The addition of the sFlt-1/PlGF ratio to the protein/creatinine ratio in multiple pregnancy: Post-hoc analysis of the PREPARE cohort study.

OBJECTIVE: To assess the predictive accuracy of the sFlt-1/PlGF ratio cut-off 38 in addition to the standard-of-care spot urine protein/creatinine ratio (PCr) for multiple pregnancies in women with suspected pre-eclampsia. STUDY DESIGN: Post-hoc analysis of a prospective cohort study. MAIN OUTCOME MEASURES: Primary outcome was the occurrence of pre-eclampsia in one and four weeks after presentation with suspected pre-eclampsia. Test characteristics with 95% confidence intervals (CI) were calculated on pre-eclampsia development in one and four weeks. RESULTS: Twenty-three multiple pregnancies with suspected pre-eclampsia between 20 and 37 weeks gestation were included for analysis. Women who eventually developed pre-eclampsia had a significantly higher PCr (34.0 vs. 16.5, p = 0.015), sFlt-1 (17033 vs. 5270 pg/ml, p = 0.047) and sFlt-1/PlGF ratio (99 vs. 25, p = 0.033) at baseline. Furthermore, PCr ≥ 30 and sFlt-1/PlGF ratio > 38 was respectively seen in 1/16 (6.3 %) and 3/16 (18.8 %) of the women who did not develop pre-eclampsia. For predicting pre-eclampsia within one week the sFlt-1/PlGF ratio sensitivity was 75.0 % [95 % CI 19.4-99.4] and the negative predictive value 93.8 % [73.0-98.8], while no pre-eclampsia developed when PCr was < 30. Consequently, the combination of these tests did not lead to an improvement in test characteristics, with non-significant differences in positive predictive value (50.0 % [29.5-70.5] versus 80.0 % [37.3-96.4]) compared to PCr alone for pre-eclampsia development in one week. CONCLUSIONS: In addition to standard-of-care spot urine PCr measurements, this study has not been able to demonstrate that the sFlt-1/PlGF ratio cut-off 38 is of added value in the prediction of pre-eclampsia in multiple pregnancy. TRIAL REGISTRATION: Netherlands Trial Register (NL8308).

Clinical value and cost analysis of the sFlt-1/PlGF ratio in addition to the spot urine protein/creatinine ratio in women with suspected pre-eclampsia: PREPARE cohort study.

BACKGROUND: This study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia. METHODS: This was a prospective cohort study performed in a tertiary referral centre. Based on the combination of PCr (< 30) and sFlt-1/PlGF (≤38) results, four groups were described: a double negative result, group A-/-; a negative PCr and positive sFlt-1/PlGF, group B-/+; a positive PCr and negative sFlt-1/PlGF, group C+/-; and a double positive result, group D+/+. The primary outcome was the proportion of false negatives of the combined tests in comparison with PCr alone in the first week after baseline. Secondary, a cost analysis comparing the costs and savings of adding the sFlt-1/PlGF ratio was performed for different follow-up scenarios. RESULTS: A total of 199 women were included. Pre-eclampsia in the first week was observed in 2 women (2%) in group A-/-, 12 (26%) in group B-/+, 4 (27%) in group C+/-, and 12 (92%) in group D+/+. The proportion of false negatives of 8.2% [95% CI 4.9-13.3] with the PCr alone was significantly reduced to 1.6% [0.4-5.7] by adding a negative sFlt-1/PlGF ratio. Furthermore, the addition of the sFlt-1/PlGF ratio to the spot urine PCr, with telemonitoring of women at risk, could result in a reduction of 41% admissions and 36% outpatient visits, leading to a cost reduction of €46,- per patient. CONCLUSIONS: Implementation of the sFlt-1/PlGF ratio in addition to the spot urine PCr, may lead to improved selection of women at low risk and a reduction of hospital care for women with suspected pre-eclampsia. TRIAL REGISTRATION: Netherlands Trial Register (NL8308).

IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management.

