Maternal iodine deficiency: a newborns' overweight risk factor? A prospective study.

OBJECTIVES: Childhood obesity and iodine deficiency are global public health concerns. Whether maternal iodine status mediates overweight in infancy has yet to be explored. We aimed to assess the relationship between maternal iodine status and infant birth weight, including small and large for gestational age (SGA and LGA, respectively). METHODS: A prospective study was carried out among 134 mother-infant pairs from Israel. Maternal iodine intake and status were estimated via questionnaire and serum thyroglobulin (Tg), respectively. Estimated iodine intake below the Recommended Daily Allowance for iodine sufficiency in pregnancy (220 µg/d) considered Inadequate. Maternal and neonatal thyroid function and anthropometric measurements, as well as maternal thyroid antibodies were also tested. RESULTS: After screening, 118 participants met the inclusion criteria (distributed trimesters I, II and III: n = 3, n = 21, and n = 94, respectively). There was a negative association of iodine intake with Tg values among the study population. Maternal median Tg value was higher than the sufficiency cutoff (16.5 vs 13 µg/L), indicating insufficient iodine status. No SGA cases were found. Inadequate iodine intake was associated with maternal isolated hypothyroxinemia (OR = 3.4; 95% CI 1.2, 9.9) and higher birthweight (including macrosomia and LGA) rates. A suggestive association of elevated Tg with a greater risk of LGA was observed. Offsprings' birth weight percentiles were associated with Tg values in pregnant women with suggestive sufficient iodine status (n = 62, R2 = 0.11, p < 0.05). CONCLUSIONS: Iodine status during pregnancy can be associated with newborn anthropometric index. Maternal inadequate iodine intake may alter fetal growth and might increase the risk of LGA among newborns. These initial findings support the need to further study the impact of iodine deficiency on newborns overweight in Israel and elsewhere.

Low intake of iodized salt and iodine containing supplements among pregnant women with apparently insufficient iodine status - time to change policy?

BACKGROUND: Iodine is an essential nutrient for human health throughout the life cycle, especially during early stages of intrauterine life and infancy, to ensure adequate neurocognitive development. The growing global reliance on desalinated iodine-diluted water raises the specter of increased iodine deficiency in several regions. The case of Israel may be instructive for exploring the link between iodine status and habitual iodine intake in the setting of extensive national reliance on desalinated water. The aim of this study was to explore the relationship between iodine intake, including iodized salt and iodine-containing supplements intake, and iodine status among pregnant women residing in a sub-district of Israel that is highly reliant on desalinated iodine-diluted water. METHODS: A total of 134 consecutive pregnant women were recruited on a voluntary basis from the obstetrics department of the Barzilai University Medical Center during 2018. Blood was drawn from participants to determine levels of serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyroglobulin (Tg). An iodine food frequency questionnaire (sIFFQ) was used to assess iodine intake from food, IS and ICS. A questionnaire was used to collect data on demographic and health characteristics. RESULTS: A total of 105 pregnant women without known or reported thyroid disease were included in the study. Elevated Tg values (≥ 13 µg/L), were found among 67% of participants, indicating insufficient iodine status. The estimated iodine intake (median, mean ± SD 189, 187 ± 106 µg/d by sIFFQ) was lower than the levels recommended by the World Health Organization and the Institute of Medicine (250 vs. 220 µg/day respectively). The prevalence of iodized salt intake and iodine containing supplement intake were 4 and 52% (respectively). Values of Tg > 13 µg/L were inversely associated with compliance with World Health Organization and Institute of Medicine recommendations. CONCLUSIONS: While the Israeli Ministry of Health has recommended the intake of iodized salt and iodine containing supplements, this is apparently insufficient for achieving optimal iodine status among Israeli pregnant women. The evidence of highly prevalent probable iodine deficiency in a sample of pregnant women suggests an urgent need for a national policy of iodized salt regulation, as well as guidelines to promote iodine containing supplements and adherence to them by caregivers. In addition, studies similar to this one should be undertaken in additional countries reliant on desalinated iodine-diluted water to further assess the impact of desalinization on maternal iodine status.

Can desalinated seawater contribute to iodine-deficiency disorders? An observation and hypothesis.

