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Biomedical subjects

M F Prummel

Publications and source records attributed to M F Prummel.

At least 73 records · Page 4Linked to original sources
PubMed1994

Molecular cloning and characterization of genes for antibodies generated by orbital tissue-infiltrating B-cells in Graves' ophthalmopathy.

Graves' ophthalmopathy is a distressing autoimmune disease of unknown etiology. Analysis of the genes for antibodies secreted by orbital tissue-infiltrating plasma cells might provide insight into the pathogenesis of this disease. We, therefore, constructed an immunoglobulin heavy (H) chain and an immunoglobulin kappa light (L) chain cDNA library from the orbital tissue of a patient with active Graves' ophthalmopathy. Analysis of 15 H (IgG1) and 15 L (kappa) chains revealed a restricted spectrum of variable region genes. Fourteen of 15 variable kappa genes were about 94% homologous to the closest known germline gene, KL012. Thirteen of 15 H chain genes were 91% and 90% homologous to the closest germline genes, DP10 and hv1263, respectively. Remarkably, these germline genes also code for other autoantibodies to striated muscle (KL012) and thyroid peroxidase (KL012 and hv1263). These studies raise the possibility that particular germline genes may be associated with autoimmunity in humans. Further, the present study opens the way to identifying ocular autoantigens that may be the target of an humoral immune response.

Amino Acid Sequence↗
PubMed1994

Recombinant thyroid peroxidase autoantibodies can be used for epitopic "fingerprinting" of thyroid peroxidase autoantibodies in the sera of individual patients.

Four human monoclonal antibodies (SP1.4, WR1.7, TR1.8, and TR1.9) map the immunodominant region on thyroid peroxidase (TPO) recognized by autoantibodies in patients' sera. We used a pool of these monoclonal antibodies, expressed in bacteria as antigen-binding fragments [F(ab)], to compete for TPO autoantibody binding to radiolabeled TPO. The F(ab) inhibited TPO binding by 32 patients' sera by 82 +/- 14% (mean +/- SD), with a range from 51-100%. When each F(ab) was tested individually for its ability to compete for autoantibody binding to TPO, F(ab) TR1.8 was the most potent among the 32 sera. However, there was a wide spectrum of TPO binding inhibition when each serum was considered individually, thereby allowing an epitopic "fingerprint" to be drawn for the TPO autoantibodies in a patient's serum. There was a close association between the proportions of TPO autoantibodies to the TR1.8 and TR1.9 epitopes as well as between those to the SP1.4 and WR1.7 epitopes. These associations correspond to the previously described A and B epitopic domains in the TPO immunodominant region. No TPO epitope was observed to be associated with clinically apparent ophthalmopathy of Graves' disease, nor was there an association between TPO epitopes and patient age or sex. In summary, the present study on a large sample of sera with TPO autoantibodies indicates that by using TPO-specific F(ab) selected to cover all regions of the TPO immunodominant region, it is possible to obtain a TPO epitopic fingerprint for each serum. These data open the way to future studies directed at testing the hypothesis of disease-associated TPO epitope(s).

Autoantibodies↗
PubMed1994

Cell-mediated or humoral immunity in Graves' ophthalmopathy? Profiles of T-cell cytokines amplified by polymerase chain reaction from orbital tissue.

Whether Graves' ophthalmopathy is the results of a cell-mediated or humoral autoimmune response is controversial. T-Lymphocytes that regulate these two mechanisms, Th1 and Th2, respectively, are characterized by the profile of cytokines that they secrete. We, therefore, investigated the spectrum of T-lymphocyte cytokines expressed in Graves' orbital tissue by means of the polymerase chain reaction using reverse transcribed mRNA as template. From three Graves' thyroid tissues (positive controls), we obtained DNA products of the predicted size for the Th1 cytokines interferon-gamma (IFN gamma) and interleukin-2 (IL-2) as well as for Th2 cytokines IL-4 and IL-5. A signal for IL-10 (Th1 and Th2) was also detected. No cytokine signals were observed in peripheral blood (negative control). Despite the presence of T-cells (CD3 delta marker) in the orbital connective tissue/fat of all five patients studied as well as in orbital muscle from one of these patients, IFN gamma reverse transcribed mRNA was notably absent from these tissues. In contrast, IL-2, IL-5, and IL-10 cDNA was present in orbital tissues from one or more patients. Of particular importance, an IL-4 signal was detected in orbital connective tissue/fat of patients 6 and 7 as well as in muscle of patient 7. The balance between IL-4 and IFN gamma determines whether an immune response is predominantly humoral or cell mediated. Our finding of IL-4, but not IFN gamma, mRNA expression in orbital tissue supports a role, at least in some patients, for humoral autoimmunity in Graves' ophthalmopathy.

