THE ROMANIAN VERSION OF THE THYROID-RELATED PATIENT-REPORTED OUTCOMES THYPRO AND THYPRO-39. TRANSLATION AND ASSESSMENT OF RELIABILITY AND CROSS-CULTURAL VALIDITY.

BACKGROUND: ThyPRO is a recently developed thyroid-specific quality of life (QoL) questionnaire applicable to patients with benign thyroid disorders(BTD). The aim of the present study was to translate ThyPRO and ThyPRO-39 into Romanian, and to evaluate reliability and cross-cultural validity. METHODS: Standard methodology for translation and linguistic validation of patient-reported outcomes (PRO) was applied. The questionnaire was completed by 130 patients with benign thyroid diseases seen at Department of Endocrinology in the Emergency County Hospital, Tîrgu Mures, Romania, between October 2015 and March 2016. Internal reliability of the Romanian version of the ThyPRO (ThyPROro) scales was assessed for multi-item scales using Cronbach's alpha coefficient. An efficient method for testing cross-cultural validity is analysis of differential item functioning (DIF). Uniform DIF between the Romanian and the original Danish sample was investigated using ordinal logistic regression. The translation process proceeded without difficulties, and any disagreements were revised by one of the developers and the language coordinator. RESULTS: Internal reliability for ThyPRO was satisfactory. Cronbach`s alpha coefficients for the 13 scales ranged from 0.78 to 0.93 for the ThyPROro and 0.78 to 0.87 for the ThyPROro-39. In the 85-item ThyPRO, nine instances of DIF were found. Most were minor, explaining <3% of the variation in scale score, but DIF in positively worded items were larger, with explained variance (R2's) around 10-15%. CONCLUSION: The ThyPROro questionnaire is ready for assessment of health-related quality of life in Romanian patients with benign thyroid diseases.

Rapid identification of Stenotrophomonas maltophilia by peptide nucleic acid fluorescence in situ hybridization.

The objective of this study was to develop a novel peptide nucleic acid (PNA) probe for Stenotrophomonas maltophilia identification by fluorescence in situ hybridization (FISH). The probe was evaluated using 33 human and veterinary clinical S. maltophilia isolates and 45 reference strains representing common bacterial species in the respiratory tract. The probe displayed 100% sensitivity and 100% specificity on pure cultures and allowed detection in sputum from cystic fibrosis patients. The detection limit was 10(4) CFU/mL in spiked tracheal aspirate and bronchoalveolar lavage from healthy horses. Altogether the study shows that this species-specific PNA FISH probe facilitates rapid detection of S. maltophilia in biological specimens.

Increased risk of long-term sickness absence, lower rate of return to work, and higher risk of unemployment and disability pensioning for thyroid patients: a Danish register-based cohort study.

CONTEXT: Little is known about how thyroid diseases affect work ability. OBJECTIVE: The objective of this study was to evaluate the risk of work disability for patients with thyroid disease compared with the general population. DESIGN, SETTING, AND PARTICIPANTS: In a longitudinal register study, outpatients (n = 862) with nontoxic goiter, hyperthyroidism, Graves' orbitopathy (GO), autoimmune hypothyroidism, or other thyroid diseases and their matched controls (n = 7043) were observed in the years 1994-2011 in Danish national registers of social benefits, health, and work characteristics. Cox regression analyses estimated adjusted hazard ratios (HRs) for the first year after diagnosis and subsequent years. MAIN OUTCOME MEASURES: Transitions between work, long-term sickness absence, unemployment, and disability pension were measured. RESULTS: Patients differed significantly from the general population with regard to sickness absence, disability pension, return from sickness absence, and unemployment. In the first year after diagnosis, higher risks of sickness absence was seen for GO (HR 6.94) and other hyperthyroid patients (HR 2.08), who also had lower probability of returning from sickness absence (HR 0.62) and higher risk of disability pension (HR 4.15). Patients with autoimmune hypothyroidism showed a lower probability of returning from sickness absence (HR 0.62). In subsequent years, GO patients had significantly higher risk of sickness absence (HR 2.08), lower probability of return from sickness absence (HR 0.51), and unemployment (HR 0.52) and a higher risk of disability pension (HR 4.40). Hyperthyroid patients also had difficulties returning from sickness absence (HR 0.71). CONCLUSIONS: Thyroid patients' risk of work disability is most pronounced in the first year after diagnosis and attenuates in subsequent years. GO patients have the highest risk of work disability.