OBJECTIVE: Over 300 million people rely on desalinated seawater and the numbers are growing. Desalination removes iodine from water and could increase the risk of iodine-deficiency disorders (IDD). The present study assessed the relationship between iodine intake and thyroid function in an area reliant on desalination. DESIGN: A case-control study was performed between March 2012 and March 2014. Thyroid function was rigorously assessed by clinical examination, ultrasound and blood tests, including serum thyroglobulin (Tg) and autoimmune antibodies. Iodine intake and the contribution made by unfiltered tap water were estimated by FFQ. The contribution of drinking-water to iodine intake was modelled using three iodine concentrations: likely, worst-case and best-case scenario. SETTING: The setting for the study was a hospital located on the southern Israeli Mediterranean coast. SUBJECTS: Adult volunteers (n 102), 21-80 years old, prospectively recruited. RESULTS: After screening, seventy-four participants met the inclusion criteria. Thirty-seven were euthyroid controls. Among those with thyroid dysfunction, twenty-nine were classified with non-autoimmune thyroid disease (NATD) after excluding eight cases with autoimmunity. Seventy per cent of all participants had iodine intake below the Estimated Average Requirement (EAR) of 95 µg/d. Participants with NATD were significantly more likely to have probable IDD with intake below the EAR (OR=5·2; 95 % CI 1·8, 15·2) and abnormal serum Tg>40 ng/ml (OR=5·8; 95 % CI 1·6, 20·8). CONCLUSIONS: Evidence of prevalent probable IDD in a population reliant on desalinated seawater supports the urgent need to probe the impact of desalinated water on thyroid health in Israel and elsewhere.

[SERUM THYROGLOBULIN LEVELS AND ESTIMATED IODINE INTAKE IN ADULTS EXPOSED TO IODINE­DILUTED DESALINATED DRINKING WATER].

AIMS: The aim of this study was to describe thyroglobulin levels and iodine intake estimations in a convenience sample of Israeli adults without TD in the Ashkelon District, where SWRO desalination has become the major source of drinking water. BACKGROUND: Iodine deficiency (ID) is a significant risk factor for thyroid disease (TD). Recently, there were increases in both selfreported use of TD medication among Israeli adults and the national use of sea water reverse osmosis (SWRO) desalinated water. METHODS: Iodine concentrations in tap water (supplied by Mekorot Israel National Water Co.) were estimated before and after SWRO desalination was implemented in the Ashkelon District. Volunteers were recruited at the Barzilai Medical Center Ashkelon between January 2012 and October 2013. Data regarding residency, BMI and use of iodine-containing or steroidal drugs were obtained for all volunteers. Blood was drawn from matching participants for determination of serum thyrotropin, thyroid peroxidase antibodies, thyroglobulin (Tg) antibodies and Tg. A semi-quantitative iodine food frequency questionnaire (sIFFQ) was administered. RESULTS: Iodine concentration estimation in tap water declined from 52 µg/L to 27 µg/L after SWRO desalination was implemented in the Ashkelon District. A total of 50 participants without reported or known TD were included in the study after screening 92 volunteers. The median serum Tg was 21 ng/mL, and 76% (35 participants) had elevated values (Tg ≥ 10 ng/mL), indicating a high prevalence of apparent ID. Iodine intake estimation (median 99 µg/d by sIFFQ) was lower than the Recommended Dietary Allowance (150 µg/d). Unfiltered tap water was estimated to provide 16% of the mean daily iodine intake. CONCLUSIONS: The finding of apparent ID in this sample, underscores the need to obtain further data regarding many other regions across Israel. This is particularly urgent in the context of Israel's increased dependence on SWRO desalination.

Elevated Serum Thyroglobulin and Low Iodine Intake Are Associated with Nontoxic Nodular Goiter among Adults Living near the Eastern Mediterranean Coast.

Background. Information about iodine intake is crucial for preventing thyroid diseases. Inadequate iodine intake can lead to thyroid diseases, including nontoxic nodular goiter (NNG). Objective. To estimate iodine intake and explore its correlation with thyroid diseases among Israeli adults living near the Mediterranean coast, where iodine-depleted desalinated water has become a major source of drinking water. Methods. Cross-sectional study of patients attending Barzilai Medical Center Ashkelon. Participants, who were classified as either NNG (n = 17), hypothyroidism (n = 14), or control (n = 31), provided serum thyroglobulin (Tg) and completed a semiquantitative iodine food frequency questionnaire. Results. Elevated serum Tg values (Tg > 60 ng/mL) were significantly more prevalent in the NNG group than in the other groups (29% versus 7% and 0% for hypothyroidism and controls, resp., P < 0.05). Mean estimated iodine intake was significantly lower in the NNG group (65 ± 30 µg/d) than in controls (115 ± 60 µg/d) (P < 0.05) with intermediate intake in the hypothyroid group (73 ± 38 µg/d). Conclusions. Elevated serum Tg values and low dietary iodine intake are associated with NNG among adult patients in Ashkelon District, Israel. Larger studies are needed in order to expand on these important initial findings.

