Association of Fetal Catecholamines With Neonatal Hypoglycemia.

Importance: Perinatal stress and fetal growth restriction increase the risk of neonatal hypoglycemia. The underlying pathomechanism is poorly understood. In a sheep model, elevated catecholamine concentrations were found to suppress intrauterine insulin secretion, followed by hyperresponsive insulin secretion once the adrenergic stimulus subsided. Objective: To determine whether neonates with risk factors for hypoglycemia have higher catecholamine concentrations in umbilical cord blood (UCB) and/or amniotic fluid (AF) and whether catecholamines are correlated with postnatal glycemia. Design, Setting, and Participants: In a prospective cohort study of 328 neonates at a tertiary perinatal center from September 2020 through May 2022 in which AF and UCB were collected immediately during and after delivery, catecholamines and metanephrines were analyzed using liquid chromatography with tandem mass spectrometry. Participants received postnatal blood glucose (BG) screenings. Exposure: Risk factor for neonatal hypoglycemia. Main Outcomes and Measures: Comparison of catecholamine and metanephrine concentrations between at-risk neonates and control participants, and correlation of concentrations of catecholamines and metanephrines with the number and severity of postnatal hypoglycemic episodes. Results: In this study of 328 neonates (234 in the risk group: median [IQR] gestational age, 270 [261-277] days; and 94 in the control group: median [IQR] gestational age, 273 [270-278] days), growth-restricted neonates showed increased UCB median (IQR) concentrations of norepinephrine (21.10 [9.15-42.33] vs 10.88 [5.78-18.03] nmol/L; P < .001), metanephrine (0.37 [0.13-1.36] vs 0.12 [0.08-0.28] nmol/L; P < .001), and 3-methoxytyramine (0.149 [0.098-0.208] vs 0.091 [0.063-0.149] nmol/L; P = .001). Neonates with perinatal stress had increased UCB median (IQR) concentrations of norepinephrine (22.55 [8.99-131.66] vs 10.88 [5.78-18.03] nmol/L; P = .001), normetanephrine (1.75 [1.16-4.93] vs 1.25 [0.86-2.56] nmol/L; P = .004), and 3-methoxytyramine (0.120 [0.085-0.228] vs 0.091 [0.063-0.149] nmol/L; P = .008) (P < .0083 was considered statistically significant). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were negatively correlated with AF C-peptide concentration (rs = -0.212, P = .005; rs = -0.182, P = .016; and rs = -0.183, P = .016, respectively [P < .017 was considered statistically significant]). Concentrations of UCB norepinephrine, metanephrine, and 3-methoxytyramine were positively correlated with the number of hypoglycemic episodes (BG concentration of 30-45 mg/dL) (rs = 0.146, P = .01; rs = 0.151, P = .009; and rs = 0.180, P = .002, respectively). Concentrations of UCB metanephrine and 3-methoxytyramine were negatively correlated with the lowest measured BG concentration (rs = -0.149, P = .01; and rs = -0.153, P = .008, respectively). Conclusions and Relevance: Neonates at risk for hypoglycemia displayed increased catecholamine and metanephrine concentrations that were correlated with postnatal hypoglycemic episodes and lower BG levels; these results are consistent with findings in a sheep model that fetal catecholamines are associated with neonatal ß-cell physiology and that perinatal stress or growth restriction is associated with subsequent neonatal hyperinsulinemic hypoglycemia. Improving the pathomechanistic understanding of neonatal hypoglycemia may help to guide management of newborns at risk for hypoglycemia.

Synovial Calprotectin is Superior to Synovial Leukocyte Count in Excluding Chronic Periprosthetic Joint Infections, a Retrospective Cohort Study.