Primary hyperparathyroidism in young people. When should we perform genetic testing for multiple endocrine neoplasia 1 (MEN-1)?

CONTEXT: Multiple endocrine neoplasia (MEN-1) is a rare, autosomal dominant inherited disorder. Primary hyperparathyroidism (pHPT) is the most frequent and usually the earliest expression of MEN-1, with typical age of onset at 20-25 years. Early detection of the disease and correct treatment are therefore of great importance. CASE PRESENTATION: A 31-year-old woman with osteogenesis imperfecta was incidentally found also to have hypercalcemia and elevated PTH (pHPT). Exploratory neck surgery showed multiglandular parathyroid affection; she turned out to have MEN-1, but she was diagnosed 7 years after her debut of pHPT. OBJECTIVE AND METHODS: The aim was to search literature on indications for performing mutational analysis in young patients with pHPT and no family history of MEN-1. PubMed was searched for English language articles, and words used were: MEN1 OR MEN-1 OR MEN type 1 OR multiple endocrine neoplasia 1 OR multiple endocrine neoplasia type 1 AND Mutational analysis OR genetic testing OR testing OR Hyperparathyroidism, primary [majr]. A total of 625 abstracts were reviewed. RESULTS AND DISCUSSION: Whether to perform screening of patients with pHPT under the age of 30, 35, or 40 years is controversial. According to international guidelines from 2001, genetic testing is indicated only in patients with pHPT below the age of 30 years. However, in updated guidelines from 2012, it is suggested to perform genetic testing in patients with pHPT below the age of 30 years, but also at any age in patients presenting with multigland parathyroid disease. CONCLUSIONS: The reviewed literature and the presented case illustrate the importance of this change in international guidelines, but they also raise concern for a potential underdiagnosing of patients before year 2012.

Central hypothyroidism and its replacement have a significant influence on cardiovascular risk factors in adult hypopituitary patients.

CONTEXT: Thyroid dysfunction may have detrimental effects on patient outcomes. Few studies have assessed this issue in patients with secondary hypothyroidism. OBJECTIVE: Our objective was to test the hypothesis that thyroid hormone status has an impact on cardiovascular risk factors in adult patients with hypopituitarism. DESIGN AND SETTING: This was a retrospective observational study (1993-2012) at a tertiary referral university hospital. PATIENTS: All GH-deficient patients starting GH replacement (1993-2009) with measured free T4 (fT4) (n = 208). Baseline fT4 defined patients as TSH-sufficient and TSH-deficient (further divided into tertiles according to baseline fT4; first tertile had lowest fT4). MAIN OUTCOME MEASURES: Anthropometric (body mass index [BMI], waist circumference, total fat (fat mass) and lean body mass [LBM]) and biochemical (lipids and fasting plasma glucose) data were collected at baseline and a median 4.1 years after commencement of GH. RESULTS: At baseline, fT4 was negatively associated with BMI and waist circumference, but positively with high-density lipoprotein, independent of age, gender, and IGF-I (SD score). Only first-tertile TSH-deficient patients had higher BMI (P = .02), fat mass (P = .03), total cholesterol (P = .05), triglycerides (P < .01), and waist circumference (P = .01), and lower high-density lipoprotein cholesterol (P = .03) as compared with TSH-sufficient patients. At follow-up, IGF-I, LBM, and plasma glucose had increased in all subgroups (P < .01). The change in fT4 (ΔfT4) (follow-up - baseline) was negatively correlated to ΔBMI, ΔLBM, Δtotal cholesterol, and Δlow-density lipoprotein cholesterol (all P < .05, adjusted for ΔIGF-I and ΔGH and hydrocortisone dose). The negative correlation to Δtotal cholesterol and Δlow-density lipoprotein cholesterol persisted only in first-tertile TSH-deficient patients. CONCLUSION: This single-center study over a 20-year period has strengthened the importance of improved awareness of thyroid status and optimal thyroid replacement of hypopituitary patients to reduce cardiovascular risks in hypopituitary patients.