Aged↗
PubMed1993

Randomized double-blind trial of prednisone versus radiotherapy in Graves' ophthalmopathy.

Corticosteroids are usually given for management of Graves' ophthalmopathy, but they have many and serious side-effects. By comparison, retrobulbar irradiation is well tolerated, although its efficacy has been evaluated only in uncontrolled studies. Therefore, we did a double-blind randomised trial, in which 28 patients with moderately severe Graves' ophthalmopathy were treated with a 3-month course of oral prednisone and sham irradiation, and 28 received retrobulbar irradiation (20 Gy) and placebo capsules. Therapeutic outcome, assessed twenty-four weeks after the start of treatment, was determined by the change in the highest NOSPECS class. A successful outcome was observed in 14 prednisone-treated and in 13 irradiated patients. Responders to treatment (but not nonresponders) in both groups showed improvements in total and subjective eye score and a decrease in eye-muscle volume. Response to either treatment was due largely to changes in soft-tissue involvement and eye-muscle motility. Mean elevation in responders to radiotherapy increased from 18.5 degrees (95% CI 14.8-22.2) at baseline to 21.8 degrees (18.6-25.0) at week twenty-four (p = 0.003), but did not change in prednisone responders. Side-effects were more frequent and severe during prednisone than during radiotherapy. Radiotherapy and oral prednisone appear to be equally effective as initial treatment in patients with moderately severe Graves' ophthalmopathy. In view of its better tolerability, radiotherapy should be considered the treatment of first choice.

Administration, Oral↗
PubMed1993

Smoking and risk of Graves' disease.

OBJECTIVE: To assess if smoking is associated with Graves' disease and, if so, to ascertain whether this association persists when controlling for confounding factors. DESIGN: Consecutive entry case-control study with two age- and sex-matched control subjects from two different populations per case patient. SETTING: University hospital. PATIENTS: Five groups were studied: (1) Graves' ophthalmopathy and Graves' hyperthyroidism (n = 100; divided in four subgroups according to the severity of the eye disease); (2) Graves' hyperthyroidism without clinical eye involvement (n = 100); (3) sporadic nontoxic goiter (n = 100); (4) autoimmune hypothyroidism (n = 75); and (5) toxic nodular goiter (n = 75). The study comprised 200 subjects from a hospital-based population, and 200 from a population-based group served as control subjects. MAIN OUTCOME MEASURE: Smoking status was determined from a questionnaire at the time of onset of the disease to exclude any effect of the disease itself on smoking. RESULTS: Smoking greatly increased the risk for Graves' ophthalmopathy (odds ratio, 7.7; 95% confidence interval, 4.3 to 13.7), but patients with Graves' hyperthyroidism alone were also more often smokers than control subjects (odds ratio, 1.9; 95% confidence interval, 1.1 to 3.2). Smoking was not associated with the other thyroid diseases studied. Essentially similar results were obtained after adjustment for differences in education between case patients and control subjects. Among the patients with Graves' ophthalmopathy, smokers had more severe eye disease than nonsmokers, but no association was found between the number of cigarettes smoked per day or the duration of smoking and the severity of the ophthalmopathy. However, there was a significant increase in the odds ratios in patients with more severe eye disease. CONCLUSIONS: Smoking is associated with Graves' disease, and it especially increases the risk for the development of more severe ophthalmopathy. Thus, smoking appears to be one of the multiple factors inducing Graves' disease in genetically predisposed individuals.

Adult↗
PubMed1993

A new ultrasonographic method to detect disease activity and predict response to immunosuppressive treatment in Graves ophthalmopathy.

PURPOSE: To determine whether the internal reflectivity of the eye muscles on A-mode ultrasonography serves as indicator for disease activity in Graves ophthalmopathy, thereby predicting response to immunosuppressive treatment. METHODS: Eye muscle reflectivity, expressed as percentage of the initial scleral spike, was measured in the superior, medial, and lateral recti, and normal values were determined in 23 healthy controls. These were compared with values in 16 consecutive patients with untreated, moderately severe Graves ophthalmopathy. The accuracy of the measurement was assessed by calculating the intra- and interobserver coefficient of repeatability. Baseline eye muscle reflectivity in the 16 patients was correlated to the therapeutic outcome 24 weeks after start of immunosuppressive therapy. The response to treatment served as indicator for pretreatment disease activity. RESULTS: Eye muscle reflectivity could be measured reliably, with an intraobserver coefficient of repeatability of 8.2% in controls and 10.2% in patients. Patients had lower reflectivity than controls (54.6 +/- 17.4% versus 70.7 +/- 6.6%; P < 0.001). Reflectivity in eye muscles with the lowest echogenicity was lower in responders than in nonresponders (25.8 +/- 8.4% versus 40.6 +/- 13.6%; P = 0.02). From the individual data, a cut-off value of 40% was derived, which appeared as an accurate predictor of outcome (positive predictive value 73%; 95% confidence interval 39%-94%). CONCLUSIONS: Measuring eye muscle reflectivity in Graves ophthalmopathy appears to be a reliable new method to determine disease activity, with a promising accuracy in predicting therapeutic outcome of immunosuppressive treatment.