BACKGROUND: Synovial calprotectin is a promising biomarker for diagnosing chronic periprosthetic joint infections (PJIs), but its diagnostic value has not been directly compared to synovial leukocyte count and polymorphonuclear neutrophils. This study aimed to: (1) evaluate and compare the diagnostic accuracy between these markers in patients undergoing revision arthroplasty for chronic PJI or aseptic reasons; and (2) determine the best rule-out and rule-in test for PJI. METHODS: Synovial fluid samples from patients undergoing revision arthroplasty in hip and knee joints were collected and analyzed. Patients diagnosed with an acute PJI, patients treated with antibiotics 2 weeks prior to revision surgery, and/or patients who had active inflammatory joint disease were excluded. Periprosthetic joint infections were diagnosed based on the presence of a sinus tract and/or positive intraoperative cultures according to the European Bone and Joint Infection Society microbiological criteria. RESULTS: A total of 137 patients were included, of whom 19 (14%) were diagnosed with a PJI. Overall, synovial calprotectin had the highest diagnostic accuracy of all studied markers (area under the curve 96%). Synovial calprotectin, with a cutoff of 50 mg/L, had the highest negative predictive value of 100%. However, PMNs (> 80%) combined with a leukocyte count (> 3,000 cells/µL) showed the highest positive predictive value of an infection (positive predictive value17). CONCLUSIONS: Synovial calprotectin is the most accurate biomarker for ruling out a chronic PJI, while the combination of synovial leukocyte count and PMN is most reliable for ruling in a chronic PJI.

Ischemia modified albumin as a marker of hypoxia in preterm infants in the first week after birth.

BACKGROUND: Tissue hypoxia remains a leading cause of morbidity and mortality in preterm infants. Current biomarkers often detect irreversible hypoxic cellular injury (i.e. lactate) and are non-specific. A new biomarker is needed which detects tissue hypoxia before irreversible damage occurs. AIMS: To investigate the relation between serum ischemia modified albumin (IMA), a marker of hypoxia; and analytic variables, patient related variables and conditions associated with hypoxia, in preterm infants. STUDY DESIGN: Retrospective cohort study. SUBJECTS: Infants with a gestational age < 30 weeks and/or birth weight < 1000 g. OUTCOME MEASURES: We collected two remnant blood samples in the first week after birth and measured IMA. IMA/albumin ratio (IMAR) was used to adjust for albumin. We assessed correlations between IMA(R) and analytic variables (albumin, lipemia- and haemolysis index); mean-2 h SpO2; mean-2 h variability of regional splanchnic oxygen saturation (rsSO2), measured using near-infrared spectroscopy; and patent ductus arteriosus (PDA). RESULTS: Sixty-five infants were included. Albumin, the lipemia- and haemolysis index correlated negatively with IMA (r:-0.620, P<0.001; r:-0.458, P<0.001; and r:-0.337, P=0.002). IMAR correlated negatively with SpO2 (rho:-0.614, P<0.001). Lower rsSO2 variability correlated with higher IMAR values (rho:-0.785, n=14, P=0.001 and rho:-0.773, n=11, P=0.005). Infants with a hemodynamic significant PDA (hsPDA) had higher IMAR values than infants without PDA (0.13 [0.11-0.28], n=16 vs. 0.11 [0.08-0.20], n=29, P=0.005 and 0.11 [0.09-0.18], n=13 vs. 0.09 [0.06-0.17], n=37, P=0.026). CONCLUSIONS: When adjusted for albumin, the lipemia- and haemolysis index, IMAR has potential value as a marker for systemic hypoxia in preterm infants, considering the associations with SpO2, variability of rsSO2, and hsPDA.

IGF-1 as screening tool for acromegaly and adult-onset growth hormone deficiency in the Netherlands.

OBJECTIVE: Insulin-like growth factor 1 (IGF-1) measurements play a central role in the diagnosis and follow-up of acromegaly and growth hormone deficiency. However, improving health care outcomes for these patients involves an intricate process of laboratory diagnostics and skilled health care professionals. The integrated effects of IGF-1 reports on diagnosis and treatment decisions are yet unknown. DESIGN, PATIENTS AND MEASUREMENTS: Extended quality assessment, distributing the description of five (real) patient cases with accompanying blood samples. Patients suspected or during follow up for acromegaly or adult onset of growth hormone deficiency were included. Laboratory specialists and endocrinologists in the same centre were asked to interpret their centre-specific IGF-1 results by using a laboratory and medical questionnaire. This way, insight could be obtained into the combined effects of different assays, assay harmonisation, reference value sets, and individual physician interpretation in relation to guidelines, thus reviewing the entire diagnostic and management process. RESULTS: Limited variation (CV 13.8 ± 2.8) was found in IGF-1 concentrations despite different use of the harmonization sample and factor among laboratories. This interlaboratory variation increased upon conversion to SD scores (CV 15.7 ± 40.7) as a consequence of the use of different reference value sets. Furthermore, there was a lack of adherence to international guidelines among endocrinologists. CONCLUSIONS: Highly variable diagnostic and treatment outcomes in acromegaly and AGHD in the Netherlands can be attributed to increased variability of IGF-1 upon conversion to SD scores and low adherence to clinical guidelines.

