case was subnormal. The distinctive biochemical phenotypes of A-R complexes in these 2 patients with androgen resistance will facilitate the definition of structure-function relations in the androgen receptor, a classical DNA-binding, transcription-regulating protein.

Adolescent↗
PubMed1979

Results of a regional cord blood screening programme for detecting neonatal hypothyroidism.

Our regional cord blood screening programme for detecting neonatal hypothyroidism using initial cord blood thyroxine (T4) determinations, with supplemental thyrotropin (TSH), and triiodothyronine resin uptake (T3U) measurements, gave an incidence of thyroid abnormalities of 1/3000 births, with 1/5000 infants having severe primary hypothyroidism. No hypothyroid infant detected in the programme had been suspected clinically before the screening and, in retrospect, only a few babies had any signs of hypothyroidism. Supplemental TSH and T3U determinations were required on 8-12% of the population screened initially with a T4 test to avoid missing affected cases. With an initial T4 and supplementary TSH and T3U testing on cord blood serum, recalls to exclude primary hypothyroidism were reduced to 0.16% of the screened population. The incidence of abnormalities detected in this cord blood screening programme was comparable with that reported by others using neonatal dried blood screening methods, indicating that cord blood screening can be effective provided the appropriate recall criteria and transport conditions are used. Nevertheless, for several practical reasons, neonatal dried blood methods are recommended as the screening test of choice for surveying large populations over extensive geographical areas.

Female↗
PubMed1979

Multiple congenital ocular anomalies with bilateral agenesis of the urinary tract.

A 1,350 gm female infant with features of the Potter syndrome (dysplasia renofacialis) had multiple ocular anomalies. Absence of keratocytes in the central corneal stroma, cataract, retinal ganglion cell and nerve fiber hypoplasia, loss of optic nerve bundles, and angiomatoid proliferation in the area of the optic disc are most striking. Some of these findings, especially in the cornea, may reflect mesoectodermal dysgenesis. Abnormal ocular angiogenesis may well comprise a part of Potter's syndrome.

Adult↗
PubMed1978

Parathyroid cysts. Medical diagnosis and management.

Two patients had asymptomatic neck masses that proved to be cystic. In each case, the lesions resolved after needle aspiration of 25 ml of clear, colorless fluid. Serum thyroid indexes and calcium levels were normal. Cyst fluid parathyroid hormone (PTH) levels were 0.56 and 1.50 ng/ml, respectively. The serum PTH level in case 1, determined at the same time, was less than 0.05 ng/ml (normal, 0 to 0.3 ng/ml). These observations indicate that (1) clear, colorless cyst fluid may indicate a parathyroid cyst, (2) serum and cyst fluid PTH levels can confirm the diagnosis, and (3) needle aspiration may be appropriate therapy for the benign, nonfunctioning parathyroid cyst.

Adult↗