CONTEXT: Mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause the X-linked IGSF1 deficiency syndrome consisting of central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasionally transient partial GH deficiency. Since our first reports, we discovered 20 new families with 18 new pathogenic IGSF1 mutations. OBJECTIVE: We aimed to share data on the largest cohort of patients with IGSF1 deficiency to date and formulate recommendations for clinical management. METHODS: We collected clinical and biochemical characteristics of 69 male patients (35 children, 34 adults) and 56 female IGSF1 mutation carriers (three children, 53 adults) from 30 unrelated families according to a standardized clinical protocol. At evaluation, boys were treated with levothyroxine in 89%, adult males in 44%, and females in 5% of cases. RESULTS: Additional symptoms in male patients included small thyroid gland volume (74%), high birth weight (25%), and large head circumference (20%). In general, the timing of pubertal testicular growth was normal or even premature, in contrast to a late rise in T levels. Late adrenarche was observed in patients with prolactin deficiency, and adult dehydroepiandrosterone concentrations were decreased in 40%. Hypocortisolism was observed in 6 of 28 evaluated newborns, although cortisol concentrations were normal later. Waist circumference of male patients was increased in 60%, but blood lipids were normal. Female carriers showed low free T4 (FT4) and low-normal FT4 in 18% and 60%, respectively, delayed age at menarche in 31%, mild prolactin deficiency in 22%, increased waist circumference in 57%, and a negative correlation between FT4 concentrations and metabolic parameters. CONCLUSION: IGSF1 deficiency represents the most common genetic cause of central hypothyroidism and is associated with multiple other characteristics. Based on these results, we provide recommendations for mutational analysis, endocrine work-up, and long-term care.

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism.

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

[Thyroid autoantibodies]. / Schildklierantistoffen.

Here we describe the role of laboratory assessment of autoantibodies against the thyroid antigens thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR) and thyroglobulin (TG) in the diagnosis of disorders of the thyroid. The practical use of these tests is illustrated by two case studies. This is followed by an in-depth discussion of the most recent literature, including national and international guidelines for thyroid disorders. The applicability of TPO antibodies in subclinical hypothyroidism, THSR antibodies in pregnant women with a history of Graves' hyperthyroidism, and TG antibodies in the follow-up of differentiated thyroid carcinoma, are highlighted.

Thyroid function, activated protein C resistance and the risk of venous thrombosis in users of hormonal contraceptives.

INTRODUCTION: Use of combined hormonal contraceptives is associated with a three- to eight-fold increased risk of venous thrombosis compared with non-use. The thrombotic risk depends on the estrogen dose as well as the progestogen type. Use of hormonal contraceptives leads to resistance to activated protein C (APC), which may serve as marker for the risk of venous thrombosis. Hyperthyroidism is also associated with an increased risk of venous thrombosis, due to increased free Thyroxine (FT4) levels which cause a hypercoagulable state. MATERIALS AND METHODS: The objective of this study was to evaluate the effects of hormonal contraceptives on levels of FT4, thyroid stimulating hormone (TSH) and thyroxine binding globulin (TBG), and to investigate the effects on APC resistance per contraceptive group. We measured FT4, TBG and TSH levels and APC resistance in 231 users of oral contraceptives. RESULTS: Users of the most thrombogenic hormonal contraceptives, i.e. containing desogestrel, cyproterone acetate or drospirenone, had higher TBG levels than users of less thrombogenic hormonal contraceptives, i.e. the levonorgestrel-containing intrauterine device. TSH levels were not significantly elevated and FT4 levels did not change. TBG levels were also associated with APC resistance. CONCLUSION: Use of hormonal contraceptives lead to elevated TBG levels, slightly elevated TSH levels and unchanged FT4 levels without causing a hyperthyroid state. Thus, the increased thrombotic risk during the use of hormonal contraceptives cannot be explained by a hyperthyroid state caused by use of these hormonal contraceptives.

Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model-based approach.

BACKGROUND/AIMS: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. METHODS: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure. RESULTS: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 ± 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 ± 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response. CONCLUSION: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects.

Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial.

BACKGROUND: The use of combined oral contraceptives is associated with a 3- to 6-fold increased risk of venous thrombosis. This increased risk depends on the estrogen dose as well as the progestogen type of combined oral contraceptives. Thrombin generation-based activated protein C resistance (APC resistance) and sex hormone-binding globulin (SHBG) levels predict the thrombotic risk of a combined hormonal contraceptive. Recently, a four-phasic oral contraceptive containing dienogest (DNG) and estradiol valerate (E2V) has been marketed. The aim of this study was to evaluate the thrombotic risk of the DNG/E2V oral contraceptive by comparing APC resistance by measuring normalized APC sensitivity ratios (nAPCsr) and SHBG levels in users of oral contraceptives containing dienogest and estradiol valerate (DNG/E2V) and oral contraceptives containing levonorgestrel and ethinyl estradiol (LNG/EE). METHODS: We conducted a single-center, randomized, open label, parallel-group study in 74 women using DNG/E2V or LNG/EE, and measured nAPCsr and SHBG levels in every phase of the regimen of DNG/E2V. RESULTS: During the pill cycle SHBG levels did not differ between DNG/E2V users and LNG/EE users. nAPCsr levels were overall slightly lower in DNG/E2V users than in LNG/EE users, mean difference -0.44 (95% CI, -1.04 to 0.17) for day 2, -0.20 (95% CI, -0.76 to 0.37) for day 7, -0.27 (95% CI, -0.81 to 0.28) for day 24 and -0.34 (95% CI, -0.91 to 0.24) for day 26. CONCLUSION: No statistical significant differences in nAPCsr and SHBG levels were found between users of the oral contraceptive containing DNG/E2V and LNG/EE, suggesting a comparable thrombotic risk.

Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives.

BACKGROUND: It takes many years to obtain reliable values for the risk of venous thrombosis of hormonal contraceptive users from clinical data. Measurement of activated protein C (APC) resistance via thrombin generation is a validated test for determining the thrombogenicity of hormonal contraceptives. Sex hormone-binding globulin (SHBG) might serve as a marker for the risk of venous thrombosis, and can be easily and rapidly measured in routine laboratories. OBJECTIVE: To determine whether SHBG is a useful marker for the thrombotic risk of hormonal contraceptive users by comparing plasma SHBG levels with normalized APC sensitivity ratio (nAPCsr) values and thrombosis risks reported in the recent literature. METHODS: We conducted an observational study in 262 users of different contraceptives, and measured nAPCsr and SHBG levels. RESULTS: Users of contraceptives with a higher risk of causing venous thrombosis, i.e. combined hormonal contraceptives containing desogestrel, cyproterone acetate or drospirenone, and the transdermal patch, had higher SHBG levels than users of combined hormonal contraceptives containing levonorgestrel, which carry a lower thrombosis risk. Users of the patch had the highest SHBG levels, with a mean difference of 246 nmol L(-1) (95% confidence interval 179-349) from that in users of levonorgestrel-containing combined hormonal contraceptives. SHBG levels were positively associated with both the nAPCsr and the risks of venous thrombosis reported in the recent literature. CONCLUSION: SHBG is a useful marker with which to estimate the thrombotic safety of a preparation.

Long-term follow-up of organ-specific antibodies and related organ dysfunction in type 1 diabetes mellitus.

OBJECTIVE: Diabetes mellitus type 1 (DM1) is associated with other autoimmune disorders. To our knowledge, there are no longitudinal data considering the long-term clinical relevance of organ-specific antibodies (OS-Ab) in DM1 patients. We performed a long-term retrospective longitudinal study in order to investigate the presence and diagnostic accuracy (positive predictive value: PPV and negative predictive value: NPV) of OS-Ab in DM1 patients. RESEARCH DESIGN AND METHODS: In a retrospective longitudinal study, the presence of OS-Ab and related organ function were analysed in 396 DM1 patients (184 F/212 M, age 44 ± 13 years, age at onset of DM1 21 ± 13 years), with a median follow-up time of 23 ± 10 years. RESULTS: OS-Ab frequencies at baseline were: antibodies against thyroglobulin (Tg-Ab) 4.3%, antibodies against thyroid peroxidase (TPO-Ab) 8.1%, Tg- and/or TPO-Ab 10.4%, antibodies against parietal cells (PCA) 5.8% and antibodies against adrenal cortex (ACA) 0.5%. The occurrence of (sub)clinical hypothyroidism was higher in patients with Tg-Ab (47%) or TPO-Ab (42%) than in those without these antibodies (6.2 and 5.1%, respectively, p<0.001). PPV and NPV for Tg-Ab were 0.60 and 0.88, respectively, for TPO -Ab 0.54 and 0.91. Also in patients with PCA, organ dysfunction occurred more often (61%) than in patients without PCA (9.7%, p<0.001). PPV for PCA was 0.61 and NPV 0.90. NPV and PPV for ACA could not be calculated because of the low prevalence. CONCLUSION: Long-term follow-up of 396 DM1 patients shows that the presence of thyroid antibodies and/ or parietal cell antibodies is clearly associated with dysfunction of the corresponding organ.

Bisphosphonate dose and incidence of fractures in postmenopausal osteoporosis.

