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1.  Assessing fear of hypoglycemia in a population-based study among parents of children with type 1 diabetes – psychometric properties of the hypoglycemia fear survey – parent version 
In the treatment of childhood type 1 diabetes, being aware of the parents’ fear of hypoglycemia is important, since the parents’ fear may influence the management of treatment and the children’s blood glucose regulation. The availability of proper instruments to assess the parents’ fear of hypoglycemia is essential. Thus, the aim of this study was to examine the psychometric properties of the Hypoglycemia Fear Survey – Parent version (HFS-P).
In a Norwegian population-based sample, 176 parents representing 102 children with type 1 diabetes (6–15 years old) completed the HFS-P, comprising a 15-item worry subscale and a 10-item behavior subscale. We performed exploratory and confirmatory factor analysis and further analysis of the scales’ construct validity, content validity and reliability.
The Norwegian version of the HFS-P had an acceptable factor structure and internal consistency for the worry subscale, whereas the structure and internal consistency of the behavior subscale was more questionable. The HFS-P subscales were significantly correlated (from moderately to weakly) with symptoms of emotional distress, as measured by the Hopkins Symptom Checklist – 25 items. The mothers scored higher than fathers on both HFS-P subscales, but the difference was not statistically significant for the worry subscale.
The HFS-P worry subscale seems to be a valid scale for measuring anxiety-provoking aspects of hypoglycemia, and the validity of the HFS-P behavior subscale needs to be investigated further.
PMCID: PMC4324848  PMID: 25599725
Hypoglycemia; Fear; Parents; HFS; HFS-P; Reliability; Validity
2.  Insulin secretion in patients with latent autoimmune diabetes (LADA): half way between type 1 and type 2 diabetes: action LADA 9 
The study of endogenous insulin secretion may provide relevant insight into the comparison of the natural history of adult onset latent autoimmune diabetes (LADA) with types 1 and 2 diabetes mellitus. The aim of this study was to compare the results of the C-peptide response to mixed-meal stimulation in LADA patients with different disease durations and subjects with type 2 and adult-onset type 1 diabetes.
Stimulated C-peptide secretion was assessed using the mixed-meal tolerance test in patients with LADA (n = 32), type 1 diabetes mellitus (n = 33) and type 2 diabetes mellitus (n = 30). All patients were 30 to 70 years old at disease onset. The duration of diabetes in all groups ranged from 6 months to 10 years. The recruitment strategy was predefined to include at least 10 subjects in the following 3 disease onset categories for each group: 6 to 18 months, 19 months to 5 years and 5 to 10 years.
At all time-points of the mixed-meal tolerance test, patients with LADA had a lower stimulated C-peptide response than the type 2 diabetes group and a higher response than the type 1 diabetes group. The same results were found when the peak or area under the C-peptide curve was measured. When the results were stratified by time since disease onset, a similar pattern of residual insulin secretory capacity was observed.
The present study shows that the magnitude of stimulated insulin secretion in LADA is intermediate between that of type 1 and type 2 diabetes mellitus.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6823-15-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4297398  PMID: 25572256
Latent autoimmune diabetes in adults; Type 1 diabetes mellitus; Type 2 diabetes mellitus; Insulin secretion; C-peptide
3.  AMPD1: a novel therapeutic target for reversing insulin resistance 
BMC Endocrine Disorders  2014;14(1):96.
Insulin resistance is one of the hallmark manifestations of obesity and Type II diabetes and reversal of this pathogenic abnormality is an attractive target for new therapies for Type II diabetes. A recent report that metformin, a drug known to reverse insulin resistance, demonstrated in vitro the metformin can inhibit AMP deaminase (AMPD) activity. Skeletal muscle is one of the primary organs contributing to insulin resistance and that the AMPD1 gene is selectively expressed at high levels in skeletal muscle.
Recognizing the background above, we asked if genetic disruption of the AMPD1 gene might ameliorate the manifestations of insulin resistance. AMPD1 deficient homozygous mice and control mice fed normal chow diet or a high-fat diet, and blood analysis, glucose tolerance test and insulin tolerance test were performed. Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions.
Disruption of the AMPD1 gene leads to a less severe state of insulin resistance, improved glucose tolerance and enhanced insulin clearance in mice fed a high fat diet. Given the central role of AMP kinase in insulin action, and its response to changes in AMP concentrations in the cell, we examined the skeletal muscle of the AMPD1 deficient mice and found that they have greater AMP kinase activity as evidenced by higher levels of phosphorylated AMP kinase.
Taken together these data suggest that AMPD may be a new drug target for the reversal of insulin resistance and the treatment of Type II diabetes.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6823-14-96) contains supplementary material, which is available to authorized users.
PMCID: PMC4274759  PMID: 25511531
AMP deaminase; Adenine nucleotide; Diabetes; Insulin resistance; AMP kinase; Glucose metabolism
4.  The second wave of the Controlled Antenatal Thyroid Screening (CATS II) study: the cognitive assessment protocol 
BMC Endocrine Disorders  2014;14(1):95.
Children whose mothers had low thyroid hormone levels during pregnancy have been reported to have decreased cognitive function. The reported research is part of the follow-on study of the Controlled Antenatal Thyroid Screening Study (CATS I), a randomised controlled trial which investigated the impact of treated vs. untreated low thyroid hormone level in women during pregnancy with the primary outcome being the child’s IQ at age 3. No significant differences in IQ were found between the treated and untreated groups. These children are now aged between 7 and 10 years and aspects of their cognitive functioning including their IQ are being reassessed as part of CATS II.
Cognitive assessments generate an IQ score and further tests administered will investigate long term memory function and motor coordination. The aim is to complete the assessments with 40% of the children born to mothers either in the treated or untreated low thyroid hormone groups (n = 120 per group). Also children born to mothers who had normal thyroid functioning during CATS I are being assessed for the first time (n = 240) to provide a comparison. Assessments are conducted either in the research facility or the participant’s home.
The study is designed to assess the cognitive functioning of children born to mothers with low thyroid hormone levels and normal thyroid functioning during pregnancy. This is the largest study of its type and also is distinguishable in its longitudinal design. The research has the potential to have a significant impact on public health policy in the UK; universal screening of thyroid hormone levels in pregnancy may be the recommendation.
PMCID: PMC4276267  PMID: 25495390
Hypothyroidism; Pregnancy; Child; Intelligence; IQ; Cognition; Motor coordination; Long term memory; Thyroid function
5.  A clinical prediction score for diagnosing unilateral primary Aldosteronism may not be generalizable 
A published clinical prediction score indicated that a unilateral adrenal adenoma and either hypokalemia or an estimated glomerular filtration rate of 100 ml/min/1.73 m2 was 100% specific for unilateral primary aldosteronism. This study aimed to validate this score in a separate cohort of patients with primary aldosteronism.
A review of patients with primary aldosteronism from June 2005 to July 2013 at a single center’s hypertension clinic. One hundred twelve patients with primary aldosteronism underwent successful adrenal vein sampling and the 110 patients with full data available were included in the final analysis. Adrenal vein sampling was performed all patients desiring surgery by the simultaneous collection of sample prior to and 15 minutes after a cosyntropin infusion with a 3:1 aldosterone/cortisol ratio diagnosing unilateral primary aldosteronism. The derived score was applied to the cohort. Sensitivity and specificity were calculated for clinical prediction score of ≥5 points.
There were 64 patients found to have unilateral primary aldosteronism and 48 had bilateral disease. A score ≥5 points had 64% sensitivity (95% confidence interval, 51–76) and 85% specificity (95% confidence interval, 71–94) for unilateral disease. Four patients had lateralization of primary aldosteronism to the side contralateral to the adenoma.
The 100% specificity of the score for the unilateral origin of primary aldosteronism was not validated in this cohort with a score of ≥5 points. At best, a high score in this prediction rule may be an additional tool for helping to confirm a decision to offer patients adrenal vein sampling.
PMCID: PMC4320464  PMID: 25495254
6.  Osteoporosis, vertebral fractures and metabolic syndrome in postmenopausal women 
BMC Endocrine Disorders  2014;14(1):93.
The combined effect of the metabolic syndrome (MS) risk factors on bone health has led to controversial results and it is still not clear whether this effect is protective or detrimental. The study aimed to examine the association between MS and bone mineral density (BMD), osteoporosis, and vertebral fractures (VFs) among ambulatory older postmenopausal women.
270 post-menopausal women with a mean age of 61.0 years ± 7.8 (50 to 90) with no prior known diagnosis of osteoporosis were recruited. BMD and Lateral vertebral fracture assessment (VFA) images were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative approach and morphometry.
