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

Use of Salivary Iodine Concentrations to Estimate the Iodine Status of Adults in Clinical Practice

BACKGROUND: Measurement of the 24-h urinary iodine concentration or urinary iodine excretion (UIE) is the gold standard to determine iodine status; however, this method is inconvenient. The use of salivary iodine could be a possible alternative since salivary glands express the sodium-iodine symporter. OBJECTIVES: We aimed to establish the correlation between the salivary iodine secretion and UIE, to evaluate the clinical applicability of the iodine saliva measurement. METHODS: We collected 24-h urine and saliva samples from 40 participants ≥18 y: 20 healthy volunteers with no specific diet (group 1), 10 patients with differentiated thyroid cancer with a low dietary intake (<50 μg/d, group 2), and 10 patients with a high iodine status as the result of the use of amiodarone (group 3). Urinary and salivary iodine were measured using a validated inductively coupled plasma MS method. To correct for differences in water content, the salivary iodine concentration (SIC) was corrected for salivary protein and urea concentrations (SI/SP and SI/SU, respectively). The intra- and inter-individual CVs were calculated, and the Kruskal-Wallis test and Spearman's correlation were used. RESULTS: The intra-individual CVs for SIC, SI/SP, and SI/SU were 63.8%, 37.7%, and 26.9%, respectively. The inter-individual CVs for SIC, SI/SP, and SI/SU were 77.5%, 41.6% and 47.0%, respectively. We found significant differences (P < 0.01) in urinary and salivary iodine concentrations between all groups [the 24-h UIE values were 176 μg/d (IQR, 96.1–213 μg/d), 26.0 μg/d (IQR, 22.0–37.0 μg/d), and 10.0*10(3) μg/d (IQR, 7.57*10(3)–11.4*10(3) μg/d) in groups 1–3, respectively; the SIC values were 136 μg/L (IQR, 86.3–308 μg/L), 71.5 μg/L (IQR, 29.5–94.5 μg/L), and 14.3*10(3) μg/L (IQR, 10.6*10(3)–25.6*10(3) μg/L) in groups 1–3, respectively]. Correlations between the 24-h UIE and SIC, SI/SP, and SI/SU values were strong (ρ = 0.80, ρ = 0.90, and ρ = 0.86, respectively; P < 0.01). CONCLUSIONS: Strong correlations were found between salivary and urinary iodine in adults with different daily iodine intakes. A salivary iodine measurement can be performed to assess the total iodine body pool, with the recommendation to correct for salivary protein or urea

Onset of hypothyroidism after total laryngectomy:Effects of thyroid gland surgery and preoperative and postoperative radiotherapy

Background: To determine time of onset and risk of hypothyroidism after total laryngectomy (TL) with and without (hemi)thyroidectomy in relation to treatment regimen, that is, preoperative radiotherapy (RT-TL), postoperative radiotherapy (TL-RT), and postoperative re-irradiation (RT-TL-RT). Methods: Retrospective review of 128 patients treated by RT-TL (51 patients), TL-RT (55 patients), and RT-TL-RT (22 patients). Risk of hypothyroidism was determined by multivariable Cox regression analysis and euthyroid survival was calculated using Kaplan-Meier method. Results: Hypothyroidism developed in 69 (54%) patients. The median onset of hypothyroidism was later (P <.01) and the risk of hypothyroidism was lower (hazard ratio 0.49; P =.014) in the TL-RT group compared to both other treatment regimens. Euthyroid survival did not differ between the treatment regimens. Two years euthyroid survival was 24% with and 61% without (hemi)thyroidectomy (P <.001). Conclusions: Patients treated with TL-RT have later onset of hypothyroidism. Higher risk for hypothyroidism is associated with salvage TL after radiotherapy and (hemi)thyroidectomy

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

CONTEXT: No consensus exists about the optimal duration of the low-iodine diet (LID) in the preparation of (131)I 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 (131)I 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 (131)I therapy in areas with sufficient iodine intake and may be beneficial to maintain a sufficient nutritional intake during DTC treatment