Evaluation of bone density in girls with precocious and early puberty during treatment with GnRH agonist.

BACKGROUND: Major changes in bone status occur during puberty. Most longitudinal studies have shown no impairment in bone mineral density (BMD) in girls with precocious (PP) and early puberty (EP) during and after GnRH agonist therapy. METHODS: In the present study we evaluated BMD, bone strength (BS) and bone metabolism in 26 girls with PP and with EP before and during treatment with GnRH agonist. BMD was measured by dual energy X-ray absorptiometry and BS was measured using the quantitative high frequency ultrasound technique at baseline, after 6 and 12 months from onset of therapy. Variables were compared with age- and sex-matched values of the same population. Biochemical markers of bone turnover were measured at the same intervals. RESULTS: Mean lumbar spine (LS) and femoral neck (FN) BMD were significantly lower at baseline (LS: p < 0.0001, FN: p < 0.0017) compared with age-matched reference values. Bone strength was significantly lower at the radius (p < 0.0001) and normal at the tibia. A non-significant increase in BMD and a significant increase in BS were observed throughout the first year of therapy with GnRH agonist. Serum bone specific alkaline phosphatase measurements were normal at baseline and remained stable. Urinary deoxypyridinoline\creatinine measurements were significantly higher (p < 0.0001) at baseline and decreased significantly (p < 0.001) during treatment. CONCLUSIONS: Girls with central idiopathic PP and EP have lower BMD and BS for chronological age and increased bone resorption markers. These parameters show a trend of normalization during the first year of therapy with GnRH agonist.

Intraoperative parathormone measurements and postoperative hypocalcemia.

BACKGROUND: Hypocalcemia following thyroid and parathyroid surgery is a well-recognized potential complication. OBJECTIVES: To determine the utility of intraoperative quick parathormone assay in predicting severe hypocalcemia development following parathyroidectomy for a single-gland adenoma causing primary hyperparathyroidism. METHODS: A retrospective cohort study was performed. IO-QPTH values were measured at time 0 (T0) before incision, and 10 (T10) and 30 minutes (T30) following excision of the hyperfunctioning gland. Percent decrease in IO-QPTH at 10 minutes (T10), maximum percent decrease of IO-QPTH value, and lowest actual IO-QPTH value obtained at surgery were used to determine any correlation with the development of postoperative hypocalcemia requiring treatment. RESULTS: Percent decrease in IO-QPTH at 10 minutes, maximum percent decrease in IO-QPTH and lowest IO-QPTH value did not correlate with the lowest postoperative calcium levels measured 18 hours after surgery (r = 0.017, P = 0.860; r = 0.018, P = 0.850; and r = 0.002, P= 0.985 respectively). For the purposes of our analysis, patients were subdivided into three groups. Group 1 comprised 68 patients with normal calcium levels (serum Ca 8.6-10.3 mg/dl), group 2 had 28 patients with hypocalcemia (8.1-8.6 mg/dl), and group 3 included 12 patients with severe hypocalcemia (calcium level < or = 8.0 mg/dl) requiring calcium supplementation due to symptoms of hypocalcemia. There was no difference between the three groups in the lowest IO-QPTH value (P = 0.378), percent decrease in IO-QPTH (P = 0.305) and maximum percent dercrease in IO-QPTH (P = 0.142). CONCLUSIONS: IO-QPTH evaluation was not useful in predicting the group of patients susceptible to develop severe postoperative hypocalcemia.

Amelioration of SLE-like manifestations in (NZBxNZW)F1 mice following treatment with a peptide based on the complementarity determining region 1 of an autoantibody is associated with a down-regulation of apoptosis and of the pro-apoptotic factor JNK kinase.