Adult↗
PubMed1993

Thyrotropin receptor autoantibodies recognizing two different epitopes on the TSH receptor: lack of relationship to patient age, sex, and ophthalmopathy.

The existence of two populations of stimulatory TSH receptor autoantibodies against different epitopes raises the possibility of a link between one type of autoantibody and the clinical manifestations of Graves' disease. To test this hypothesis, serum immunoglobulins from 48 patients with Graves' disease were assayed for TSH binding inhibition (TBI) activity with two different recombinant TSH receptor variants (TSH-LHR-6 and TSH-LHR-6-A1) expressed on Chinese hamster ovary cells. The activity of 27 of the 48 patients' immunoglobulin samples was significantly less (difference in TBI value of 9% or greater) with chimera 6-A1 than with chimera 6. No immunoglobulin sample had significantly greater TSH binding inhibitory activity with chimera 6-A1 than with chimera 6. Sensitivity to the 6-A1 epitope substitution did not correlate with patient age, sex, or the presence or absence of hyperthyroidism. Further, there was no segregation of individual patients with TSH receptor autoantibodies with 6-A1 epitope sensitivity in terms of the past or present occurrence of ophthalmopathy, including the severity (total eye score), clinical activity, duration, and type of therapy. These data indicate that recognition by autoantibodies of the 6-A1 epitope on the TSH receptor is not associated with the ophthalmopathy of Graves' disease. However, the possibility cannot be excluded that other functional (or even nonfunctional receptor autoantibodies that are not detectable by present assays) may still play a role in the pathogenesis of Graves' ophthalmopathy.

Adult↗
PubMed1993

Effect of prednisone on renal function in man.

To clarify the rise in plasma creatinine concentration previously observed during prednisone treatment, we studied changes in renal function in Graves' ophthalmopathy patients before and after 2 weeks of either prednisone 60 mg/day or retrobulbar radiotherapy (controls). Compared to retrobulbar radiotherapy, prednisone treatment was associated with an increase in: (a) plasma creatinine concentration (from 68 +/- 4 to 76 +/- 4 mumol/l), (b) glomerular filtration rate (GFR, from 93 +/- 4 to 102 +/- 5 ml/min/1.73 m2), and (c) urinary creatinine excretion rate (from 510 +/- 40 to 570 +/- 40 mumol/h). We conclude that GFR rises during 2 weeks of high-dose prednisone administration, a rise that is not reflected by a decrease in plasma creatine concentration. On the contrary, both plasma creatinine concentration and urinary creatinine excretion increase, probably as a result of the catabolic effect of prednisone. As established by the present study, prednisone 60 mg/day is associated with protein wasting, also after 14 days of treatment.

Adult↗
PubMed1993

Treatment of amiodarone-induced hypothyroidism with potassium perchlorate.

The antiarrhythmic drug, amiodarone, induces thyroid dysfunction, which is potentially dangerous in cardiac patients. After discontinuation of the drug it takes several months before euthyroidism is restored. The potent antithyroid drug, potassium perchlorate (KClO4), is used successfully to treat amiodarone-induced thyrotoxicosis, but it is less well known as potential treatment in amiodarone-induced hypothyroidism. In this case report we describe the successful use of two courses of KClO4 treatment in a cardiac patient with severe amiodarone-induced hypothyroidism. The mechanisms responsible for the amiodarone-induced hypothyroidism and rationale for the use of KClO4 in this condition are discussed.

Amiodarone↗
PubMed1992

Soluble IL-2 receptor levels in patients with Graves' ophthalmopathy.

In various autoimmune diseases circulating levels of soluble IL-2 receptor (sIL-2R) seem to be related to disease activity. Because reliable parameters of disease activity in Graves' ophthalmopathy are lacking, we measured sIL-2R levels in 47 patients with this disorder. The patients had Graves' disease, but no other immune-mediated diseases, had not yet received specific treatment for their ophthalmopathy and were euthyroid during the entire study period. Twenty-one of the 47 patients (45%) had sIL-2R values above the upper normal limit of 650 U/ml, as established in 20 healthy controls. There were no differences between patients with normal (median 469, range 280-644 U/ml) and elevated (median 946, range 678-1588 U/ml) sIL-2R levels regarding duration or severity of the eye disease (as assessed clinically from the total eye score). However, patients with severely enlarged eye muscles had higher sIL-2R values than patients with less severely enlarged eye muscles on CT scan. Patients with elevated sIL-2R tended to have a higher response rate (71%) to a 3-month course of prednisone, than those with normal levels (46%; P = 0.081). Since a successful outcome of prednisone treatment might be representative for disease activity, the elevated sIL-2R levels seem to reflect active inflammation. Although the practical relevance of this finding in individual patients is limited, it underscores the importance of cell-mediated immune responses in this thyroid-related eye disease.

Adult↗
PubMed1991

Bone-alkaline phosphatase as indicator of bone formation.

Bone-alkaline phosphatase was determined in patients at risk of osteoporosis due to treatment with oral corticosteroids, and in patients at risk of increased bone synthesis because of treatment with cyclosporin. Both a significant decrease of bone-alkaline phosphatase during corticosteroid treatment, and a significant increase of bone-alkaline phosphatase during cyclosporin treatment could be demonstrated. It is concluded that bone-alkaline phosphatase is a useful parameter for monitoring changes in bone formation.

Adult↗
PubMed1991

Classification of the eye changes of Graves' disease.

Classification of the eye changes of Graves' disease may have clinical use in the description of the present eye state, in the assessment of treatment results, and in the choice of therapy. Requirements for any classification system should include simplicity, clinical nature (i.e., easily carried out by any physician equipped with ordinary noninvasive techniques), reproducibility and meaningfulness (i.e., objective and of clinical relevance to the patient). The NOSPECS system (although it can be improved) is suitable for pure description. It is not very helpful in the assessment of treatment results. Therapeutic outcome probably is best described by measuring quantitatively changes in visual acuity, eye muscle motility, and proptosis. Such an approach, however, does not solve the problem of whether or not the overall outcome is a success in the patient with improvement in one aspect but worsening in another item. A recently developed clinical activity score may be helpful in the selection of therapy, especially for deciding whether or not immunosuppressive therapy should be instituted.

Graves Disease↗
PubMed1991

Bilateral adrenal tumours in primary aldosteronism: localization of a unilateral aldosteronoma by dexamethasone suppression scan.

In a patient with primary aldosteronism, in which the postural endocrine tests suggested the presence of an aldosteronoma rather than hyperplasia, bilateral adrenal tumours were found by computer tomography. Adrenal scintigraphy using 6-131I-iodomethyl-19-norcholesterol (NP59) during dexamethasone suppression showed early unilateral adrenal visualization on the left side. After removal of the left adrenal gland, which contained a 2 x 2 x 2 cm adenoma, the blood pressure and aldosterone levels returned to normal. A CT-scan, performed 1 year after the pre-operative CT-scan, showed no change in size of the right adrenal tumour, consistent with a non-functioning adenoma. In this patient, the NP59 scan adequately distinguished a non-functioning from an aldosterone-producing adrenal tumour.

Adenoma↗
PubMed1991

The course of biochemical parameters of bone turnover during treatment with corticosteroids.

The mechanisms by which glucocorticoids cause osteopenia are incompletely understood. It is generally accepted that bone formation is depressed during corticosteroid treatment, but the cause of the ongoing bone resorption is less clear. Secondary hyperparathyroidism and changes in vitamin D metabolism are thought to play a role. This is based mostly on data from cross-sectional studies in heterogeneous patient groups. We, therefore, studied longitudinally the course of biochemical parameters and the hormones influencing bone turnover in a homogeneous group of 10 euthyroid patients with Graves' ophthalmopathy, all euthyroid for at least 1 yr before, during, and after a 12-week course of prednisone. Bone formation was depressed as reflected by a fall in serum osteocalcin (3.0 +/- 2.1, 1.7 +/- 1.1, and 2.4 +/- 1.9 micrograms/L at weeks 0, 4, and 12, respectively; P = 0.02) and in total alkaline phosphatase (1.15 +/- 0.33, 0.83 +/- 0.22, and 0.88 +/- 0.40 mukat/L; P = 0.001). Parameters of bone resorption (urinary hydroxyproline/creatinine ratio, serum acid phosphatase) and the levels of vitamin D metabolites remained unchanged. Serum intact PTH seemed to decrease slightly. Our findings suggest that glucocorticoid induced osteopenia is caused by a depressed bone formation in the presence of an unaltered but ongoing bone resorption. Secondary hyperparathyroidism and changes in vitamin D metabolism are apparently not involved.

Acid Phosphatase↗