Cigarette smoking is associated with higher thyroid hormone and lower TSH levels:The PREVEND study

PURPOSE: The extent to which smoking is associated with thyroid stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) when taking account of clinical variables including alcohol consumption is unclear. We aimed to determine associations of TSH, FT4, and FT3 levels with current smoking. METHODS: A cross-sectional study was performed in 5766 euthyroid participants (Prevention of Renal and Vascular End-Stage Disease cohort). Current smoking was determined by self-report, categorized as never, former, and current (≤20 and >20 cigarettes per day). Smoke exposure was determined by urinary cotinine. RESULTS: Current smoking of ≤20 and >20 cigarettes per day was associated with lower TSH and higher FT3 levels. FT4 levels were higher in subjects smoking 20 cigarettes per day. In agreement, TSH was inversely, whereas FT4 and FT3 levels were positively associated with urinary cotinine (P 30 g per day conferred higher TSH and lower FT3 levels. CONCLUSIONS: Cigarette smoking is associated with modestly higher FT4 and FT3, and lower TSH levels, partly opposing effects of alcohol consumption

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

The effect of metformin on cardiovascular risk profile in patients without diabetes presenting with acute myocardial infarction:data from the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) trial

Objective: In patients with diabetes mellitus, metformin treatment is associated with reduced mortality and attenuation of cardiovascular risk. As a subanalysis of the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) study, we evaluated whether metformin treatment in patients with ST-segment elevation myocardial infarction (STEMI) without diabetes improves the cardiovascular risk profile. Methods: A total of 379 patients, without known diabetes, presenting with STEMI were randomly allocated to receive metformin 500 mg twice daily or placebo for 4 months. Results: After 4 months, the cardiovascular risk profile of patients receiving metformin (n= 172) was improved compared with placebo (n= 174); glycated hemoglobin (5.83% (95% CI 5.79% to 5.87%) vs 5.89% (95% CI 5.85% to 5.92%); 40.2 mmol/mol (95% CI 39.8 to 40.6) vs 40.9 mmol/mol (40.4 to 41.2), p= 0.049); total cholesterol (3.85 mmol/L (95% CI 3.73 to 3.97) vs 4.02 mmol/L (95% CI 3.90 to 4.14), p= 0.045); low-density lipoprotein cholesterol (2.10 mmol/L (95% CI 1.99 to 2.20) vs 2.3 mmol/L (95% CI 2.20 to 2.40), p= 0.007); body weight (83.8 kg (95% CI 83.0 to 84.7) vs 85.2 kg (95% CI 84.4 to 86.1), p= 0.024); body mass index (26.8 kg/m(2) (95% CI 26.5 to 27.0) vs 27.2 kg/m(2) (95% CI 27.0 to 27.5), p= 0.014). Levels of fasting glucose, postchallenge glucose, insulin, high-density lipoprotein cholesterol, and blood pressure were similar in both groups. Conclusions: Among patients with STEMI without diabetes, treatment with metformin for 4 months resulted in a modest improvement of the cardiovascular risk profile compared with placebo

A Genome-Wide Association Study of Circulating Galectin-3

Galectin-3 is a lectin involved in fibrosis, inflammation and proliferation. Increased circulating levels of galectin-3 have been associated with various diseases, including cancer, immunological disorders, and cardiovascular disease. To enhance our knowledge on galectin-3 biology we performed the first genome-wide association study (GWAS) using the Illumina HumanCytoSNP-12 array imputed with the HapMap 2 CEU panel on plasma galectin-3 levels in 3,776 subjects and follow-up genotyping in an additional 3,516 subjects. We identified 2 genome wide significant loci associated with plasma galectin-3 levels. One locus harbours the LGALS3 gene (rs2274273; P = 2.35 × 10(-188)) and the other locus the ABO gene (rs644234; P = 3.65 × 10(-47)). The variance explained by the LGALS3 locus was 25.6% and by the ABO locus 3.8% and jointly they explained 29.2%. Rs2274273 lies in high linkage disequilibrium with two non-synonymous SNPs (rs4644; r(2) = 1.0, and rs4652; r(2) = 0.91) and wet lab follow-up genotyping revealed that both are strongly associated with galectin-3 levels (rs4644; P = 4.97 × 10(-465) and rs4652 P = 1.50 × 10(-421)) and were also associated with LGALS3 gene-expression. The origins of our associations should be further validated by means of functional experiments

