Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors that cause TIO and is, at least partly, responsible for the manifestations of TIO. OBJECTIVE: The objective of this study was to determine the sensitivity of FGF23 measurements in TIO. DESIGN: FGF23 concentrations were measured on stored samples with three ELISAs. SETTING: This study was conducted at subspecialty referral centers. PATIENTS: Twenty-two patients with suspected TIO, 13 with confirmed tumors, were studied. INTERVENTIONS: There were no interventions in this study. MAIN OUTCOME MEASURE: FGF23 concentration was the main outcome measure of this study. RESULTS: Elevated FGF23 concentrations were detected using the Immunotopics C-terminal assay in 16 of 22 TIO patients (for a sensitivity of 73%), the Immunotopics Intact assay in five of 22 patients (sensitivity, 23%), and the Kainos Intact assay in 19 of 22 patients (sensitivity, 86%). In the 13 patients with confirmed tumors, the sensitivity was higher with all assays: 92% for the Immunotopics C-terminal assay, 38% for the Immunotopics Intact assay, and 100% for the Kainos assay. CONCLUSION: The Kainos Intact assay was the most sensitive, followed by the Immunotopics C-terminal assay. The findings of normal FGF23 concentrations in some patients with TIO may indicate that FGF 23 is not responsible for the hypophosphatemia in these patients or that FGF23 secretion by some tumors is partially responsive to serum phosphate. Normal FGF23 concentrations should be interpreted in relation to the serum phosphate and 1,25-dihydryxyvitamin-D concentrations.

Thyroid function and prevalence of anti-thyroperoxidase antibodies in a population with borderline sufficient iodine intake: influences of age and sex.

BACKGROUND: We present a large European population-based study of thyroid function, performed in a population with longstanding borderline sufficient iodine intake. METHODS: The Nijmegen Biomedical Study is a population-based survey conducted in the eastern part of The Netherlands. Randomly selected inhabitants received a postal questionnaire on lifestyle and medical history, which was filled out by 9371 individuals (41.7%). We measured serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and anti-thyroperoxidase antibodies (TPOAbs) in 6434 responders. A reference population of 5167 individuals was selected by excluding those at risk for thyroid disease. RESULTS: Overt thyrotoxicosis was found in 0.4% of the total population and subclinical thyrotoxicosis in 0.8%. Overt hypothyroidism was found in 0.4% and subclinical hypothyroidism in 4.0%. In individuals older than 60 years, mean FT4 concentrations increased with age. Mean TSH decreased with age, from 1.46 mIU/L at 18-24 years to 1.07 mIU/L after 85 years. The mean TSH in the total population did not differ from the mean TSH in the reference population; the exclusion of those at risk for thyroid disease, however, lowered the upper limit of the TSH reference interval considerably. In the total population, 8.6% of males and 18.5% of females had positive TPOAbs. The presence of TPOAbs was associated with abnormally high and low TSH concentrations. CONCLUSION: In inhabitants of the eastern part of The Netherlands, serum TSH gradually decreases with age, whereas after age 60, serum FT4 increases, possibly because of the development of thyroid autonomy after longstanding borderline sufficient iodine intake.

Sequential balancing: a simple method for treatment allocation in clinical trials.

Although minimisation methods have frequently been advocated for treatment allocation in clinical trials, they are not widely used. As this may partly be due to the complexity of the methods, we devised a new and simple minimisation method to balance for prognostic factors, called sequential balancing. Each factor is dealt with sequentially and when a new subject enters the trial, he or she is allocated the treatment that leads to improved balance of the first factor over the treatments. If the balance of the first factor was already satisfactory, then the treatment is allocated that leads to improved balance of the second factor and so on. The algorithm requires no calculations. We simulated a realistic trial and compared the performance of this method to the performance of alternative allocation strategies: the variance minimisation method, simple randomisation and stratification. The sequential balancing method led to better balance than randomisation and stratification. In the case of four factors or less, the performance of the sequential balancing method and the variance minimisation method were comparable and the sequence of the factors was not very relevant. When more factors were introduced, the balance of the sequential method remained comparable with the balance achieved with the variance minimisation method for the first four factors, but it started to decrease from the fifth factor onwards. We conclude that the ease and simplicity of the new method make it an attractive option when balance is required for four factors or less. If there are more than four factors, the sequential balancing method may still be an acceptable option, but the advantage of simplicity has to be weighed against the loss of performance compared to other minimisation methods.

Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon- gamma therapy.

BACKGROUND: Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense. METHODS: We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity. RESULTS: Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- gamma and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- gamma . Administration of recombinant IFN- gamma resulted in both restoration of immunological parameters and a sustained clinical recovery. CONCLUSIONS: Refractory meningitis may be due to defective TNF and IFN- gamma production, and IFN- gamma treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis.