Iodine status of teenage girls on the island of Ireland.

PURPOSE: The trace element iodine is a vital constituent of thyroid hormones. Iodine requirements increase during pregnancy, when even mild deficiency may affect the neurocognitive development of the offspring. Urinary iodine concentration (UIC) is the means of assessing iodine status in population surveys; a median UIC of 100-199 µg/L is deemed sufficient in a non-pregnant population. Milk is the main dietary source of iodine in the UK and Ireland. METHODS: We surveyed the iodine status of 903 girls aged 14-15 years in seven sites across the island of Ireland. Urine iodine concentration was measured in spot-urine samples collected between March 2014 and October 2015. Food group intake was estimated from iodine-specific food-frequency questionnaire. Milk-iodine concentration was measured at each site in summer and winter. RESULTS: The median UIC overall was 111 µg/L. Galway was the only site in the deficient range (median UIC 98 µg/L). All five of the Republic of Ireland sites had UIC ≤ 105 µg/L. In the two sites surveyed twice, UIC was lower in summer vs winter months [117 µg/L (IQR 76-165) vs 130 µg/L (IQR 91-194) (p < 0.01)]. Milk samples collected from Galway and Roscommon had a lower mean iodine concentration than those from Derry/Londonderry (p < 0.05). Milk intake was positively associated with UIC (p < 0.001). CONCLUSIONS: This is the largest survey of its kind on the island of Ireland, which currently has no iodine-fortification programme. Overall, the results suggest that this young female population sits at the low end of sufficiency, which has implications if, in future, they enter pregnancy with borderline status.

Does diabetic ketoacidosis at diagnosis of type 1 diabetes mellitus predict poorer long-term glycemic control.

BACKGROUND: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus. AIMS: This study aimed to determine (1) whether DKA at diagnosis of type 1 diabetes is associated with poorer long-term glycemic control and (2) whether there are confounding factors which may impact the mode of presentation of type 1 diabetes mellitus or subsequent glycemic control. METHODS: This study was conducted via review of 102 patient files extracted from the Young Person's Type 1 Diabetes Clinic at Cork University Hospital. Glycemic control was measured using the average of the patient's three most recent HbA1C levels, recorded a median of 11 years post-diagnosis of type 1 diabetes mellitus. RESULTS: Data analysis revealed a positive association between DKA at diagnosis and poorer long-term glycemic control, with HbA1c levels tracking 6.58 mmol/mol (0.6%) higher at follow up in the group with DKA compared to the group without DKA at diagnosis. Certain sociodemographic factors were found to predict worse glycemic control at follow-up: Individuals using recreational drugs and those reporting mental health difficulties were found to have higher levels of HbA1C at follow up (p = ·006,·012, respectively) compared to individuals who did not. CONCLUSIONS: Diabetic ketoacidosis at diagnosis of type 1 diabetes mellitus was shown to be associated with poorer long-term glycemic control in this study. Furthermore, individuals who utilize recreational drugs or have mental health difficulties had significantly worse glycemic control at follow-up.

Herpes Simplex Virus Diencephalitis Leading to Panhypopituitarism.

Herpes simplex virus (HSV) is one of the most common causes of viral encephalitis. Hypothalamic-pituitary dysfunction has rarely been reported in HSV encephalitis, with few reports into the longer term outcomes for these patients. A 46-year-old male presented with a 10-day history of delirium, fever, and polydipsia. Initial computed tomography of the brain and cerebrospinal fluid cell counts were normal. Magnetic resonance imaging showed T2-hyperintensity affecting bilateral infundibuli, hypothalami, subthalamic nuclei, and optic radiations. Serial cerebrospinal fluid detected HSV1 DNA and we diagnosed him with HSV diencephalitis. He had marked biochemical abnormalities from the outset, with dramatic changes in serum sodium levels. He was ultimately diagnosed with permanent central diabetes insipidus and panhypopituitarism following evidence of central hypothyroidism, hypogonadotrophic hypogonadism, and a flat cortisol response to an insulin tolerance test. Neurocognitive recovery took several months, but subtle deficits in executive function and information processing remain. Hypothalamic hyperphagia developed as well as temperature dysregulation. He requires lifelong hormonal replacement and is undergoing regular endocrine follow up. This case highlights hypothalamic-pituitary dysfunction as a rare endocrine complication of HSV diencephalitis and illustrates the complexity of managing this in the long term.

Abnormal glucose tolerance in women with prior gestational diabetes mellitus: a 4-year follow-up study.

BACKGROUND: Adoption of the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria for diagnosis of gestational diabetes mellitus (GDM) varies worldwide. Early detection of women at increased risk of developing type 2 diabetes mellitus (T2DM) following GDM enables initiation of measures to delay disease onset. OBJECTIVES: To determine the 4-year cumulative incidence and risk factors for developing abnormal glucose tolerance (AGT) among women with previous GDM using modified IADPSG criteria. Additionally, to review post-natal attendance at diabetes screening and the impact of post-partum lifestyle modifications and breastfeeding on the risk of T2DM development. METHODS: Four hundred twenty-six women with a prior history of GDM were invited to participate in the study, 4 years after the index pregnancy. The following were completed: body measurements, oral glucose tolerance test (OGTT), glycated haemoglobin (HbA1c), vitamin D, and other biochemistry measurements. Participants also completed a lifestyle questionnaire. RESULTS: Of the 74 women who participated, 15 (20%) had AGT. Predictive factors for AGT development were as follows: fasting glucose levels (p = 0.004), HbA1c (p = 0.008) at GDM diagnosis, and early pregnancy BMI (p = 0.001). Thirty-three (45%) women had not attended their postnatal screening. The odds ratio of the association between breastfeeding and AGT development was 0.16 (95% CI: 0.05 to 0.53). CONCLUSION: The proportion of women who develop AGT after a diagnosis of GDM remains high. The factors associated with progression to AGT are available at GDM diagnosis. Preventing AGT in this group is possible by supporting breastfeeding. Attendance at post-natal screening should also be encouraged.

Appropriateness of aspirin prescribing for primary and secondary prevention of cardiovascular disease in type 2 diabetes in different care settings.

BACKGROUND: Type 2 diabetes is associated with an increased cardiovascular risk. Use of aspirin has been shown to be of benefit for secondary prevention of cardiovascular disease in patients with type 2 diabetes; benefits in primary prevention have not been clearly proven. AIMS: This study aims to (a) determine if aspirin is prescribed appropriately in type 2 diabetes for primary or secondary prevention of cardiovascular disease (CVD) and (b) evaluate whether there are differences in aspirin prescribing according to where people receive their care. DESIGN: Cross-sectional study METHODS: The medical records of individuals with type 2 diabetes aged over 18 years and attending Elmwood Primary Care Centre and Cork University Hospital Diabetes outpatient clinics (n = 400) between February and August 2017 were reviewed. RESULTS: There were 90 individuals exclusively attending primary care and 310 persons attending shared care. Overall, 49.0% (n = 196) of those were prescribed aspirin, of whom 42.3% were using it for secondary prevention. Aspirin was used significantly more in people attending shared care (p < 0.001). About 10.8% of individuals with diabetes and CVD attending shared care met guidelines for, but were not prescribed aspirin. CONCLUSION: A significant number of people with type 2 diabetes who should have been prescribed aspirin for secondary prevention were not receiving it at the time of study assessment. In contrast, a substantial proportion who did not meet criteria for aspirin use was prescribed it for primary prevention.

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.

Outcome of Subclassification of Indeterminate (Thy-3) Thyroid Cytology into Thy-3a and Thy-3f.

OBJECTIVES: The British Thy system is a widely used classification system for reporting thyroid fine-needle aspiration (FNA) cytology. The Royal College of Pathologists in 2009 recommended the subdivision of the Thy-3 (indeterminate) category into Thy-3a (atypia) and Thy-3f (follicular neoplasm). Our objective was to examine the malignancy rates of Thy-3a and Thy-3f cases at our institution and to investigate whether the risk of malignancy in Thy-3a cases is reduced by FNA on a different occasion showing benign cytology. METHODS: This is a retrospective study of 748 thyroid nodules undergoing 1,032 FNAs, with indeterminate (Thy-3) cytology subdivided into Thy-3a and Thy-3f. Cases were correlated with final histology in surgical cases. Incidental carcinomas occurring outside the biopsied nodule were discounted. RESULTS: A total of 109 nodules had a final cytological diagnosis of Thy-3a, of which 67 underwent surgery, with an incidence of malignancy of 13.4% (9/67); 90 nodules had a final cytological diagnosis of Thy-3f, of which 84 underwent surgery, with an incidence of malignancy of 17.9% (15/84). The difference in malignancy rates was not significant (p = 0.51). The incidence of malignancy in nodules with benign and Thy-3a cytology on separate occasions was not significantly different from cases with a single Thy-3a cytology. CONCLUSIONS: Thyroid nodules with Thy-3a cytology have a slightly lower risk of malignancy than Thy-3f cases. However, the difference is not significant and does not appear to be reduced by FNA on a separate occasion showing benign cytology. Management decisions for patients with Thy-3a cytology should be taken carefully to avoid missing cancers.

Follicular variant of papillary thyroid carcinoma: differences from conventional disease in cytologic findings and high-risk features.

IMPORTANCE: The follicular variant (FV) of papillary thyroid carcinoma (PTC) is an important subtype that can be difficult to diagnose using preoperative cytologic analysis. OBJECTIVE: To compare conventional and FV PTC with regard to preoperative cytologic diagnosis using a tiered thyroid cytologic reporting system, tumor size at diagnosis, presence of invasion, and implications on prognostic scores. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study was conducted in an academic teaching hospital and included 99 patients with conventional (n = 65) or FV (n = 34) PTC. INTERVENTIONS: Preoperative thyroid cytologic findings, originally reported using the tiered British Thy system, were recategorized according to the Bethesda classification system. Pathologic features recorded included tumor size, presence of extrathyroid extension (ETE), and metastases. Prognostic scores were calculated according to the MACIS system. MAIN OUTCOMES AND MEASURES: Differences in patient demographics, preoperative cytologic findings, tumor pathologic features, and prognostic risk categories between conventional and FV PTC were studied. RESULTS: There were no differences in patient age or sex. Cytologic findings from FV PTC were significantly more likely to be reported in a lower-risk category than those from conventional PTC for (1) malignant vs lower-risk category (22 [56%] vs 2 [8%]); (2) suspected malignant or malignant vs lower-risk category (26 [66%] vs 6 [23%]); and (3) follicular neoplasm or higher-risk category vs lower-risk category (34 [87%] vs 10 [38%]) (P < .001 for all 3 comparisons). There was also a significantly higher likelihood of false-negative cytologic findings among FV PTC cases (5 [19%] vs 1 [3%]) (P = .03). The mean size of FV PTC lesions (25.9 mm) at the time of pathologic diagnosis was significantly greater than that of conventional PTC lesions (15.5 mm) (P = .02). Even after exclusion of "coincidental" carcinomas, FV PTC tumors were significantly larger than conventional PTC tumors (31.7 vs 22.4 mm; P = .03). In contrast, FV PTC was significantly less likely to show ETE (0 of 34 vs 10 of 65; P = .01). There were no significant differences between FV PTC and conventional PTC in proportion of patients in intermediate- and high-risk prognostic groups combined (21 [62%] vs 38 [58%]) (P = .83) or in mean MACIS scores (4.68 and 4.38, respectively; P = .18). CONCLUSIONS AND RELEVANCE: Preoperative cytologic findings from FV PTC were more likely than those from conventional PTC to indicate a lower risk category, and FV PTC tumors were larger at time of diagnosis. On the other hand, owing to a lower incidence of ETE in conventional PTC, there was no difference in prognostic score at diagnosis.

Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation.

CONTEXT: Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner. OBJECTIVE: Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL. METHODS: In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications. RESULTS: A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation. CONCLUSION: This study supports the value of universal genetic screening for all patients with PC/PGL.

False negatives in thyroid cytology: impact of large nodule size and follicular variant of papillary carcinoma.

OBJECTIVES/HYPOTHESIS: Fine-needle aspiration (FNA) cytology is well established in the diagnosis of thyroid nodules. However, false-negative rates for malignancy of 3% to 10% are reported. The purpose of the present study was to investigate the impact of nodule size and follicular variant of papillary carcinoma (FVPTC) on false-negative FNA rates in thyroid nodules and on malignancy rates in nodules with indeterminate cytology. STUDY DESIGN: Retrospective study. METHODS: A total of 765 consecutive ultrasound-guided FNAs were reviewed. Histological correlation was available in 262 cases. RESULTS: The overall sensitivity of FNA for malignancy was 84%, and the false-negative rate 9.1%. Nodules ≥ 3 cm were significantly more likely to ultimately be diagnosed as cancer by histology than nodules <3 cm (14% vs. 6.8%, P = .006); however, they were also significantly more likely to undergo surgery than smaller nodules (P < .0001). Among the surgical series, the false-negative rate was 10.9% in nodules ≥ 3 cm and 6.1% in nodules <3 cm (P = .71). Most false negatives were due to FVPTC. FVPTC was significantly more likely to be missed by preoperative cytology than conventional or other variants of papillary carcinoma (P < .001). Among cases with indeterminate cytology, nodule size and Thy-3f versus Thy-3a subclassification did not have any significant impact on likelihood of malignancy. CONCLUSIONS: The sensitivity of FNA for detection of FVPTC is reduced compared to conventional papillary carcinoma. The impact of nodule size is not significant. LEVEL OF EVIDENCE: 4.

Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity.

The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represent an adaptive response that preserves WAT lipid homeostasis in obese and insulin-resistant states. In our experiments, we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance and from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 downregulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation and facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation, partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.

CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance.

We show here high levels of expression and secretion of the chemokine CXC ligand 5 (CXCL5) in the macrophage fraction of white adipose tissue (WAT). Moreover, we find that CXCL5 is dramatically increased in serum of human obese compared to lean subjects. Conversely, CXCL5 concentration is decreased in obese subjects after a weight reduction program, or in obese non-insulin-resistant, compared to insulin-resistant, subjects. Most importantly we demonstrate that treatment with recombinant CXCL5 blocks insulin-stimulated glucose uptake in muscle in mice. CXCL5 blocks insulin signaling by activating the Jak2/STAT5/SOCS2 pathway. Finally, by treating obese, insulin-resistant mice with either anti-CXCL5 neutralizing antibodies or antagonists of CXCR2, which is the CXCL5 receptor, we demonstrate that CXCL5 mediates insulin resistance. Furthermore CXCR2-/- mice are protected against obesity-induced insulin resistance. Taken together, these results show that secretion of CXCL5 by WAT resident macrophages represents a link between obesity, inflammation, and insulin resistance.

The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation.

OBJECTIVE: Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is a recessive disorder featuring near complete absence of adipose tissue. Remarkably, although the causative gene, BSCL2, has been known for several years, its molecular function and its role in adipose tissue development have not been elucidated. Therefore, we examined whether BSCL2 is involved in the regulation of adipocyte differentiation and the mechanism whereby pathogenic mutations in BSCL2 cause lipodystrophy. RESEARCH DESIGN AND METHODS: Following the characterization of BSCL2 expression in developing adipocytes, C3H10T1/2 mesenchymal stem cells were generated in which BSCL2 expression was knocked down using short hairpin RNA (shRNA). These cells were used to investigate whether BSCL2 is required for adipogenesis. BSCL2 constructs harboring pathogenic mutations known to cause lipodystrophy were also generated and characterized. RESULTS: BSCL2 expression was strongly induced during adipocyte differentiation, and the induction of BSCL2 expression was essential for adipogenesis to occur. The initial induction of key adipogenic transcription factors, including peroxisome proliferator-activated receptor (PPAR)gamma and CAAT/enhancer-binding protein-alpha, was preserved in cells lacking BSCL2. However, the expression of these critical factors was not sustained, suggesting that the activity of PPARgamma was impaired. Moreover, expression of key genes mediating triglyceride synthesis, including AGPAT2, lipin 1, and DGAT2, was persistently reduced and lipid accumulation was inhibited. Analysis of pathogenic missense mutants of BSCL2 revealed that the amino acid substitution A212P causes aberrant targeting of BSCL2 within the cell, suggesting that subcellular localization of BSCL2 may be critical to its function. CONCLUSIONS: This study demonstrates that BSCL2 is an essential, cell-autonomous regulator of adipogenesis.