Treatment with peptides based on the complementarity determining regions (CDR) of murine and human monoclonal anti-DNA antibodies that bear the common idiotype, 16/6 Id, ameliorates disease manifestations of mice with either induced or spontaneous SLE. Aberrant expression and function of the p21Ras/MAP kinase pathway are associated with active SLE. Therefore, we examined the effect of treatment with a CDR1-based peptide of a human autoantibody (hCDR1) on the p21Ras pathway and SLE manifestations of SLE-prone (NZBxNZW)F1 mice. Untreated SLE-afflicted mice demonstrated increased expression of p21Ras and the phosphorylated active form of its down-stream element JNK kinase in conjunction with reduced hSOS and unchanged p120GAP, as compared to healthy controls. Amelioration of SLE manifestations following treatment with hCDR1 was associated with a diminished expression of phosphorylated JNK kinase, mainly in the T cell population that also exhibited reduced rates of apoptosis. Thus, hCDR1 therapy ameliorates SLE, at least in part, via down-regulation of the activity of the pro-apoptotic JNK kinase.

TH1/TH2 cytokine secretion of first degree relatives of T1DM patients.

Th1/Th2 cytokine imbalance has been demonstrated in Type 1 diabetes (T1DM) patients. We characterized the peak levels, secretory pattern and total cytokine production of the Th1 cytokines (IL-2 and IFN gamma) and Th2 cytokines (IL-4 and IL-10), by stimulated peripheral blood mononuclear cells of twenty six first-degree relatives of T1DM patients, and eleven matched controls. At enrollment, first degree relatives demonstrated a significant increase in peak and overall secretion of IL-2; P<0.01 and P<0.005 respectively and IL-4 cytokine; P<0.05 and P<0.01 respectively, as compared to normal controls. Their mean IFN gamma secretion increased significantly, P<0.05, after one year while their higher IL-2 and IL-4 secretion remained unchanged. Ab-negative and Ab-positive relatives demonstrated a similar cytokine secretion pattern. Four relatives all Ab positive, developed diabetes: Peak IL-4 levels were low in three and markedly decreased within one year in one of these relatives, while peak IL-2 and IFN gamma levels were elevated in all of them. These data demonstrate that secretion of both Th1 and Th2 cytokines is increased in first-degree relatives of T1DM patients independently of their diabetes-associated autoantibodies. The presence of low IL-4 and elevated IL-2 and IFN gamma levels in autoAb positive relatives is associated with progression to overt disease.

Low stimulated IL-4 secretion in PBMC from patients with chronic idiopathic urticaria.

An imbalance between the Th1 and Th2 arms of the cellular immune system has been reported in several autoimmune diseases but not in chronic idiopathic urticaria (CIU). Peak, total secretion and secretory pattern of the Th1 cytokines (IFNgamma and IL-2) and Th2 cytokines (IL-4 and IL-10) were determined in resting and stimulated peripheral blood mononuclear cells (PBMC) from nineteen CIU patients, six acute urticaria patients and twelve controls. Stimulated IL-4 secretion was significantly reduced in CIU patients as indicated by their five- and three-fold lower peak levels and total IL-4 secretion, respectively. The IL-4 secretory pattern overtime was also markedly different in patients and controls. The late secretion of IFNgamma at 144 h was also reduced in CIU patients. These aberrations were not detectable in AU patients. Secretion of IL-2 was lower in CIU and AU patients as compared to controls while IL-10 secretion was comparable in the three groups. Our data demonstrate for the first time a predominantly reduced IL-4 secretion in CIU patients. This is associated with reduced secretion of both IL-2 and IFNgamma. These findings indicate a generalized down-regulation of both Th1 and Th2 cytokines' secretion in CIU.

Steroidogenesis and apoptosis in the mammalian ovary.