Fabry disease in children: agalsidase-beta enzyme replacement therapy.

Fabry disease is a rare, multiorgan disease. The most serious complications involve the kidney, brain and heart. This study aims to assess the effect of enzyme replacement therapy (ERT) using agalsidase-beta in children with Fabry disease. We carried out a nationwide, descriptive and observational retrospective cohort study of 10 children (9-16 years at baseline), who underwent regular systematic investigations for 1-8 years after initiation of ERT with agalsidase-beta (Fabryzyme®, Genzyme). Ophthalmological, echocardiographic abnormalities and hypohidrosis were found at baseline and during the follow-up period. Serious kidney, heart or brain involvement had not developed at the last follow-up examination. For the majority of the patients improvements were found concerning headache, acroparaesthesias and gastrointestinal pain during the follow-up period. The level of energy and physical activity also increased. Treatment with agalsidase-beta was associated with a reduction of neuropathic and abdominal pain and headache. Although all aspects of the Fabry pain phenotype cannot be treated with ERT, the observed effects were clinically significant in the lives of the majority of Fabry children and together with the absence of serious Fabry manifestations at last follow-up, we argue that early initiation of ERT may be considered.

Hair removal in hirsute women with normal testosterone levels: a randomized controlled trial of long-pulsed diode laser vs. intense pulsed light.

BACKGROUND: Hirsutism is a common disorder in women of reproductive age, and androgen disturbances may aggravate the condition. Limited evidence exists regarding efficacy of hair removal in this specific population and no data are available for patients with verified normal testosterone levels. OBJECTIVES: To compare efficacy and safety of intense pulsed light (IPL) vs. long-pulsed diode laser (LPDL) in a well-defined group of hirsute women with normal testosterone levels. METHODS: Thirty-one hirsute women received six allocated split-face treatments with IPL (525-1200 nm; Palomar Starlux IPL system) and LPDL (810 nm; Asclepion MeDioStar XT diode laser). Testosterone levels were measured three times during the study period. Patients with intrinsically normal or medically normalized testosterone levels throughout the study were included in efficacy assessments (n = 23). Endpoints were reduction in hair counts assessed by blinded photoevaluations at baseline and 1, 3 and 6 months after final treatment, patient-evaluated reduction in hairiness, patient satisfaction, treatment-related pain and adverse effects. RESULTS: IPL and LPDL reduced hair counts significantly, with median reductions from baseline of 77%, 53% and 40% for IPL and 68%, 60% and 34% for LDPL at 1, 3 and 6 months, respectively. At 6 months follow-up, there was no significant difference between treatments in terms of hair reduction (P = 0·427), patient assessment of hairiness (P = 0·250) and patient satisfaction (P = 0·125). Pain scores were consistently higher for IPL [median 6, interquartile range (IQR) 4-7] than LPDL (median 3, IQR 2-5) (P < 0·001). CONCLUSION: Hirsute women with normal or medically normalized testosterone levels responded equally well to IPL and LPDL treatments of facial hairiness, but the efficacy declined over 6 months.

Fractionated stereotactic radiotherapy in patients with acromegaly: an interim single-centre audit.

AIM: To evaluate the effect of fractionated stereotactic radiotherapy (FSRT) in acromegaly in a retrospective analysis. PATIENTS AND METHODS: Thirty-four patients (17 females, median 43 years (range 30-74)) with acromegaly were treated with FSRT (conformal dynamic arcing, dose 54 Gy, 27-30 fractions) between January 1998 and April 2007. Of the 34 patients, 32 had undergone transsphenoidal adenotomy, and 28 were on medical therapy before FSRT. Patients on medical therapy continued this during and after the irradiation. The treatment was gradually decreased/withdrawn after careful assessment. RESULTS: Magnetic resonance scanning of the pituitary gland 34 months (median, range 11-95) after irradiation showed stable or reduced volume of the remaining tumour tissue in 31 of 34 patients (91%). Seventeen patients (50%) were biochemically controlled (normalised nadir GH during oral glucose tolerance test and IGF1 <+2 S.D.) 30 months after FSRT (median, range 6-60), and ten of them had true biochemical remission (off medical therapy) 30 months after FSRT (median, range 12-69). Of 28 patients with one or more functioning pituitary axes before irradiation, 8 (29%) developed further deficit of one or two pituitary axes 48 months (median, range 6-102) after FSRT. Of 34 patients, 20 still required medical treatment for acromegaly at the end of this study, mainly those with a short follow-up period after irradiation. CONCLUSION: The FSRT seems promising in terms of treatment of acromegaly. Longer follow-up is, however, needed to assess the overall efficacy and safety of FSRT for acromegaly.

