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Biomedical subjects

Klaus Mann

Publications and source records attributed to Klaus Mann.

At least 55 records · Page 3Linked to original sources
PubMed2004

Influence of age on the interrelation between EEG frequency bands during NREM and REM sleep.

The age-dependence of temporal interrelations between distinct frequency bands of sleep EEG was investigated in a group of 59 healthy young and middle-aged males via cross correlation analysis. Based on global evaluation throughout the entire night, a highly significant decline of the delta/theta correlation with increasing age was found. A separate analysis for non-rapid eye movement (NREM) and rapid eye movement (REM) sleep revealed different changes with aging. During NREM sleep, the correlation between the delta and theta frequency bands decreased with increasing age. In contrast, during REM sleep, a stronger correlation became obvious between the theta, alpha, and beta frequency bands with increasing age, whereas the lower frequency components were not affected. These findings indicate that aging processes seem to interact with sleep EEG rhythms in a complex manner, where most conspicuous is a disintegration of the activities in the lower frequency range, both concerning the successive sleep cycles across the night and the micro-structure of NREM sleep.

Adolescent↗
PubMed2004

Heart rate variability during sleep in patients with schizophrenia treated with olanzapine.

Cardiac adverse events in patients treated with atypical antipsychotics have gained increasing interest in recent years. In the present study, heart rate variability (HRV), which is a sensitive parameter reflecting central autonomic cardiac control, was investigated during treatment with olanzapine. Ten physically healthy male patients with schizophrenia, who displayed predominantly negative symptoms, were studied in the sleep laboratory under drug-free baseline conditions and after 4 weeks of olanzapine medication. HRV was assessed during different sleep stages both in the time and frequency domains. Only slight changes in HRV were shown during treatment, and appeared to be independent of sleep stages. Spectral analysis indicated a slight shift of the sympathovagal balance in favour of the sympathetic tone, which was consistent with an elevation of heart rate in the time domain; total HRV was not altered. These changes are in accordance with olanzapine's receptor profile exerting anticholinergic and anti-adrenergic properties. In conclusion, taken together with findings from previous studies demonstrating that olanzapine does not cause clinically significant changes of the QTc interval, the present results are consistent with the known cardiac safety profile of olanzapine.

Adolescent↗
PubMed2004

Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies.

OBJECTIVE: Graves' ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH-receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti-inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO. DESIGN PATIENTS AND MEASUREMENTS: Clinical activity score (CAS) and the severity of GO (modified NOSPECS score) were assessed in 108 patients with GO after steroid therapy and, if indicated, orbital irradiation. Patients were grouped according to their clinical presentation and autoantibody levels (TBII, TSAb, TPOAb and TGAb) were measured. After therapy for hyperthyroidism, all patients were clinically euthyroid but showed clear heterogeneity for GO 4-12 months after the end of anti-inflammatory therapy. Fifty-two patients had inactive GO, 41 had moderately active and 15 still had very active (non-responsive) GO. Concerning severity, 27 patients had mild GO, 64 moderately severe and 17 severe GO. RESULTS: TBII titres were still positive in 14 (93%) of 15 patients in the non-responsive group (CAS > 6) compared to 22 (42%) of 52 patients (P < 0.001) with post-therapeutic inactive GO (CAS </= 2). A similar result was seen between TBII levels and the NOSPECS score. The simultaneous presence of TBII and TSAb was associated with significantly higher activity and severity [odds ratios: 4.9 (activity); 9.0 (severity)] than the presence of TBII without measurable TSAb [odds ratios: 2.1 (activity), 2.0 (severity)] in comparison to absence of both antibodies. Only TBII and TSAb, but not TPOAb or TGAb medians, increased statistically significantly with CAS or NOSPECS scores. Both scores were positively associated with TBII (CAS: r = 0.31 P < 0.001; NOSPECS: r = 0.38, P < 0.0001) and, to a lesser degree, with TSAb (CAS: r = 0.27, P < 0.007, and NOSPECS: r = 0.29, P < 0.003). This association was independent of the treatment of hyperthyroidism, although highest levels of TBII were seen after radioiodine treatment. The NOSPECS score was negatively associated with TGAb (r =-0.27, P < 0.01) but not with TPOAb, while both showed no association with the CAS score. CONCLUSIONS: We conclude that the persistence of TBII and TSAb levels in patients with therapy-resistant disease in comparison to patients with inactive disease supports the role of TRAb in the pathogenesis of GO. Furthermore, the fact that, even after anti-inflammatory therapy, TBII and TSAb levels and prevalence still correlate with the severity and activity of GO suggests not only a trigger but also a possible role in the maintenance of the autoimmune process in the orbits.

Anti-Inflammatory Agents↗
PubMed2004

Comparison of active renin concentration and plasma renin activity for the diagnosis of primary hyperaldosteronism in patients with an adrenal mass.

OBJECTIVE: Plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio is an established screening test for primary hyperaldosteronism. Due to the increased recognition of adrenal incidentalomas, reliable parameters are required. Determination of active renin concentration (ARC) in contrast to PRA offers advantages with regard to processing and standardization. The present study compared PRA and ARC under random conditions to establish thresholds for the diagnosis of primary hyperaldosteronism. DESIGN AND METHODS: Fifty patients with various adrenal tumors, including ten patients with aldosterone-secreting adrenal adenomas, as well as ten hypertensive patients and 23 normotensive volunteers were studied. PAC and PRA were measured by radioimmunoassay. ARC was determined by an immunoluminometric assay. RESULTS: Receiver operating curve (ROC) analysis suggested a PAC to ARC ratio threshold of 90 ((ng/l)/(ng/l)) (sensitivity 100%, specificity 98.6%) and a ratio threshold of 62 by additional consideration of PAC > or =200 ng/l (sensitivity 100%, specificity 100%) for the diagnosis of aldosterone-secreting adrenal adenomas. CONCLUSIONS: A PAC to ARC ratio of > or =62 in patients with PAC levels > or =200 ng/l is a reliable screening method for primary hyperaldosteronism in patients with an aldosterone-producing adenoma under random conditions. Because of its advantages with regard to probe processing and its independence from endogenous angiotensinogen levels, ARC may be preferred to PRA.

Adenoma↗
PubMed2003

Interleukin-2 given to asymptomatic HIV-infected individuals leads to an exaggerated response of the pituitary gland to the action of CRH.

BACKGROUND AND AIMS: Studies investigating the impact of interleukin-2 (IL-2) on the corticotroph axis have shown that IL-2 can stimulate cortisol and ACTH secretion. However, the site, the time course and the mechanisms of IL-2 stimulation of the corticotroph axis are still not known. The aim of this study was to gain insight into the mechanisms of IL-2 stimulation of the corticotroph axis. PATIENTS AND METHODS: A total of 9 x 10(6) IU/day IL-2 were given to 18 male HIV-infected patients treated with a combination of HIV antiviral drugs (usually two reverse-transcriptase inhibitors and one protease-inhibitor) over a course of 4-5 days. Seven of these 18 patients received a second course of IL-2. RESULTS: Cortisol levels increased significantly (P < 0.001) from baseline levels (427 +/- 118 nmol/l) to 746 +/- 132 nmol/l after 4 days of IL-2 therapy with a gradual decrease to baseline within 10 days after the end of therapy. ACTH showed a similar pattern rising from 5.9 +/- 1.9 pmol/l at baseline to 12.4 +/- 4.6 pmol/l on day 4 (P < 0.001). The cortisol response after CRH application (carried out at 15.00 h) was significantly more pronounced at the end of IL-2 application (CRH test B, baseline: 330 +/- 59 nmol/l, peak 774 +/- 134 nmol/l, 135% increase) when compared to pretreatment (CRH test A, baseline: 226 +/- 73 nmol/l, peak 459 +/- 103 nmol/l, 103% increase, P </= 0.0001). The cortisol response 9 days after the end of IL-2 administration showed a similar pattern when compared to pretreatment values. The ACTH response after CRH was essentially paralleled by the cortisol response (CRH test B, baseline: 6.1 +/- 2.8 pmol/l, peak 16.0 +/- 4.4 pmol/l, 170% increase; CRH test A, baseline: 4.3 +/- 1.9 pmol/l, peak 9.2 +/- 3.1 pmol/l, 110% increase, P = 0.0005). Furthermore, we observed higher ACTH and cortisol concentrations in the morning when compared to late afternoon values during treatment with IL-2 [cortisol: baseline: 426 +/- 73 nmol/l (8.00 h); 226 +/- 73 nmol/l (15.00 h)]; day 4: [746 +/- 132 nmol/l (8.00 h); 339 +/- 59 nmol/l (15.00 h)]; ACTH: baseline: [5.9 +/- 1.9 pmol/l (8.00 h); 4.3 +/- 1.9 pmol/l (15.00 h)]; day 4: [12.4 +/- 4.7 pmol/l (8.00 h); 6.1 +/- 2.8 pmol/l (15.00 h)]. CONCLUSION: The data from this in vivo study suggest that IL-2 most likely resulted in corticotroph hyperplasia leading to an exaggerated response of the pituitary gland to the action of CRH.

Adrenocorticotropic Hormone↗
PubMed2003

Temporal relationship between nocturnal erections and rapid eye movement episodes in healthy men.

The exact temporal relationship between spontaneous nocturnal erections and rapid eye movement (REM) sleep was studied in healthy men with the aim of creating a basis for a more sophisticated analysis of nocturnal erection measurements in physiological research and clinical applications. The vast majority of erectile events was coupled to REM episodes, where the latency between the beginning of erections and REM episodes showed a large variability. Moreover, a correlation analysis revealed a highly significant decrease of the latency over the course of the night. The time variant properties of the coupling between erections and REM sleep point to more complex dynamics of the central control of erections with regard to sleep regulation, indicating that REM sleep and REM-related erections are not completely interdependent. Beside the possibility of obtaining further insight into the physiological mechanisms underlying erectile function, the consideration of dynamic aspects in the assessment of nocturnal erection measurements might have potential clinical implications regarding both the diagnosis and the evaluation of therapies for erectile dysfunction.

Adult↗
PubMed2003

Quality of life, psychosocial well-being, and sexual satisfaction in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic anovulation and hyperandrogenism. PCOS is one of the leading causes of infertility and manifests with hirsutism, acne, and obesity. To investigate its impact on health-related quality of life and sexuality, 50 women with PCOS and 50 controls were evaluated with standardized questionnaires (36-item short-form health survey, symptom checklist revised, and life satisfaction questionnaire). The impact of hirsutism, obesity, and infertility was assessed using five-point rating scales, and sexual satisfaction was analyzed with visual analog scales. Patients showed greater psychological disturbances on the symptom checklist revised dimensions, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, aggression, and psychoticism, along with a lower degree of life satisfaction in the life satisfaction questionnaire scales health, self, and sex. Health-related quality of life measured with the 36-item short-form health survey revealed significantly decreased scores for physical role function, bodily pain, vitality, social function, emotional role function, and mental health in patients with PCOS. Although patients had the same partner status and frequency of sexual intercourse, they were significantly less satisfied with their sex life and found themselves less attractive. Most of the differences were not affected by correction for body weight. In conclusion, PCOS causes a major reduction in the quality of life and severely limits sexual satisfaction.

Adult↗
PubMed2003

Autoantibodies to thyroperoxidase (TPOAb) in a large population of euthyroid subjects: implications for the definition of TPOAb reference intervals.

OBJECTIVE: Measurement of autoantibodies against thyroperoxidase (TPOAb) plays an important role in the diagnosis of autoimmune thyroid disease. The assessment of reference intervals for TPOAb, however, is a controversial issue since elevated TPOAb values are sometimes found in subjects without other evidence of thyroid disease. METHODS: TPOAb were measured in 1,295 euthyroid individuals using a highly sensitive, fully automated chemiluminescence assay (Advantage A-TPO, Nichols Institute Diagnostics, CA, USA). The study subjects participated in a population study on the prevalence of thyroid disorders in the German federal state of Saxony, an area of mild iodine deficiency. RESULTS: TPOAb above the detection limit of 0.45 IU/ml were found in 1,277/1,295 euthyroid individuals. TPOAb values in the low measurable range below 1.1 IU/ml followed a normal distribution, and this was independent of age and sex. When using a cut-off value of 1.1 IU/ml, which corresponds to a sensitivity of 79% and a specificity of 95% resulting from the receiver-operator characteristic plot for discrimination between a main type and other types with a higher mean value of TPOAb, elevated TPOAb were found in 14.4% of euthyroid men and in 25.8% of euthyroid women. CONCLUSIONS: The results demonstrate for the first time that TPOAb are detectable in nearly all euthyroid individuals and that TPOAb values in the low measurable range are normally distributed. The distribution of TPOAb values in the low range is independent of age and sex. Based on these data, reference intervals for TPOAb can be defined that are independent of the population investigated. The clinical significance of slightly elevated TPOAb, however, has still to be defined by prospective studies.

Adult↗
PubMed2002

Endoscopic treatment of solitary, bilateral, multiple, and recurrent pheochromocytomas and paragangliomas.

Because of extensive intraoperative catecholamine release, extreme vascularization, and demanding localization, laparoscopic and retroperitoneoscopic excision of pheochromocytomas and retroperitoneal paragangliomas is challenging. In a prospective clinical study, 61 chromaffin neoplasms (52 pheochromocytomas, 9 paragangliomas) were removed endoscopically from 52 patients (30 males, 22 females; age 44.4 +/- 16.3 years) at 55 operations. Six patients showed multiple (two to five) tumors. Tumor size ranged from 1 to 7 cm (mean 3.6 +/- 1.4 cm). Twelve patients suffered from hereditary diseases. Seven patients had bilateral adrenal diseases; in three patients pheochromocytomas were removed on both sides synchronously. Four neoplasias were local recurrences (three pheochromocytomas, one paraganglioma). The laparoscopic route was chosen for six operations, and the retroperitoneoscopic technique was performed in 49 procedures. Partial adrenalectomy was performed in 19 operations (in all patients with bilateral diseases). High-dosage a-blockage with phenoxybenzamine was routinely used. There were no conversions to open surgery. Perioperative complications were minor (23%), and mortality was zero. The operating time for unilateral pheochromocytomas was 116 +/- 52 minutes (range 35-285 minutes) and depended on tumor size (<3 cm vs. > or = 3 cm; p <0.01), gender (p <0.01), and extent of resection (partial vs. complete; p <0.05). The operating time for bilateral pheochromocytomas ranged from 285 to 385 minutes, and it was 75 to 600 minutes for paragangliomas. Blood loss was 100 +/- 171 ml. Consumption of analgesics was low (mean 7 mg piritramide postoperatively). The median duration of postoperative hospitalization was 4 days. In six of seven patients with bilateral disease complete preservation of cortical function was achieved. Locoregional metastatic recurrence was found in one patient 3 years after retroperitoneoscopic adrenalectomy. Endoscopic removal of solitary, bilateral, multiple, and recurrent pheochromocytomas and retroperitoneal paragangliomas is feasible and safe but requires extensive experience in minimally invasive and endocrine surgery.

Adolescent↗
PubMed2002

Determination of beam parameters and coherence properties of laser radiation by use of an extended Hartmann-Shack wave-front sensor.

A combination of a Hartmann-Shack sensor and a standard far-field measurement on one single detector is proposed. The technique is fast and operates without movable parts, thus permitting a compact design. It is not only suited for characterization of the wave-front distribution but may also be considered for determination of the important parameters of beam width, beam divergence, and beam propagation ratio M2 of partially coherent laser beams. First results indicate that a fairly thorough beam characterization, including spatial coherence, propagation characteristics, and beam quality, can be achieved with this method.

Journal Article↗
PubMed2002

Characterization and primary structures of bovine and porcine thyroxine-binding globulin.

Thyroxine-binding globulin (TBG) is the major serum transport protein for iodothyronines in most of the large, omni- or herbivorous mammals. Characterization of human TBG (hTBG), including its 20 known natural variants, allowed the identification of the ligand-binding site and a correlation of diminished synthesis or loss of function with mutations in the TBG gene. Further refinement of the structure-function correlation, especially the high binding affinity and heat stability, requires characterization of other mammalian TBGs, of which only rat and sheep TBG were available. We now present some of the chemical and physical properties of bovine TBG (bTBG) and porcine TBG (pTBG) and their primary structures deduced from their cDNA sequences. The serum concentrations of bTBG and pTBG estimated by Scatchard analysis of T(4)-binding were similar to hTBG. The T(4)-binding affinity of human, bovine and porcine TBGs were all similar, at 1.2x10(10) M(-1). However, heat stability of the animal TBGs was reduced, with a half life of denaturation of 7 min (bTBG) and 5 min (pTBG) at 55 degreeC, compared with 21 min for hTBG. Nucleotide alignment revealed identity with hTBG of 85.5% (bTBG) and 83.7% (pTBG) and amino acid identity of 82.8% (bTBG) and 82.6% (pTBG). As expected, the relevant parts of the ligand-binding domain (amino acids 215-291, and 363-395) were highly conserved at more than 95% similarity. Comparison of the five known mammalian TBGs allows focusing of future mutagenesis experiments to further characterize the properties of the molecule.