Hypothyroidism, comorbidity and health-related quality of life: a population-based study.

Hypothyroidism is associated with a decreased health-related quality of life (HRQoL). We hypothesized that individuals with hypothyroidism (defined as use of thyroid hormone (TH)) and especially those having an impaired HRQoL are characterized by a high prevalence of comorbid disorders and that the impact of hypothyroidism and comorbidity on HRQoL is synergistic. Presence of comorbidity was based on data obtained using structured questionnaires, physical examination, biochemical measurements and verified medication use. Single morbidities were clustered into 14 different disease domains. HRQoL was measured using the RAND-36. Logistic regression analyses were used to determine the effect of TH use on the odds of having an affected disease domain and a lower score than an age- and sex-specific reference value for HRQoL. TH was used by 4537/14,7201 participants of the population-based Lifelines cohort with a mean (± s.d.) age of 51.0 ± 12.8 years (88% females). Eighty-five percent of the TH users had ≥1 affected disease domain in contrast to 71% of nonusers. TH use was associated with a higher odds of 13 out of 14 affected disease domains independent of age and sex. In a multivariable model, TH use was associated with a decreased HRQoL across six out of eight dimensions. No significant interactions between TH use and affected disease domains were observed. TH users with an impaired HRQoL had significantly more comorbidity than those not having an impaired HRQoL. In this large, population-based study, we demonstrated that TH users had more comorbidity than individuals not using TH. The coexistence of other chronic medical conditions in subjects with TH use led to further lowering of HRQoL in an additive manner.

Unexpected high troponin T and I values in a child with hypertrophic cardiomyopathy and acute chest pain: a case report.

Background: Elevated troponin T (cTnT) and/or troponin I (cTnI) can be ascribed to multiple causes, mostly resulting from cardiac tissue damage and in lesser numbers resulting from non-cardiac related causes. The presence of macrotroponins is easily overlooked, with potentially negative consequences. Case summary: This case report presents a case study of a 12-year-old child known to have MYH7 gene-associated hypertrophic cardiomyopathy with acute chest pain combined with an unexpected high cTnT and cTnI. A cardiac cause was deemed unlikely after additional investigation, as these showed no abnormalities. After consulting a laboratory specialist, it could be concluded that the high cTnT and cTnI were a result of macrotroponin complexes, a protein complex consisting of circulating protein and endogenous autoantibodies against that protein, resulting in elevated values with misguiding and uncertain clinical significance. Discussion: Awareness of the existence of macrotroponins could have prevented costly diagnostics and prolonged hospital admission with grave psychological impact, especially in children.

Systemic Oxidative Stress in Severe Early-Onset Fetal Growth Restriction Associates with Concomitant Pre-Eclampsia, Not with Severity of Fetal Growth Restriction.

BACKGROUND: Placental insufficiency is an important mechanism underlying early-onset fetal growth restriction (eoFGR). Reduced placental function causes impaired metabolic and gaseous exchange. This unfavorable placental environment is among other processes characterized by increased oxidative stress. Systemic free thiols (FT) are known for their reactive oxygen species scavenging capacity, and higher plasma levels of FT are associated with a better outcome in a multitude of ischemic and inflammatory diseases. We aimed to investigate the relationships between systemic FT levels and maternal and perinatal clinical characteristics and outcomes. STUDY DESIGN: In a post hoc analysis of the Dutch Strider study, a cohort of women with eoFGR, we investigated the association between the maternal redox status (FT) levels at study inclusion, placental biomarkers, and maternal and neonatal outcomes in 108 patients. RESULTS: FT were significantly lower in pregnancies complicated with eoFGR with concurrent maternal hypertensive disorders (pregnancy-induced hypertension; ρ = -0.281 p = 0.004, pre-eclampsia; ρ = -0.505 p = 0.000). In addition, lower FT levels were significantly associated with higher systolic (ρ = -0.348 p = 0.001) and diastolic blood pressure (ρ = -0.266 p = 0.014), but not with the severity of eoFGR. FT levels were inversely associated with sFlt (ρ = -0.366, p < 0.001). A strong relation between systemic FT levels and PlGF levels was observed in women with pre-eclampsia at delivery (ρ = 0.452, p = 0.002), which was not found in women without hypertensive disorders (ρ = 0.008, p = 0.958). CONCLUSIONS: In women with pregnancies complicated with eoFGR, FT levels reflect the severity of maternal disease related to the underlying placental insufficiency rather than the severity of the placental dysfunction as reflected in eoFGR or perinatal outcomes.

Clinical irrelevance of lower titer thyroglobulin autoantibodies in patients with differentiated thyroid carcinoma.

Objective: Thyroglobulin (Tg) is an established tumor marker for differentiated thyroid carcinoma (DTC) patients. However, Tg immunoassays can be subject to Tg autoantibody (TgAb) interference resulting in incorrect Tg values. Therefore, Tg measurement with liquid chromatography-tandem mass spectrometry (LC-MS/MS) could be promising in patients with TgAbs. In this study, we compared Tg IRMA and Tg-LC-MS/MS analytically in the presence of TgAbs. Furthermore, we compared the clinical interpretation of results obtained by both Tg assays in DTC patients with lower TgAbs titers (<10 U/mL) during 131I ablation therapy. Methods: Totally 118 DTC patients diagnosed between 2006 and 2014 in a University Medical Center were followed with the Tg-IRMA (Thermo Fischer Scientific) and ARCHITECT anti-Tg (Abbott Laboratories) assays. We re-analyzed their samples with a sensitive Tg-LC-MS/MS method (Labcorp, limit of quantification of 0.02 ng/mL). Passing-Bablok regression analysis was performed on samples obtained during 131I ablation therapy and follow-up. Results: In 304 samples with lower TgAb titers, a good analytical agreement was found between both Tg assays (slope of 1.09 (95% CI: 1.05-1.16)). Fifty-five samples with potentially interfering TgAbs showed higher Tg-LC-MS/MS values than Tg-IRMA (slope of 1.45 (95% CI: 1.12->>100)). In patients(n = 91) with lower TgAb titers at the time of 131I ablation therapy, the Tg assays showed a clinical concordance of 91.2, 87.9, and 98.9%, respectively, using a Tg cut-off value of 1.0, 2.0, and 5.0 ng/mL. Conclusions: In DTC patients with lower titer TgAbs, Tg-IRMA is still a reliable and useful tumor marker. In DTC patients with potentially interfering TgAbs, Tg-IRMA values decreased due to TgAb interference.

Progressive diastolic dysfunction in survivors of pediatric differentiated thyroid carcinoma.

Background: Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. Methods: This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e' mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Results: Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8-60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2-48.8). Between the first and second evaluation, the e' mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e' mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e' mean (ß coefficient: -0.169, 95% CI: -0.292; -0.047, P = 0.008 and ß coefficient: -0.177, 95% CI: -0.240; -0.113, P < 0.001, respectively). Conclusions and relevance: In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Prenatal Environmental Exposure to Persistent Organic Pollutants and Reproductive Hormone Profile and Pubertal Development in Dutch Adolescents.

Persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), may interfere with hormonal processes. Knowledge about the effects of prenatal exposure to PCBs and their hydroxylated metabolites (OH-PCBs) on pubertal development is limited. Therefore, the aim of the current study was to determine whether prenatal environmental PCB and OH-PCB exposure are associated with reproductive hormone levels and pubertal characteristics in 13- to 15-year-old children. In this Dutch observational cohort study, 194 mother-infant pairs were included (1998-2002). Maternal pregnancy serum levels of PCBs, OH-PCBs, and other POPs were measured. At follow-up (2014-2016), we measured serum or plasma levels of reproductive hormones in their children. We assessed Tanner stages and testicular volume (by clinician or standardized self-assessment), and participants completed questionnaires on pubertal onset. In total, 101 adolescents (14.4 ± 0.8 years; 53.7% of invited) participated, and 55 were boys. In boys, higher prenatal PCB levels were associated with higher testosterone levels, higher pubic hair stage, larger testicular volume, and younger age at onset of growth spurt and voice break. In girls, higher prenatal PCB levels were associated with higher stages for breast development. In conclusion, higher prenatal PCB exposure could be associated with more advanced pubertal development in 13- to 15-year-old children.

Impact of Preanalytical Factors on Calprotectin Concentration in Stool: A Multiassay Comparison.

BACKGROUND: Measuring calprotectin concentration in stool is increasingly important in monitoring disease activity and treatment response in inflammatory bowel disease. This study evaluates the impact of preanalytical storage conditions on reliability of calprotectin testing using 5 different calprotectin immunoassays. METHODS: Aliquots of homogenized fresh fecal samples in untreated or extracted form were stored at room temperature or 4°C. Calprotectin concentration was measured day 0 to 4 and 8. Five different immunoassays and accompanying extraction buffers were used (CALiaGold, Phadia EliA, Bühlmann fCal turbo, ELISA Bühlmann, Inova Quanta Flash). Repeated measurements of change from baseline calprotectin levels over time were analyzed using a mixed model analysis. RESULTS: Calprotectin concentrations declined over time under all preanalytical conditions with all assays, except for extracted feces stored at 4°C. The rate of decline was greatest in untreated stool kept at room temperature, reaching significant difference from baseline already after 1 day (P < 0.001). In extracted feces kept at room temperature, significant difference from baseline was reached after 2 days, and in untreated feces at 4°C, after 4 days. However, the results differed significantly between assays. After 4 days of storage at room temperature, the mean calprotectin decline from baseline differed between 30% and 60%, dependent on the assay used. CONCLUSIONS: Fecal calprotectin concentration in stool samples declines over time, and the rate of decline is greater at higher temperatures. In extracted feces stored at 4°C, calprotectin is most stable. It is assay-dependent how long extracted feces stored at 4°C give reliable test results.

Mediators of Obesity Do Not Influence SARS-CoV-2 Infection or Activation of Primary Human Lung Microvascular Endothelial Cells In Vitro.

Clinical observations have shown that obesity is associated with the severe outcome of SARS-CoV-2 infection hallmarked by microvascular dysfunction in the lungs and other organs. Excess visceral fat and high systemic levels of adipose tissue (AT) derived mediators such as leptin and other adipokines have also been linked to endothelial dysfunction. Consequently, we hypothesized that AT-derived mediators may exacerbate microvascular dysfunction during of SARS-CoV-2 infection and tested this in a primary human lung microvascular endothelial (HLMVEC) cell model. Our results indicate that HLMVEC are not susceptible to SARS-CoV-2 infection since no expression of viral proteins and no newly produced virus was detected. In addition, exposure to the virus did not induce endothelial activation as evidenced by a lack of adhesion molecule, E-selectin, VCAM-1, ICAM-1, and inflammatory cytokine IL-6 induction. Incubation of endothelial cells with the pro-inflammatory AT-derived mediator, leptin, prior to virus inoculation, did not alter the expression of endothelial SARS-CoV-2 entry receptors and did not alter their susceptibility to infection. Furthermore, it did not induce inflammatory activation of endothelial cells. To verify if the lack of activated phenotype in the presence of adipokines was not leptin-specific, we exposed endothelial cells to plasma obtained from critically ill obese COVID-19 patients. Plasma exposure did not result in E-selectin, VCAM-1, ICAM-1, or IL-6 induction. Together our results strongly suggest that aberrant inflammatory endothelial responses are not mounted by direct SARS-CoV-2 infection of endothelial cells, even in the presence of leptin and other mediators of obesity. Instead, endothelial activation associated with COVID-19 is likely a result of inflammatory responses initiated by other cells. Further studies are required to investigate the mechanisms regulating endothelial behavior in COVID-19 and the mechanisms driving severe disease in obese individuals.

Macro-B12 masking B12 deficiency.

In clinical practice, the finding of an elevated serum B12 concentration is often the consequence of supplementation with B12 in either oral form or injections. Also, elevated serum B12 may be associated with underlying disorders, like liver diseases or a (haematologic) malignancy. Only a few studies have shown that it may also be the consequence of complex formation of B12-vitamin binding proteins with immunoglobulins, the so-called macro-B12 We describe a young woman who previously was diagnosed with B12 deficiency, and in whom, after cessation of B12 injection treatment, neurologic symptoms re-appeared, and despite this, repeatedly elevated serum B12 concentrations above the upper limit of the assay were found. We demonstrated that this was caused by the presence of macro-B12, which not only resulted in erroneous and longstanding elevated serum B12, but also masked her underlying B12 deficiency.

Low-Iodine Diet of 4 Days Is Sufficient Preparation for 131I Therapy in Differentiated Thyroid Cancer Patients.

CONTEXT: No consensus exists about the optimal duration of the low-iodine diet (LID) in the preparation of 131I therapy in differentiated thyroid cancer (DTC) patients. OBJECTIVE: This work aimed to investigate if a LID of 4 days is enough to achieve adequate iodine depletion in preparation for 131I therapy. In addition, the nutritional status of the LID was evaluated. METHODS: In this prospective study, 65 DTC patients treated at 2 university medical centers were included between 2018 and 2021. The patients collected 24-hour urine on days 4 and 7 of the LID and kept a food diary before and during the LID. The primary outcome was the difference between the 24-hour urinary iodine excretion (UIE) on both days. RESULTS: The median 24-hour UIE on days 4 and 7 of the LID were not significantly different (36.1 mcg [interquartile range, 25.4-51.2 mcg] and 36.5 mcg [interquartile range, 23.9-47.7 mcg], respectively, P = .43). On day 4 of the LID, 72.1% of the DTC patients were adequately prepared (24-hour UIE < 50 mcg), and 82.0% of the DTC patients on day 7 (P = .18). Compared to the self-reported regular diet, DTC patients showed a significantly (P < .01) lower percentage of nutrient intake (calories, protein, calcium, iodine, and water) during the LID. CONCLUSION: The 24-hour UIE on day 4 of the LID did not differ from day 7, and therefore shortening the LID from 7 to 4 days seems justified to prepare DTC patients for 131I therapy in areas with sufficient iodine intake and may be beneficial to maintain a sufficient nutritional intake during DTC treatment.

Bone Mineral Density in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma: A Longitudinal Follow-Up Study.

Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [ß-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers ß-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Oxidative stress biomarkers in fetal growth restriction with and without preeclampsia.

INTRODUCTION: Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics. METHODS: A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed. RESULTS: Mothers with both severe FGR and PE had significantly reduced FT levels (p < 0.001) and PlGF levels (p < 0.001), and increased levels of plasma IMA (p < 0.05), sFlt (p < 0.001), leptin (p < 0.05) and sRAGE (p < 0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p < 0.01) and plasma IMA (p < 0.001), leptin (p = 0.01) and sRAGE (p < 0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only. DISCUSSION: There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.

Long-term male fertility after treatment with radioactive iodine for differentiated thyroid carcinoma.

CONTEXT: Whilst radioactive iodine (RAI) is often administered in the treatment for differentiated thyroid carcinoma (DTC), long-term data on male fertility after RAI are scarce. OBJECTIVE: To evaluate long-term male fertility after RAI for DTC, and to compare semen quality before and after RAI. DESIGN, SETTING, AND PATIENTS: Multicenter study including males with DTC ≥2 years after their final RAI treatment with a cumulative activity of ≥3.7 GBq. MAIN OUTCOME MEASURE(S): Semen analysis, hormonal evaluation, and a fertility-focused questionnaire. Cut-off scores for 'low semen quality' were based on reference values of the general population as defined by the World Health Organization (WHO). RESULTS: Fifty-one participants had a median age of 40.5 (interquartile range (IQR): 34.0-49.6) years upon evaluation and a median follow-up of 5.8 (IQR: 3.0-9.5) years after their last RAI administration. The median cumulative administered activity of RAI was 7.4 (range: 3.7-23.3) GBq. The proportion of males with a low semen volume, concentration, progressive motility, or total motile sperm count did not differ from the 10th percentile cut-off of a general population (P = 0.500, P = 0.131, P = 0.094, and P = 0.500, respectively). Cryopreserved semen was used by 1 participant of the 20 who had preserved semen. CONCLUSIONS: Participants had a normal long-term semen quality. The proportion of participants with low semen quality parameters scoring below the 10th percentile did not differ from the general population. Cryopreservation of semen of males with DTC is not crucial for conceiving a child after RAI administration but may be considered in individual cases.

Circulating adrenomedullin and B-type natriuretic peptide do not predict blood pressure fluctuations during pheochromocytoma resection: a cross-sectional study.

BACKGROUND: Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection. METHODS: Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events. RESULTS: A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41-0.63) nmol/L and 68.7 (27.9-150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P =0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P =0.013 and OR: 1.54, P =0.017, respectively). CONCLUSIONS: plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.