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M F Prummel

Publications and source records attributed to M F Prummel.

At least 55 records · Page 3Linked to original sources
PubMed1998

Establishment of reference values for endocrine tests. I: Cushing's syndrome.

BACKGROUND: For diagnostic tests used in the evaluation of patients with Cushing's syndrome, well defined reference values were lacking in our laboratory. In the present study, we established reference values based upon test results of 50 subjects recruited from the general population. METHODS: We studied 50 subjects not suspected of having Cushing's syndrome, equally distributed according to sex and age between 20 and 69 years. In addition to 24 h urinary excretion of free cortisol for two days, a low-dose (1 mg) overnight dexamethasone suppression test, a corticotropin releasing hormone stimulation test (CRH test) and a high-dose (7 mg) intravenous dexamethasone suppression test were performed. Reference values are given as the observed range. RESULTS: There was considerable intra-subject variation in 24 h urinary cortisol excretion which could not be merely attributed to incompleteness of the urine collection. The following reference values were established: 24 h urinary free cortisol excretion: 15-145 nmol/24 h; overnight dexamethasone suppression test: cortisol on day 2 < 50-230 nmol/l; CRH test: cortisol increase 15-289%, ACTH increase 36-12.100%; high-dose, intravenous dexamethasone suppression test: cortisol after 7 h < 50-97 nmol/l; cortisol after 24 h < 50-50 nmol/l. There were no significant effects of age on any of the parameters studied. Apart from higher basal ACTH plasma concentrations in men, no sex differences were observed. CONCLUSION: We established reference values for tests that can be useful in the evaluation of patients with possible Cushing's syndrome.

Adrenocorticotropic Hormone↗
PubMed1998

Development of a disease specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO-QOL.

AIM: To develop a reliable and valid disease specific quality of life questionnaire (the GO-QOL) for patients with Graves' ophthalmopathy (GO), that can be used to describe the health related quality of life and changes in health related quality of life over time as a consequence of disease and treatment. METHODS: 70 consecutive GO patients (age > 18 years) who were referred for the first time to the combined outpatient clinic of the orbital centre and the department of endocrinology completed the 16 questions of the GO-QOL. Additional information on general quality of life and disease characteristics was obtained. Construct validity and internal consistency of the disease specific questionnaire was determined, based on principal component analysis, Cronbach alphas and correlations with MOS-24, three subscales of the SIP, demographic, and clinical measures. RESULTS: The a priori expected subdivision of the questionnaire in two subscales, one measuring the consequences of double vision and decreased visual acuity on visual functioning, and one measuring the psychosocial consequences of a changed appearance, was confirmed in the principal component analysis. Both scales had a good reliability and high face validity. Correlations with other measures supported construct validity. Mean scores (range 0-100) were 54.7 (SD 22.8) for visual functioning and 60.1 (24.8) for appearance (higher score = better health). CONCLUSION: The GO-QOL is a promising tool to measure disease specific aspects of quality of life in patients with GO and provides additional information to traditional physiological or biological measures of health status.

Activities of Daily Living↗
PubMed1997

Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy.

OBJECTIVE: Approximately 35% of patients with Graves' ophthalmopathy do not respond to immunosuppressive treatment. A possible explanation for this finding is that only patients with active ophthalmopathy respond to immunosuppressive treatment, whereas patients with fibrotic end stage disease do not. To distinguish between these two groups and to predict the outcome of immunosuppressive treatment, we developed a clinical activity score (CAS) based on four of the five classical signs of inflammation and tested its efficacy in a double-blind, prospective study. DESIGN, PATIENTS AND MEASUREMENTS: The CAS was determined by an opthalmologist before, on the day of, and after the start of either oral prednisone or retrobulbar irradiation in 43 patients with moderate to severe Graves' ophthalmopathy. The therapeutic outcome was determined by a second ophthalmologist unaware of the CAS stores given. Success of treatment was defined as an improvement in NOSPECS class or grade. RESULTS: Responders (22) and non-responders (21) did not differ in age, sex, duration or severity of their Graves' ophthalmopathy. The pretreatment CAS, however, was significantly higher in responders than in non-responders. Twelve of 22 responders and three of 21 non-responders had a CAS > or = 4 (55% vs 14%; P < 0.01) [corrected]. Using this CAS cut-off point, the accuracy of CAS in predicting the therapeutic outcome was: specificity 86%, sensitivity 55%, positive predictive value 80%, negative predictive value 64%. Patients with a CAS > or = 4 had a similar duration of Graves' ophthalmopathy as patients with a CAS < 4. CONCLUSIONS: The clinical activity score has a high predictive value for the outcome of immunosuppressive treatment in Graves' ophthalmopathy. Disease activity, and not disease duration, is the prime determinant of therapeutic outcome.