Variability of biomarkers in patients with chronic heart failure and healthy controls

Aims Biomarkers can be used for diagnosis, risk stratification, or management of patients with heart failure (HF). Knowledge about the biological variation is needed for proper interpretation of serial measurements. Therefore, we aimed to determine and compare the biological variation of a large panel of biomarkers in healthy subjects and in patients with chronic HF. Methods and results The biological variability of established biomarkers [NT-proBNP and high-sensitivity troponin T (hsTnT)], novel biomarkers [galectin-3, suppression of tumorigenicity 2 (ST2), and growth differentiation factor 15 (GDF-15)], and renal/neurohormonal biomarkers (aldosterone, phosphate, parathyroid hormone, plasma renin concentration, and creatinine) was determined in 28 healthy subjects and 83 HF patients, over a period of 4 months and 6 weeks, respectively. The analytical (CVa), intraindividual (CVi), and interindividual (CVg) variations were calculated, as well as the reference change value (RCV), which reflects the percentage of change that may indicate a 'relevant' change. All crude biomarker levels were significantly increased or decreased in HF patients compared with controls (all P <0.01). Variation indices were comparable in healthy individuals and HF patients. CVi was not influenced by the individual levels of the biomarker itself. NT-proBNP and GDF-15 had relatively high CVi (21.8% and 16.6%) and RCV (61.7% and 64.3%), whereas ST2 (CVi, 15.0; RCV, 42.9%), hsTnT (CVi, 11.1; RCV, 31.4%), and galectin-3 (CVi, 8.1; RCV, 25.0%) had lower indices of variation. Conclusion Biological variation indices are comparable between healthy subjects and HF patients for a broad spectrum of biomarkers. NT-proBNP and GDF-15 have substantial variation, with lower variation for ST2, hsTnT, and galectin-3. These data are instrumental in proper interpretation of biomarker levels in HF patients

Age dependency of plasma vitamin B12 status markers in Dutch children and adolescents

BACKGROUND: Vitamin B12 deficiency in children may be associated with (severe) neurological manifestations, therefore recognition is important. Diagnosing vitamin B12 deficiency in children is challenging. This study aimed to investigate plasma methylmalonic acid, holotranscobalamin, and total cobalamin in children 0–18 years of age and to estimate age-dependent reference intervals. METHODS: Plasma vitamin B12 markers were measured in collected plasma samples of 170 children 0–18 years visiting a local primary care laboratory. All had within-reference hemoglobin and MCV values. Pediatric plasma vitamin B12 biomarkers were measured and reference values were derived thereof. RESULTS: Plasma methylmalonic acid was higher in young children, in particular between 1 and 6 months of age; total cobalamin and holotranscobalamin were highest from 0.5 to 4 years and decreased till 10 years of age. Plasma holotranscobalamin was highly correlated with plasma total cobalamin; their ratio was independent of age. Plasma methylmalonic acid was slightly more related to total cobalamin than to holotranscobalamin. A large proportion of mainly young children would be misclassified when adult references are applied. CONCLUSIONS: Pediatric reference values for cobalamin markers are necessary to allow for early recognition and monitoring of children suspect of (clinical) cobalamin deficiency. IMPACT: We analyzed three plasma vitamin B12 status markers, i.e., total cobalamin, holotranscobalamin, and methylmalonic acid, in the plasma of 170 children 0–18 years of age and were able to derive reference intervals thereof. Recognition of vitamin B12 deficiency in children is important but challenging as pediatric reference intervals for plasma vitamin B12 status markers, particularly plasma holotranscobalamin, are not well described. We think that our results may help early recognition and monitoring of children suspect of (clinical) vitamin B12 deficiency