Amino Acid Sequence↗
PubMed2002

The sleep EEG's microstructure in depression: alterations of the phase relations between EEG rhythms during REM and NREM sleep.

OBJECTIVE: We investigated the microstructure of sleep electroencephalograms (EEGs) of 13 unmedicated depressive inpatients and 13 healthy controls matched in sex and age, hypothesizing that depressives depict an alteration of certain EEG oscillations across the night. METHODS: We digitized the sleep EEGs with a sampling rate of 100 Hz (bipolar derivation C(z)-P(z), 1440 single sweeps; 2048 data points each), calculated the time course of delta (1-3.5 Hz), theta (3.5-7.5 Hz), alpha (7.5-15 Hz), and beta (15-35 Hz) activity over the night, and determined the correlation coefficients of these different EEG rhythms separately for rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. RESULTS: For both groups we detected a clear difference between REM and NREM sleep cycles at certain frequency bands. The most impressive changes occurred for the delta/beta and theta/beta correlations, which change their signs between NREM (negatively correlated) and REM (positively correlated) sleep cycles. Following an analysis of variance model with repeated measurement design, a statistically significant group effect (P=0.024) between depressives and controls was observable during NREM sleep for the delta/beta (P=0.010) and theta/beta (P=0.018) interactions. CONCLUSION: We detected alterations of certain sleep EEG oscillations during the NREM sleep cycle, where the delta/beta as well as the theta/beta activities were higher (negatively) compared to healthy controls. Together with previous investigations on the influence of antidepressants on the microstructure of sleep EEGs, this is another hint that the NREM sleep cycle plays a major role in depression.

Journal Article↗
PubMed2002

Impact of disease activity on left ventricular performance in patients with acromegaly.

BACKGROUND: In patients with acromegaly, abnormalities of systolic and diastolic left ventricular (LV) performance, mostly associated with hypertension or LV hypertrophy, have been reported. We used 2-dimensional/Doppler echocardiographic methods and tissue Doppler imaging (TDI) to elucidate the impact of disease activity on LV function in patients with acromegaly. METHODS: In a prospective study design, 15 patients with active acromegaly (AA group; mean age-adjusted serum insuline-like growth factor-I [IGF-I] level, 420 +/- 170 ng/mL, mean growth hormone nadir during 75-g oral glucose load, 12.3 +/- 30.1 microg/L), 18 patients with cured (n = 14, mean IGF-I level 205 +/- 115 ng/mL, mean growth hormone nadir during glucose load 0.72 +/- 0.34 microg/L) or well-controlled (n = 4, normal age-adjusted ranges of IGF-I levels with medication with somatostatin analogues 354 +/- 88 ng/mL) acromegaly (CA group), and 24 control subjects (control group) underwent 2-dimensional/Doppler echocardiographic measurements, including assessment of the Tei index (isovolumic contraction time and isovolumic relaxation time divided by ejection time). Systolic and diastolic mitral annular velocities (peak systolic velocity, peak early diastolic velocity [E'], peak late diastolic velocity [A'], E'/A' ratio) were derived from pulsed TDI. RESULTS: No significant differences between study groups were observed with respect to muscle mass and systolic parameters, such as ejection fraction, fractional shortening, and peak systolic velocity. In patients with AA, E' and the E'/A' ratio were lower than in control and CA subjects (AA 6.8 +/- 1.7 cm/s, control 10.0 +/- 1.7 cm/s, CA 9.1+/- 3.0 cm/s, P <.01 AA vs control, P <.05 AA versus CA, AA 0.68 +/- 0.22, control 0.98 +/- 0.16, CA 0.89 +/- 0.37, P <.01 AA vs control and CA, respectively). In comparison with control subjects and patients with CA, patients with AA had a reduced mitral peak velocity of early/late filling ratio (AA 0.78 +/- 0.22 m/s, control 1.12 +/- 0.33 m/s, CA 1.11 +/- 0.36 m/s, P <.05 AA vs control and CA) and a prolonged deceleration time (AA 223 +/- 41 ms, control 188 +/- 26 ms, CA 185 +/- 25 ms, P <.05 AA vs control and CA). The Tei index was significantly elevated in patients with AA in comparison with control subjects and patients with CA (AA 0.54 +/- 0.13, control 0.40 +/- 0.09, CA 0.44 +/- 0.10, P <.05 AA vs control and CA). No significant differences were observed between control subjects and patients with CA with respect to mitral flow-derived variables, TDI parameters, and the Tei index. CONCLUSION: Disease activity has a significant impact on LV performance in patients with acromegaly. In subjects with active disease, diastolic dysfunction and beginning impairment of overall LV performance are present. In patients with cured/well-controlled disease, systolic and diastolic function appear normal.