Adult↗
PubMed1997

Quality of life in patients with Graves' ophthalmopathy is markedly decreased: measurement by the medical outcomes study instrument.

To assess the impact of Graves' ophthalmopathy (GO) on quality of life using a general questionnaire, we performed a descriptive study on consecutive ophthalmopathy patients. We included 70 consecutive, euthyroid patients (age >18 years, 50 females, 20 males, mean +/- SD age 53 +/- 13 years) with varying degrees of severity of GO. General quality of life was assessed with the brief survey (24 questions) from the Medical Outcomes Study (MOS-24), and three subscales of the Sickness Impact Profile (SIP). In comparison with a large published reference group, low scores on the MOS-24 were found. Mean +/- SD scores (difference from reference group) were: physical functioning 58 +/- 31 (-28), role functioning 72 +/- 40 (-15), social functioning 78 +/- 25 (-14), mental health 67 +/- 18 (-10), health perceptions 46 +/- 22 (-26), and bodily pain 68 +/- 28 (-6). MOS-24 and SIP scores did not correlate with the duration, severity, or activity of the ophthalmopathy. In conclusion, we have shown that mild to moderately severe GO has a large influence on the quality of life of these patients. The negative impact on well-being seems not to be related to the usual clinical assessment. These results underscore the need for quality-of-life measurements in clinical trials.

Activities of Daily Living↗
PubMed1997

Anti-heat shock protein (hsp)72 antibodies are present in patients with Graves' disease (GD) and in smoking control subjects.

Hsp72 is expressed in thyroidal tissue and on retroocular fibroblasts from patients with GD. In this study we investigated whether GD patients have hsp72 antibodies, and if they correlate with disease characteristics. Because smoking is associated with GD and might up-regulate hsp72 expression, we also studied the effect of smoking on hsp antibody levels. Hsp72 IgG antibodies were determined by dot-blotting, using recombinant human stress-inducible hsp72. Dot-blot densities were measured using a videoimaging system in 38 healthy controls, 45 patients with GD, including 34 with varying degrees of ophthalmopathy, and in 13 GD patients before and after treatment of thyrotoxicosis with methimazole. Hsp72 antibodies were detectable more frequently in GD patients (26/45, 58%), than in controls (12/38, 32%; P < 0.02). GD patients had higher antibody levels than controls; mean +/- s.e.m. optical densities: 26.8 +/- 2.6 versus 18.8 +/- 2.4 (P = 0.018). Levels did not correlate with any parameter of disease severity or activity. Hsp72 antibody levels did not change upon reaching euthyroidism. In controls, but not in patients, hsp72 antibodies could be detected more frequently in smokers (6/10, 60%) versus nonsmokers (6/28, 21%; P = 0.024). Patients with GD have higher hsp72 IgG antibody levels than controls, without correlation with any disease characteristic. Among healthy controls, smoking is associated with elevated hsp72 antibodies. This suggests that these antibodies might be a marker for autoimmune susceptibility.

Adult↗
PubMed1996

The effect of long-term prednisone treatment on growth hormone and insulin-like growth factor-1.

Due to a lack of longitudinal data the precise effect of long-term corticosteroid treatment on serum levels of the anabolic hormones Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1) is unknown. Therefore, we prospectively followed GH and IGF-1 levels over a six month period in 18 euthyroid patients with Graves' ophthalmopathy. Ten patients were treated with a three month course of prednisone; eight patients receiving retrobulbar irradiation served as controls. Baseline serum GH and IGF-1 levels were similar in both groups. Whereas no changes were seen in controls, prednisone induced a rapid increase in serum IGF-1 levels, which was sustained during the entire treatment period: 18.2 +/- 5.2 at baseline vs 24.1 +/- 6.7 nmol/l after 12 weeks of treatment (p < 0.001). After discontinuation of prednisone IGF-1 returned to baseline levels. Basal GH levels were frequently undetectable, but during treatment GH values were lower in the prednisone group (median of detectable values 4.0 mU/L [range 2.0-26.0]) than in controls (11.8 [2.8-44.0]; p < 0.01). In conclusion, long-term prednisone treatment is associated with suppressed GH levels and with an increase in total IGF-1 levels. This suggests that prednisone can disrupt the GH/IGF 1 axis.

Adult↗
PubMed1995

Molecular cloning and characterization of human thyroid peroxidase autoantibodies of lambda light chain type.