Frequency and motives of blood glucose self-monitoring in type 1 diabetes.

AIMS: Recommendations for self-monitoring of blood glucose (SMBG) from the DCCT have not been implemented with the same rigour as recommendations for intensifying insulin therapy. We assessed the frequency of and motives for SMBG and compared SMBG behaviour with clinical, behavioural and demographic characteristics. METHODS: Cross-sectional Danish-British multicentre survey of 1076 consecutive patients with type 1 diabetes, who completed a detailed questionnaire on SMBG and related issues. The key variables were test frequency and motive. RESULTS: SMBG was performed daily by 39% of the patients and less than weekly by 24%. Sixty-seven percent reported to perform routine testing, while the remaining 33% only tested when hypo- or hyperglycaemia was suspected. Age, gender, and level of diabetes-related concern were associated with test pattern. Reported frequencies of mild and severe hypoglycaemia and awareness of hypoglycaemia were independently associated with testing behaviour, whereas the presence of late diabetic complications was not. Lower HbA1c was associated with more frequent testing. CONCLUSION: Patient compliance regarding SMBG is limited. Thus, almost two thirds of the patients do not perform daily SMBG and one third do not perform routine tests.

Reduced parietooccipital white matter glutamine measured by proton magnetic resonance spectroscopy in treated graves' disease patients.

CONTEXT: Graves' disease is an autoimmune disease of the thyroid gland. Patients often have affective and cognitive complaints, whether these disappear after treatment remains disputed. OBJECTIVE: Our objective was to evaluate cerebral biochemistry in acute and treated Graves' disease. DESIGN: We conducted a prospective study, investigating volunteers once and patients before and 1 yr after treatment. SETTING: The study was performed at a radiology department, a memory disorder clinic, and two endocrinology clinics. PATIENTS AND OTHER PARTICIPANTS: Of 53 consecutively referred, newly diagnosed, and untreated patients with Graves' thyrotoxicosis, 27 patients (34 +/- 8 yr) and 33 matched volunteers were included. INTERVENTIONS: Patients were treated with thionamide. MAIN OUTCOME MEASURES: We assessed brain metabolite concentrations. METHODS: Proton magnetic resonance spectroscopy of the brain and a battery of biochemical, affective, and cognitive tests were used. RESULTS: Previously reported findings of reduced choline and myo-inositol in acute Graves' disease were confirmed and reversibility was demonstrated. Parieto-occipital white matter glutamine was and remained significantly reduced (P < 0.01). Acute phase parieto-occipital white matter total choline correlated significantly (r = -0.57; P < 0.01) with impaired thyroid function. Pretreatment total T(3) predicted posttreatment occipital gray matter glutamine (r = -0.52; P < 0.01). Occipital gray matter total choline (r = -0.53; P < 0.01) and parietooccipital white matter glutamate (r = -0.54; P < 0.01) correlated with initial values of selected attention and concentration cognitive scores and predicted them at follow-up. CONCLUSIONS: The persistent reduction of glutamine in white matter, the decreasing glutamate in occipital gray matter, and the correlation with severity of the initial disease as well as with attention and concentration cognitive scores indicated that there was a persistent and possibly progressive disturbance of the glutamate glutamine cycling in Graves' disease.

Immunohistochemical staining for thyroid peroxidase (TPO) of needle core biopsies in the diagnosis of scintigraphically cold thyroid nodules.