Acromegaly↗
PubMed2002

Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL Study. Risk Factors, Evaluation of Coronary Calcium and Lifestyle.

BACKGROUND: In view of consistently high cardiovascular morbidity and mortality rates, international efforts are aimed at developing tools for more precise risk prediction to allow preventive treatment targeted at high-risk individuals. Direct visualization of anatomic, preclinical atherosclerotic disease has the potential for individualized risk discrimination. Further, a variety of risk factors are actively evaluated, including markers of the activity of atherosclerotic disease, thrombogenic risk, and genetic polymorphisms. METHODS: The Heinz Nixdorf RECALL (Risk Factors, Evaluation of Coronary Calcium and Lifestyle) study is a population-based, prospective cohort study of the comparative value of modern risk stratification techniques for "hard" cardiac events. It is designed and powered to define the relative risk associated with the specific extent of coronary atherosclerosis measured by means of electron-beam computed tomography (EBCT)-derived coronary calcium quantities for myocardial infarction and cardiac death in 5 years in 4200 males and females aged 45 to 75 years in an unselected urban population from the large, heavily industrialized Ruhr area. Additionally, the predictive values of conventional cardiovascular risk factors, new candidate and socioeconomic risk factors, certain genetic polymorphisms, and direct signs of subclinical disease are examined with the ankle-brachial index, resting and stress electrocardiograms, and determination of carotid artery intima-media thickness. Prospective clinical risk-benefit and health economic analyses are an inherent part of the study. Study findings with established clinical significance are reported to the participants, but the EBCT findings are withheld until the conclusion of the study. CONCLUSIONS: The Heinz Nixdorf RECALL study will define appropriate methods for identifying high-risk subgroups in the general urban population who may derive the greatest benefit from preventive treatment.

Aged↗
PubMed2002

Relapse of Graves' disease after successful outcome of antithyroid drug therapy: results of a prospective randomized study on the use of levothyroxine.

Antithyroid drugs are effective in restoring euthyroidism in Graves' disease, but many patients experience relapse after withdrawal. Prevention of recurrence would therefore be a desirable goal. In a prospective study, patients with successful outcome of 12 to 15 months antithyroid drug therapy were stratified for risk factors and randomly assigned to receive levothyroxine in a variable thyrotropin (TSH)-suppressive dose for 2 years or no treatment. The levothyroxine group was randomized to continue or discontinue levothyroxine after 1 year. End points included relapse of overt hyperthyroidism. Of 346 patients with Graves' disease enrolled 225 were euthyroid 4 weeks after antithyroid drug withdrawal and were randomly assigned to receive levothyroxine (114 patients) or no treatment (controls, 111 patients). Of those not randomized, 39 patients showed early relapse within 4 weeks, 61 endogenous TSH suppression, 7 TSH elevation, and 14 had to be excluded. Dropout rate during the study were 13.3%. Kaplan-Meier analyses showed relapse rates to be similar in the levothyroxine group (20% after 1 year, 32% after 2 years) and the randomized controls (18%, 24%), whereas relapses were significantly more frequent in the follow-up group of patients with endogenously suppressed TSH (33%, 49%). Levothyroxine therapy did not influence TSH-receptor antibody, nor did it reduce goiter size. The best prognostic marker available was basal TSH determined 4 weeks after withdrawal of antithyroid drugs (posttreatment TSH). The study demonstrates that levothyroxine does not prevent relapse of hyperthyroidism after successful restoration of euthyroid function by antithyroid drugs and characterizes posttreatment TSH as a main prognostic marker.