INTRODUCTION: The specific pharmacological properties of bisphosphonates have raised concerns about their long-term effects on skeletal fragility that may be related to the total dose of bisphosphonate given. However, the effect of different doses on the incidence of osteoporotic fractures has not been adequately studied. METHODS: In this retrospective analysis, we investigated the effect of different doses of intravenous pamidronate given at 3-monthly intervals on the incidence of fractures in 92 women with severe postmenopausal osteoporosis. RESULTS: The risk of sustaining a new vertebral fracture on treatment was significantly increased by 32% for every prevalent vertebral fracture (OR: 1.32, CI: 1.05, 1.66; p=0.02). Patients with nonvertebral fractures received a significantly lower dose of pamidronate and their risk for these fractures increased by 25% for every prevalent vertebral fracture at baseline (OR: 1.25, CI: 1.01, 1.53; p=0.03). Patients who had received oral bisphosphonate before intravenous pamidronate had a significantly higher incidence of nonvertebral fractures which, however, did not hold true after adjustment for baseline BMD and prevalent fractures. CONCLUSIONS: In patients with established osteoporosis bone fragility during treatment with intravenous pamidronate is mainly determined by the severity of the disease, assessed by the presence and numbers of prevalent fractures, rather than the dose of the bisphosphonate or the rate of bone turnover.

Evaluation of biomarkers for cardiotoxicity of anthracyclin-based chemotherapy.

INTRODUCTION: The clinical assessment of the myocardial damage caused by anthracyclin (ANT)-therapy is difficult. Therefore a study was performed to evaluate non-invasive markers of anthracyclin-induced cardiac effects, with emphasis on course-to-course variation. METHODS: Eligible for study participation were patients, without known cardiologic abnormalities who did not use cardiotoxic medication (except for ANT-therapy), who had previously completed at least three cycles of anthracyclin-containing chemotherapy (n = 14) and patients who were ANT-naïve and who were scheduled to receive doxorubicin-containing chemotherapy (n = 12). Seven patients in this last group also completed at least three cycles and were available for follow-up assessments; thus a total population of 21 patients (12F/9M) completed at least three courses ANT-chemotherapy. In these patients blood samples and ECG-recordings were taken within 6 months after completion of ANT-therapy. In 12 patients (10F/2M) assessments were also done before, immediately afterwards and at 24 h after each course of ANT. RESULTS AND CONCLUSIONS: In the patients who completed chemotherapy, NT-proBNP was 277% (n = 21; 95% CI: 86-661%, P < 0.001) higher compared to healthy volunteers. During the first course NT-proBNP rose 269% (n = 12; 167-409%, P < 0.0001) at 24 h post-administration. The linear corrected QT (QTcL) directly after the first administration of ANT increased by 9.56 ms (n = 12; 3.85-15.27, P < 0.001) and this prolongation was still present at 24 h, 11.48 ms (n = 12; 5.61-17.34, P < 0.0001). Both NT-proBNP and QTcL returned to baseline before the start of the next course and a similar pattern was observed during each course. NT-proBNP and QTcL may be useful markers for course-to-course evaluation of anthracyclin-induced cardiotoxicity.

Is stress a trigger factor for migraine?

BACKGROUND: Although mental stress is commonly considered to be an important trigger factor for migraine, experimental evidence for this belief is yet lacking. OBJECTIVE: To study the temporal relationship between changes in stress-related parameters (both subjective and objective) and the onset of a migraine attack. METHODS: This was a prospective, ambulatory study in 17 migraine patients. We assessed changes in perceived stress and objective biological measures for stress (saliva cortisol, heart rate average [HRA], and heart rate variability [low-frequency power and high-frequency power]) over 4 days prior to the onset of spontaneous migraine attacks. Analyses were repeated for subgroups of patients according to whether or not they felt their migraine to be triggered by stress. RESULTS: There were no significant temporal changes over time for the whole group in perceived stress (p=0.50), morning cortisol (p=0.73), evening cortisol (p=0.55), HRA (p=0.83), low-frequency power (p=0.99) and high-frequency power (p=0.97) prior to or during an attack. Post hoc analysis of the subgroup of nine stress-sensitive patients who felt that >2/3 of their migraine attacks were triggered by psychosocial stress, revealed an increase for perceived stress (p=0.04) but no changes in objective stress response measures. At baseline, this group also showed higher scores on the Penn State Worry Questionnaire (p=0.003) and the Cohen Perceived Stress Scale (p=0.001) compared to non-stress-sensitive patients. CONCLUSIONS: Although stress-sensitive patients, in contrast to non-stress-sensitive patients, may perceive more stress in the days before an impending migraine attack, we failed to detect any objective evidence for a biological stress response before or during migraine attacks.

Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14-DQ5.