BACKGROUND: Cold thyroid nodules are common, in particular in iodine-deficient areas, but only a minority of them are malignant requiring surgery. Thyroid peroxidase (TPO) immunostaining of fine-needle aspiration cytology (FNAC) material has proven helpful in diagnosing cells from malignant lesions, but the procedure has its limitations in a routine setting. PURPOSE: To improve diagnosis and reduce surgery rate, the FNAC procedure was replaced by needle core biopsy (NCB), which was routinely stained for TPO by the monoclonal antibody mAb 47. MATERIALS AND METHODS: During a 5-year period 427 consecutive patients with a cold thyroid nodule were evaluated by ultrasound-guided NCB, which had been routinely stained for TPO in an automated immunostainer. Sensitivity and specificity and predictive values of the TPO immunostaining were estimated, based on the final diagnosis obtained from surgical resection. RESULTS: The majority of nodules with benign NCB diagnosis were not surgically removed, and thus a subgroup of 140 operated nodules formed the basis for the calculations. Sensitivity and specificity for benign and malignant lesions were 100% if the oxyphilic variant of adenomas and minimally invasive follicular carcinomas were excluded. By inclusion of these, the values fell to 89% and 97%, respectively. The predictive value of a positive test was 96% and the predictive value of a negative test was 97%. CONCLUSION: TPO immunostaining was found to be a valuable adjunct to morphology in the diagnosis of cold thyroid nodules of the nonoxyphilic type.

Estimation of number of follicles, volume of colloid and inner follicular surface area in the thyroid gland of rats.

Volume is an important variable in assessing the growth and involution of the thyroid gland. The functional unit in the thyroid is the follicle, which consists of thyrocytes surrounding colloid. The size of a follicle depends on the number of cells and the amount of colloid. These are interchangeable and vary according to biological activity. Direct measurements of these variables provide information on structures involved in thyroid hormone synthesis, storage and secretion, and also on changes at the morphological and functional levels. Stereological methods are developed to obtain information on three-dimensional structures from two-dimensional sections and to achieve information on an entire organ by examining a minor part of it. Full-grown male Sprague-Dawley rats were used to develop a set of methods relying on unbiased stereological principles to determine the number of follicles, the total volume of colloid and the inner follicular surface area in the thyroid gland. The total volume of colloid was positively correlated (P < 0.021) with the number of follicles and the inner follicular surface area (P < 0.002) but not to the mean volume of colloid in each follicle. Thus under physiological conditions an increase in the total volume of colloid is associated with an increased number of follicles with a constant size distribution rather than a larger volume of colloid in each follicle. This implies that under physiological conditions there is equilibrium in the size distribution of the volume of colloid in each follicle.

Impaired health-related quality of life in Graves' disease. A prospective study.

OBJECTIVE: In the acute, thyrotoxic phase, patients with Graves' disease often have both thyrotoxic and neuropsychiatric symptoms. The purpose of this prospective study was to examine health-related quality of life (HRQOL) in newly diagnosed and untreated Graves' patients and the effect of antithyroid medical treatment on HRQOL. In addition, we examined the potential influence of thyroid hormones and psychiatric symptoms on the impairment of HRQOL in the thyrotoxic phase. METHODS: A total of 30 consecutively referred patients with newly diagnosed and untreated Graves' disease and 34 age-, sex- and education-matched healthy volunteers were included in the study. HRQOL was assessed with the Medical Outcome Study 36-item Short-Form Health Status Survey (SF-36) before treatment, after reaching euthyroidism and 1 year after initiation of treatment. RESULTS: In the thyrotoxic phase of Graves' disease, HRQOL was significantly impaired, in physical, mental and social dimensions. After reaching euthyroidism, the patients reported much fewer limitations on the subscales of SF-36. One year after initiation of treatment, all SF-36 scores had normalized. However, in some patients, HRQOL continues to be impaired even 1 year after initiation of treatment, as reviewed by the individual analysis. The reduced HRQOL in the acute phase of Graves' disease was correlated to depressive and anxiety symptoms, but thyroid-associated orbitopathy also influenced HLQOL. CONCLUSIONS: Impaired HRQOL is common in the acute phase of Graves' disease. A significant proportion of the patients demonstrated persistent HRQOL impairment 1 year after initiation of treatment. Improvement of HRQOL in these patients remains a challenge for the clinician.