Ovarian cell death is an essential process for the homeostasis of ovarian function in human and other mammalian species. It ensures the selection of the dominant follicle and the demise of excess follicles. In turn, this process minimizes the possibility of multiple embryo development during pregnancy and assures the development of few, but healthy embryos. Degeneration of the old corpora lutea in each estrous/menstrual cycle by programmed cell death is essential to maintain the normal cyclicity of ovarian steroidogenesis. Although there are multiple pathways that can determine cell death or survival, crosstalk among endocrine, paracrine and autocrine factors, as well as among protooncogenes, tumor suppressor genes, survival genes and death genes, plays an important role in determining the fate of ovarian somatic and germ cells. The establishment of immortalized rat and human steroidogenic granulosa cell lines and the investigation of pure populations of primary granulosa cells allows systematic studies of the mechanisms that control steroidogenesis and apoptosis in granulosa cells. We have discovered that during initial stages of granulosa cell apoptosis progesterone production does not decrease. In contrast, we found that it is elevated up to 24h following the onset of the apoptotic stimuli exerted by starvation, cAMP, p53 or TNF-alpha stimulation, before total cell collapse. These observations raise the possibility for an alternative unique apoptotic pathway, one not involving mitochondrial Cyt C release associated with the destruction of mitochondrial structure and steroidogenic function. Using mRNA from apoptotic cells and affymetrix DNA microarray technology we discovered that granzyme B, a protease that normally resides in T cytotoxic lymphocytes and natural killer cells of the immune system is expressed and activated in granulosa cells. Thus, the apoptotic signals could bypass mitochondrial signals for apoptosis, which can preserve their steroidogenic activity until complete cell destruction. This unique apoptotic pathway assures cyclicity of estradiol and progesterone release in the estrous/menstruous cycle even during the initial stages of apoptosis.

Constitutive up-regulated activity of MAP kinase is associated with down-regulated early p21Ras pathway in lymphocytes of SLE patients.

Aberrant expression of the p21Ras proto-oncogene has been reported in lymphoid cells of SLE patients. We previously showed that the expression of the p21Ras stimulatory element, hSOS1, is reduced in PBMC from SLE patients with non-active disease. However, the significance of this finding regarding the regulation and function of the p21Ras pathway and its correlation to disease activity remained unclear. The expression, regulation and function of the p21Ras pathway were determined in 23 ambulatory SLE patients with active and non-active disease and eleven controls. Levels of p21Ras stimulatory element hSOS1 but not p21Ras and its inhibitory element p120GAP were significantly decreased in SLE patients. Early p21Ras signalling was down-regulated in SLE patients with active disease as indicated by the decreased membrane/cytoplasmic (M/C) ratios of the p21Ras regulatory elements hSOS1 and p120GAP and by the non-responsiveness of these ratios to cellular stimulation. Anchorage of p21Ras to the cellular membrane was also significantly decreased in these patients. In contrast, the late p21Ras signalling was up-regulated in SLE patients as indicated by the significantly higher constitutive activity of the p21Ras down stream key regulator enzyme MAP Kinase. Taken together, our data demonstrate for the first time a disease associated functional defect in p21Ras signalling in lymphocytes of SLE patients.

Evidence for aberrant regulation of the p21Ras pathway in PBMCs of patients with chronic idiopathic urticaria.

BACKGROUND: Recent data suggest that a subpopulation of patients with chronic urticaria has an autoimmune disorder. Aberrant expression and regulation of the p21Ras pathway has been reported in lymphoid cells in a variety of systemic autoimmune diseases but not in chronic idiopathic urticaria (CIU). OBJECTIVES: The aim of this study was to examine the expression, regulation, and function of the p21Ras pathway in patients with CIU. METHODS: Twenty-four patients with CIU and 14 control subjects were enrolled. All patients and 9 control subjects were intradermally injected with autologous serum. PBMCs were isolated, and the p21Ras and its regulatory proteins were studied. RESULTS: We found increased expression of the p21ras proto-oncogene in patients with CIU. This was associated with a low expression of the p21Ras stimulatory element human son of sevenless (hSOS1) but normally expressed p21Ras inhibitory element p120GTPase-activating protein. The basal nonstimulated membrane/cytoplasmic ratio of hSOS1, which indicates the p21Ras pathway activity, was higher in patients compared with that seen in control subjects. Moreover, after stimulation, both patients and control subjects decreased their hSOS1 membrane/cytoplasmic ratio. The magnitude of this decrease was much higher in patients than in control subjects: 14- and approximately 2-fold, respectively. The basal and stimulated activities of the p21Ras downstream key regulatory enzyme mitogen-activated protein kinase were comparable in patients and control subjects, as was their in vitro mitogen-stimulated lymphocyte proliferation. CONCLUSION: Our data demonstrate for the first time an aberrant signaling through the p21Ras pathway in lymphocytes of patients with CIU. This finding further supports the autoimmune basis of this disease.