Adult↗
PubMed2002

Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene.

Recent reports of the impact of estrogen receptor alpha and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man. We describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of consanguinous parents. A C to A substitution in intron V, at position -3 of the splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of loss of aromatase activity. The mRNA of the patient leads to a frameshift and a premature stop codon 8 nucleotides downstream the end of exon V. Both parents were shown to be heterozygous for the same mutation. Apart from genua valga, kyphoscoliosis, and pectus carniatus, the physical examination was normal including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 micro g transdermal estradiol twice weekly for 3 months, followed by 25 micro g twice weekly. After 6 months estrogen levels (<20 at baseline and 45 pg/ml at 6 months; normal range, 10-50) and estrone levels (17 and 34 ng/ml; normal range, 30-85) had normalized. Bone maturation progressed and the initially unfused carpal and phalangeal epiphyses began to close within 3 months and were almost completely closed after 6 months. The bone age, assessed by roentgenographic standards for bone development by Gruelich and Pyle, was 16.5 at baseline and 18-18.5 yr after 6 months of treatment. Bone density of the distal radius (left), assessed by quantitative computed tomography, increased from 52 to 83 mg/cm(3) (normal range, 120-160) and bone mineral density of the lumbar spine, assessed by dual-energy x-ray-absorptiometry, increased from 0.971 to 1.043 g/cm(2) (normal range, >1.150). Osteocalcin as a bone formation parameter increased from 13 to 52 micro g/l (normal range, 24-70) and aminoterminal collagen type I telopeptide as a bone resorption parameter increased from 62.9 to 92.4 nmol/mmol creatinine (normal range, 5-54). Semen analysis revealed oligoazoospermia (17.4 million/ml; normal >20) at baseline. After 3 months of treatment, the sperm count increased (23.1 million/ml) and decreased rapidly (1.1 million/ml) during the following 3 months. The sperm motility was reduced at baseline and decreased further during treatment. Area under the curve of insulin, C-peptide, and blood glucose levels during oral glucose tolerance test decreased after 6 months (insulin: 277 vs. 139 micro U/ml.h; C-peptide 52 vs. 15 ng/m.h; area under the curve glucose: 17316 vs. 12780 mg/d.min). Triglycerides (268 vs. 261 mmol/liter) and total cholesterol levels (176 vs. 198 mmol/liter) did not change significantly, but the low-density lipoprotein/high-density lipoprotein ratio decreased from 5.37 to 3.56 and lipoprotein (a) increased from 19.9 to 60.0 mg/dl (normal range, <30). In this rare incidence of estrogen deficiency, estrogen replacement demonstrated its importance for bone mineralization and maturation and glucose metabolism in a male carrying a novel mutation in the CYP19 gene.

Adult↗
PubMed2002

Characterization of T(4)-binding globulin cleaved by human leukocyte elastase.

T(4)-binding globulin (TBG) serves to maintain an important serum pool of thyroid hormones and to prevent their excessive loss in urine. TBG has also been implicated in the tissue distribution and targeted delivery of the hormones, the mechanisms of which remain unclear. By virtue of sequence homology, TBG belongs to the serine proteinase inhibitors superfamily of proteins that are characterized by a reactive site loop serving as a recognition site for serine proteinases. However, both TBG and another serpin with hormone transport function, corticosteroid-binding globulin, are noninhibitory. Cleavage of corticosteroid-binding globulin by human leukocyte elastase results in the reduction of its hormone-binding affinity and capacity. In this communication we confirm previous observations that TBG is also cleaved by elastase and undergoes the characteristic conformational changes. In addition, contrary to a previous report, the present work demonstrates that the cleaved product has reduced T(4)-binding affinity and, as expected, increased heat stability. Additional fragmentation of the molecule results in the loss of the hormone-binding site that is in agreement with a recent in vivo observation of apparent consumption at sites of inflammation. These data suggest that TBG may play a role in the targeted delivery of thyroid hormones to tissues rich in proteinases.

Binding Sites↗