Neonatal stimulation of the thyroid gland with iodine or suppression during adolescence with triiodothyronine changes the prevalence of autoimmune thyroiditis in BB rats.

OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.

Assessment of the hypothalamo-pituitary-adrenal axis in patients treated with radiotherapy and chemotherapy for childhood brain tumor.

The impact of cranial irradiation (CIR) and chemotherapy on the hypothalamo-pituitary (HP)-adrenal (HPA) axis was assessed in a population-based follow-up study of patients treated for childhood brain tumor not directly involving the HP axis. HPA function was evaluated and compared with that in healthy controls (n = 17), measuring basal cortisol and the peak cortisol response to an insulin tolerance test (ITT) and an ACTH test(.) The cortisol cut-off level was 500 nmol/liter. The biological effective dose (BED) of radiotherapy was determined for the HP region and spine and was expressed in Gray units, as BED gives a means of expressing the biological effects of different dosage schedules in a uniform way. Seventy-three children (46 males and 27 females), less than 15 yr of age when diagnosed during 1970-1997 in the Eastern part of Denmark, were included. The median age at time of radiotherapy was 8.4 yr (range, 0.8-14.9). The median length of follow-up was 15 yr (range, 2-29). Fourteen patients (19%) had basal cortisol levels below 500 nmol/liter and did not respond with a peak cortisol above the cut-off level to either an ACTH test (30 or 60 min) or an ITT, and thus, they had insufficiency of the HPA axis. Even though a peak cortisol above 500 nmol/liter was reached in the rest of the cohort (n = 59) after either an ACTH test (30 or 60 min) or an ITT, they had significantly lower peak cortisol levels compared with controls (P = 0.0099). Thirteen patients failed the ACTH test (30 min), but passed the ACTH test (60 min), implying a risk of misinterpreting the cortisol capacity of the patient if only the ACTH test (30 min) is obtained. The basal cortisol levels and the cortisol levels in the ACTH test (30 min) and the ACTH test (60 min) were significantly lower in the patient group compared with controls. There was a significant correlation between the peak cortisol after the ITT compared with the peak cortisol after the ACTH test (30 or 60 min; r(s) = 0.56; P = 0.0006), but 48% failed the ITT, and there was discordance in 10 of 33 (30%) patients who passed the ACTH but failed the ITT, indicating the recommendation of continuous use of the ITT as the gold standard for evaluation of the HPA axis. Stepwise backward multiple linear regression analysis showed that the best-fit model to predict the peak cortisol level after an ITT included BED (P = 0.04) and length of follow-up (P = 0.06). In contrast, age at RT, chemotherapy, BED to the spine, and gender were not included in the model. In conclusion, these data suggest that CIR for a childhood brain tumor may affect the HPA axis, resulting in secondary adrenal insufficiency, whereas adjuvant chemotherapy does not seem to add to the deleterious effect of CIR. We recommend life-long surveillance of the HPA axis and performing regular ITTs.

Reduced myo-inositol and total choline measured with cerebral MRS in acute thyrotoxic Graves' disease.

Neuropsychiatric symptoms in the acute thyrotoxic phase of Graves' disease suggest involvement of brain processes. Short-echo-time proton MRS was used to measure the cerebral metabolite profile in newly diagnosed and untreated Graves' disease. Sixteen patients with Graves' disease and 18 age- and sex-matched healthy volunteers were studied. The patients had significantly reduced total choline and myo-inositol in the acute phase of Graves' thyrotoxicosis compared with the healthy volunteers.

A population-based study of thyroid function after radiotherapy and chemotherapy for a childhood brain tumor.