The authors studied the HLA profile of 23 white Dutch patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK Ab+ MG) and found an association with HLA-DR14-DQ5 (odds ratio 8.5; 95% CI 3.9 to 18.7; p = 4.9 x 10(-5)). Fifty-two percent of the patients carried the DR14 allele compared with 5% of the controls (p = 1.0 x 10(-8)). This association between MuSK Ab+ MG and a relatively rare HLA haplotype differs from the previously described association of early-onset acetylcholine receptor Ab+ MG with HLA-B8-DR3.

A bioluminescence assay for thyrotropin receptor antibodies predicts serum thyroid hormone levels in patients with de novo Graves' disease.

BACKGROUND: TSH receptor antibodies (TBII) in Graves' disease (GD) may be TSH receptor stimulating (TSAb) and blocking (TBAb) antibodies. In commercially available assays however, only total TBII titres can be measured, without discriminating between TSAb and TBAb. OBJECTIVE: To design a TBII bioassay to detect of TSAb and to correlate TSAb activity with severity of hyperthyroidism in de novo GD patients. PATIENTS: Thirty-five patients with de novo GD and 27 controls. METHODS: The JP-26-26 cell line, which constitutively expresses the TSH receptor (TSHR), was stably transfected with a cyclic adenosine monophosphate responsive element--luciferase construct. The clone B1 exhibited a near linear increase in luminescence from 0.2 mU/l to 50 mU/l bovine TSH and was used as a TBII bioassay. TBII, free T4 and TSH were measured in the sera of all patients and controls. RESULTS: In the sera of 35 GD patients, TBII titres did not correlate with serum free T4 concentrations. In contrast, a strong and highly significant correlation was found between TSHR stimulating activity (luminescence) as measured with the TBII bioassay and serum free T4 levels (R = 0.80, P < 0.001). Interestingly, the luminescence/TBII ratio had a wide range at low TBII titres, whereas high TBII titres were associated with a low degree of TSHR activation. The TBII bioassay also detected TBAb in GD patients who spontaneously developed hypothyroidism. CONCLUSIONS: The B1-TBII-bioassay as developed in our laboratory has a high sensitivity for the detection of TSAb in GD and predicts the severity of hyperthyroidism in untreated GD patients. In addition, we found that high TBII titres are associated with weak TSHR activation.

Hematology patterns of migrating European eels and the role of EVEX virus.

We show that European eels infected with the rhabdovirus EVEX (Eel Virus European X) virus, developed hemorrhage and anemia during simulated migration in large swim tunnels, and died after 1000-1500 km. In contrast, virus-negative animals swam 5500 km, the estimated distance to the spawning ground of the European eel in the Sargasso Sea. Virus-positive eels showed a decline in hematocrit, which was related to the swim distance. Virus-negative eels showed a slightly increased hematocrit. Observed changes in plasma lactate dehydrogenase (LDH), total protein and aspartate aminotransferase (AAT) are indicative of a serious viral infection. Based on these observations, we conclude that eel virus infections may adversely affect the spawning migration of eels, and could be a contributing factor to the worldwide decline of eel.

Octreotide long-acting repeatable and lanreotide Autogel are equally effective in controlling growth hormone secretion in acromegalic patients.

OBJECTIVE: Recently a new depot preparation of the long-acting somatostatin analogue, lanreotide Autogel was introduced for the treatment of acromegaly. Like octreotide long-acting repeatable (LAR), it has high binding affinity for the somatostatin receptor subtype SSTR 2 and less binding affinity for SSTR 5. We hypothesized that the ability to suppress growth hormone (GH) secretion in patients with acromegaly would be similar for these depot preparations. PATIENTS AND STUDY DESIGN: Seven patients (mean age+/-S.E.M. 48.4+/-7 years) on long-term octreotide LAR treatment at a monthly injection interval for a mean of 2.8 years were enrolled in the study. They underwent a GH secretory profile study with 10 min sampling for 24 h, 28 days after an injection. At 2, 4 and 6 weeks after the next injection fasting GH profiles (every 30 min for 3.5 h) and serum IGF-I measurements were measured. These investigations were repeated 12 months later, when the patients were on an individually titrated stable dose of lanreotide Autogel. RESULTS: Secretory characteristics and total 24 h GH secretion, estimated by deconvolution analysis of the 10 min 24 h plasma GH concentrations, did not show differences between these two long-acting somatostatin analogues. Both drugs were equally effective in GH and IGF-I suppression as measured at 2, 4 and also at 6 weeks following an injection. CONCLUSION: The efficacy of lanreotide Autogel and octreotide LAR was equal, notwithstanding that these drugs are administered in a different way and have different pharmacokinetics.