IgG class thyroid peroxidase (TPO) autoantibodies with kappa light (L) chains predominate in serum and the genes for a large repertoire of such autoantibodies have been characterized. The present study was performed to clone and characterize TPO autoantibodies with lambda L chains which comprise approximately 20% of serum TPO autoantibodies. From a combinatorial IgG H/lambda L chain cDNA library in the phage display vector pComb3, 24 TPO-binding clones with lambda L chains were isolated, comprising three different heavy (H) and light (L) chain combinations. These combinations utilized two genes from the Vlambda II and IIIb families (closest germline genes DPL11 and hsigg11150) and three genes from the VH1, VH3 and VH4 families (VH26, 4.34 and hv1L1). The deduced amino acid sequences of these H chains were quite different from those of kappa F(ab) isolated using the same H chain library. We expressed the proteins for these three lambda F(ab), as well as for a lambda F(ab) (Humlv318 L chain/DP10-like H chain) previously isolated from another patient. The affinities for TPO of the lambda F(ab) (Kd 8 x 10(-10) M to 10(-7) M) were lower than those of the kappa F(ab) (Kd approximately 10(-10) M). For two lambda F(ab), both H and L chain genes were close to germline configuration, but there was no straightforward relationship between the extent of somatic mutation from germline configuration and affinity for TPO. All four lambda F(ab) bound less well to denatured TPO as to native TPO. The three F(ab) for which sufficient protein could be expressed for competition studies all recognized domain B within the immunodominant region on TPO previously identified using F(ab) with kappa L chains. Aside from these TPO-specific F(ab), only a few other human IgG class, organ-specific autoantibodies with lambda L chains have been characterized at the molecular level. Our study significantly augments the small database on this category of autoantibodies in general.

Amino Acid Sequence↗
PubMed1995

Medical management of Graves' ophthalmopathy.

In most patients with Graves' hyperthyroidism the eye signs are self-limiting and mostly subclinical. However, about one-third of the patients have clinically relevant ophthalmopathy, which can be disabling and disfiguring. The mechanical causes of the symptoms and signs of the eye disease are largely understood, but the best way to manage the ophthalmopathy is still a matter of much debate. Adequate treatment of hyperthyroidism can aleviate the eye symptoms to some extent, but it is less clear which kind of antithyroid treatment is to be preferred in patients with ophthalmopathy. There is particular controversy about the possibly deleterious effect of radioiodine therapy on the ophthalmopathy; in view of the present evidence it seems prudent to refrain from using 131I and to prefer antithyroid drugs in patients with clinical ophthalmopathy. Further medical management can include immunosuppressive treatment (such as corticosteroids) that results in improvement in roughly two-thirds of the patients. Orbital irradiation appears to be the first choice for treatment in moderately severe ophthalmopathy because it is equally effective and much better tolerated than classical corticosteroid treatment. However, to really improve the efficacy of such interventions we should be able to select those patients that are likely to respond to immunomodulatory therapy. Disease activity is probably the prime determinant of response and it is a challenge for the future to develop reliable parameters of disease activity on the basis of which patients can be selected for further medical treatment, or can be subjected to rehabilitative surgery without prior immunosuppression.

Eye Diseases↗
PubMed1994

Immunoglobulin A in Graves' orbital tissue: deoxyribonucleic acid amplification by polymerase chain reaction.

A role for IgA autoantibodies in Graves' ophthalmopathy is suggested by the presence of immunoglobulins of this class in Graves' orbital tissue, as detected by immunohistochemistry. We, therefore, investigated the possibility of using the polymerase chain reaction (PCR) to amplify IgA immunoglobulin genes from plasma cells infiltrating Graves' eye tissue. Template cDNA was reverse-transcribed from orbital muscle (M) mRNA of one patient (#7) and from orbital connective tissue/fat (F) mRNA of two patients (#1 and #7), both undergoing surgery for exophthalmos because of severe infiltrative ophthalmopathy. Preliminary studies to establish the PCR procedure were performed for kappa light chain DNA amplification. With the very small amount of orbital tissue template available, the sensitive "hot start" modification of the PCR was necessary to amplify significant amounts of kappa light chain DNA. Using this procedure, IgA heavy chain DNA was amplified from both connective tissue/fat (F7) and muscle (M7) cDNA of patient #7. The DNA yield was less for IgA than for IgG using the same template. There was no significant IgA (or IgG) DNA product using the connective tissue/fat cDNA of patient #1. While not implying that IgA-infiltrating plasma cells are specific for Graves' orbital tissue, our studies nevertheless demonstrate the feasibility of amplifying the genes coding for IgA antibodies from Graves' orbital tissue plasma cells. Expression of these immunoglobulin genes in future studies will make it possible to determine the antigen specificity of the antibodies expressed by Graves' orbital tissue plasma cells.

Aged↗
PubMed1994

Profile of lambda light chain variable region genes in Graves' orbital tissue.