The effect of craniospinal irradiation (CSI) vs. cranial irradiation (CIR) only with or without chemotherapy (CT) on the hypothalamus/pituitary (HP) thyroid axis was assessed in a population-based study of patients treated for a childhood brain tumor not directly involving the HP axis. Thyroid function was evaluated and compared with that in healthy controls (n = 27), measuring TSH, free T4, total T4, total T3, and TRH. The biological effective dose (BED) of radiotherapy, determined for the HP region and spine and expressed in grays (Gy) as BED, gives a means of expressing the biological effects of different dosage schedules in a uniform way. Seventy-one children (45 males and 26 females), less than 15 yr of age when diagnosed between 1970-1997 in the eastern part of Denmark, were included. Twenty-nine had received CSI, and 42 had received CIR only. The median age at time of radiotherapy was 8.4 yr (range, 0.8-14.9). The median length of follow-up was 12.0 yr (range, 2.0-28.0). There was no significant difference between CSI and the CIR only patients with respect to median BED to the HP region. Primary hypothyroidism was found in 24%, of whom 71% had been treated with CSI and 29% with CIR only; 73% had compensated hypothyroidism, and 27% had overt primary hypothyroidism. Central hypothyroidism was found in 6%. Free T4 and total T3 were significantly lower in the CSI and CIR only groups compared with controls. As the CIR only group had significantly higher median basal TSH levels compared with controls and as the CSI compared with the CIR only group and controls had significantly higher median basal TSH levels, we speculate that this was probably due to scattered irradiation from both cranial and spinal fields to the thyroid gland. There was a significant relation between basal TSH and time of follow-up (r(s) = -0.39; P = 0.001). Stepwise backward multiple linear regression analysis showed that the best-fit model to predict basal TSH was free T4 (P < 0.0001), the length of follow-up (P = 0.02), and total T3 (P = 0.06). In contrast, age at radiotherapy, BED to the HP region and spine, and whether the patient had been treated with CT were not included in the model. The TRH test showed significantly exaggerated and prolonged TSH responses for the CSI and CIR only groups compared with controls, indicating HP dysfunction. In conclusion, these data suggest that both CSI and CIR for childhood brain tumor may affect the HP-thyroid axis, resulting in hypothyroidism. CT had no significant influence on HP-thyroid function. We recommend prolonged surveillance of pituitary-thyroid function in long-term survivors of childhood brain tumor and institution of thyroid hormone replacement if the levels of TSH and free T4 are above and below the normal range, respectively, to ensure normal growth and metabolism.

Fabry disease--a metabolic disorder with a challenge for endocrinologists?

OBJECTIVE: To revisit Fabry disease, a rare X-linked metabolic glycosphingolipid storage disease caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). METHOD: Summary of the existing knowledge of Fabry disease including the clinical feature of Fabry disease and the recent breakthrough in the treatment of Fabry patients with the development of recombinant human alpha-gal A. CONCLUSION: The diffuse organ manifestations of Fabry disease resemble medical endocrinological diseases, and medical endocrinology might be an appropriate speciality to manage the treatment in collaboration with other specialists and clinical geneticists.

The influence of alpha1-acid glycoprotein (orosomucoid) and its glycoforms on the function of human thyrocytes and CHO cells transfected with the human TSH receptor.

Local immunological reactions might influence the structure of alpha1-acid glycoprotein (AGP, orosomucoid) leading to a pathological condition in e.g. the thyroid. The aim of this study was to investigate whether the AGP molecule had a direct effect on thyroid cell function in vitro. The influence of AGP and its three glycoforms, TSH (1.0 U/l), serum samples and several sugars (methyl-mannose, methyl-glycoside, N-acetyl-D-galactose, N-acetyl-D-glycoside, neuramidase) were studied with respect to their influence on the function of the Chinese Hamster Ovary (CHO) cell line transfected with the human TSH receptor (hTSHr) and on human thyroid follicular epithelial cells (TFEC) in secondary cultures. We found that low concentrations of AGP (0.001-0.05 microg/l) stimulated while high concentrations of AGP (0.25-1.0 microg/l) inhibited cAMP accumulation in both cell systems (n=24, P<0.0002). In CHO cells (JP26) and TFEC glycoforms 1 (n=9), 2 (n=12) or 3 (n=11) significantly inhibited the TSH stimulated cAMP production, respectively, compared to controls (P<0.0001) and was partially reversed by mannose (P<0.0004). Control CHO cells (JP02) without the hTSHr showed no response. The specificity of the reaction was further confirmed by binding of biotinylated glycoforms and streptavidin conjugated FITC to both cell systems. This is the first report demonstrating that AGP and/or its glycoforms affects thyroid cell function in vitro and that it does so by influencing the second messenger cAMP probably by interacting directly with the TSH receptor.