Graves' ophthalmopathy, a human autoimmune disease of unknown etiology, is strongly associated with autoimmune hyperthyroidism. A major controversy is whether retro-ocular muscle or orbital fat/connective tissue is the target of the immune response. Previously, we observed preferential PCR amplification of lambda (relative to kappa) light chain DNA from cDNA of Graves' orbital tissue-infiltrating B cells/plasma cells. There is little information on V lambda gene usage in man and none in diseased tissue. To characterize the orbital lambda light chains, we constructed cDNA libraries using PCR-amplified DNA from three tissues and sequenced the variable region genes from randomly selected clones. Analysis of 27 clones from orbital fat/connective tissue libraries from two patients with acute inflammatory eye disease, and 15 clones from orbital muscle of one of these patients, revealed a diverse spectrum of lambda V region genes. The nucleotide sequences of these 42 clones were most homologous to 12 different germline genes: four family I (subfamilies I-a, -b and -c), three family II, two family III and one family VII germline genes. Each orbital tissue had a distinct profile of V lambda sequences. However, all clones used J lambda 2/3 and all three orbital tissues contained clones related to family II genes. Although some clones had V region sequences in near germline conformation, the majority differed from the closest germline gene in both framework and complementarity determining regions. Whether or not these differences result from multiple germline gene usage or somatic mutation of a smaller number of germline genes cannot be determined until information on the V lambda repertoire and its polymorphisms is complete. However, the V lambda gene diversity we observed in both orbital muscle and orbital fat/connective tissue suggests a role for lambda autoantibodies in the pathogenesis of Graves' ophthalmopathy.

Adipose Tissue↗
PubMed1994

Isolation and characterization of a monoclonal human thyroid peroxidase autoantibody of lambda light chain type.

Thyroid peroxidase (TPO) autoantibodies, a hallmark of human autoimmune thyroid disease, may have kappa or lambda light chains. Monoclonal human TPO autoantibodies with kappa light chains have previously been developed by cloning and expressing "combinatorial" libraries of immunoglobulin genes in bacteria. In the present study, an IgG1/lambda combinatorial library was generated from thyroid cDNA of a Graves' patient whose serum contained lambda TPO antibodies. Screening the bacteriophage library with 125I-TPO yielded one clone, TR1.41. The oligonucleotide sequence of TR1.41 was determined and the nature of its interaction with TPO was investigated. The affinity of TR1.41 for TPO is high (Kd approximately 10(-9) M), comparable to that of monoclonal kappa TPO autoantibodies derived from the same patient. The genes encoding the heavy and light chains of TR1.41 differ in a number of respects from the closest available germline genes. Such differences are consistent with somatic mutation in a high-affinity antibody. An important characteristic of TR1.41 is its interaction with the immunodominant domain on TPO recognized by approximately 80% of serum TPO autoantibodies. The frequency of TPO-specific F(ab) generated from the thyroid gland of patient TR was much lower for F(ab) with lambda light chains (1:150,000) than for F(ab) with kappa light chains (1:13,000). Despite this low frequency, the high affinity of TR1.41 and its recognition of the immunodominant region on TPO indicate that lambda autoantibodies of this type may represent an important constituent of the TPO autoantibody response in man. In conclusion, this is the first report on the molecular cloning and characterization of a thyroid autoantibody of lambda L chain type by the combinatorial library approach.

Amino Acid Sequence↗
PubMed1994

Measuring eye movements in Graves ophthalmopathy.

BACKGROUND: The current grading of class IV (extraocular muscle involvement) of the NO SPECS classification for Graves ophthalmopathy is subjective and, in practice, virtually limited to three grades (grade c rarely occurs). The subjectiveness results in a high degree of observer disagreement, as illustrated by kappa values of 0.48 to 0.64 for the agreement between the authors in grading of class IV changes in 13 patients. METHODS: The authors investigated the significance of a quantitative approach in assessing eye motility and modified a hand perimeter to measure the monocular eye movements in degrees. RESULTS: The mean maximal excursions in the four main directions of gaze, obtained with this device in 40 healthy control subjects (5 men and 5 women from each decade between 20 and 60 years of age), were as follows: elevation = 34 degrees, depression = 58 degrees, adduction = 48 degrees, and abduction = 46 degrees. The ductions showed an age-related decline. The intraobserver and interobserver variations were assessed in 12 and 18 patients with Graves ophthalmopathy, respectively, by calculating the coefficients of repeatability, which varied from 5 degrees to 8 degrees. The authors compared the current grading of NO SPECS class IV with quantitative measurements of elevation in 11 patients by calculating the kappa values for agreement. These were found to be 0.57 and 0.80, respectively. CONCLUSIONS: The quantitative measurement of eye movements with a modified perimeter appears to be precise and reproducible. In addition, it should replace the current grading of the extraocular muscle movements of Graves ophthalmopathy patients in the NO SPECS classification, which is less reliable, as evidenced by a higher degree of observer disagreement.

Adult↗