The MS as defined by the NCEP-ATP III was present in 62 women (23.0%). According to the WHO classification, 82 had osteoporosis at any site (30.4%). VFs were identified in 116 (43.0%): 80 (29.6%) had grade 1 and 36 (13.3%) had grade 2 or 3. Women with MS had a significantly higher BMD and lower prevalence of osteoporosis (17.7% vs. 34.1%) than those without MS. No significant statistical difference was noted in prevalence of VFs (14.5 vs. 13.0%). There were significantly less women with MS among the group of osteoporotic women (13% vs. 27%; p = 0.018). Conditional regression binary analysis assessing the presence of osteoporosis as the dependent variable showed that women with a MS had a significant 71% decrease in the odds of being osteoporotic by BMD compared with women who had not MS accounting for age, BMI, number of parities and years since menopause.
Women with MS had higher BMD at the hip and spine, suggesting a protective effect of MS on bone. However, the prevalence of VFs was similar between women with or without MS.
PMCID: PMC4268881  PMID: 25492884
Metabolic syndrome; Vertebral fracture assessment (VFA); Dual-energy X-ray absorptiometry (DXA); Osteoporosis; Women; Vertebral fractures
7.  The association between improved quality diabetes indicators, health outcomes and costs: towards constructing a “business case” for quality of diabetes care - a time series study 
BMC Endocrine Disorders  2014;14(1):92.
In primary health care systems where member’s turnover is relatively low, the question, whether investment in quality of care improvement can make a business case, or is cost effective, has not been fully answered.
The objectives of this study were: (1) to investigate the relationship between improvement in selected measures of diabetes (type 2) care and patients’ health outcomes; and (2) to estimate the association between improvement in performance and direct medical costs.
A time series study with three quality indicators – Hemoglobin A1c (HbA1c) testing, HbA1C and LDL- cholesterol (LDL-C) control - which were analyzed in patients with diabetes, insured by a large health fund. Health outcomes measures used: hospitalization days, Emergency Department (ED) visits and mortality. Poisson, GEE and Cox regression models were employed. Covariates: age, gender and socio-economic rank.
96,553 adult (age >18) patients with diabetes were analyzed. The performance of the study indicators, significantly and steadily improved during the study period (2003–2009). Poor HbA1C (>9%) and inappropriate LDL-C control (>100 mg/dl) were significantly associated with number of hospitalization days. ED visits did not achieve statistical significance. Improvement in HbA1C control was associated with an annual average of 2% reduction in hospitalization days, leading to substantial reduction in tertiary costs. The Hazard ratio for mortality, associated with poor HbA1C and LDL-C, control was 1.78 and 1.17, respectively.
Our study demonstrates the effect of continuous improvement in quality care indicators, on health outcomes and resource utilization, among patients with diabetes. These findings support the business case for quality, especially in healthcare systems with relatively low enrollee turnover, where providers, in the long term, could “harvest” their investments in improving quality.
PMCID: PMC4265437  PMID: 25434420
8.  Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers 
BMC Endocrine Disorders  2014;14(1):91.
Glucocorticoid replacement is essential in patients with primary and secondary adrenal insufficiency, but many patients remain on higher than recommended dose regimens. There is no uniformly accepted method to monitor the dose in individual patients. We have compared cortisol concentrations in plasma, saliva and urine achieved following “physiological” and “stress” doses of hydrocortisone as potential methods for monitoring glucocorticoid replacement.
Cortisol profiles were measured in plasma, saliva and urine following “physiological” (20 mg oral) or “stress” (50 mg intravenous) doses of hydrocortisone in dexamethasone-suppressed healthy subjects (8 in each group), compared to endogenous cortisol levels (12 subjects). Total plasma cortisol was measured half-hourly, and salivary cortisol and urinary cortisol:creatinine ratio were measured hourly from time 0 (between 0830 and 0900) to 5 h. Endogenous plasma corticosteroid-binding globulin (CBG) levels were measured at time 0 and 5 h, and hourly from time 0 to 5 h following administration of oral or intravenous hydrocortisone. Plasma free cortisol was calculated using Coolens’ equation.
Plasma, salivary and urine cortisol at 2 h after oral hydrocortisone gave a good indication of peak cortisol concentrations, which were uniformly supraphysiological. Intravenous hydrocortisone administration achieved very high 30 minute cortisol concentrations. Total plasma cortisol correlated significantly with both saliva and urine cortisol after oral and intravenous hydrocortisone (P <0.0001, correlation coefficient between 0.61 and 0.94). There was no difference in CBG levels across the sampling period.
An oral dose of hydrocortisone 20 mg is supraphysiological for routine maintenance, while stress doses above 50 mg 6-hourly would rarely be necessary in managing acute illness. Salivary cortisol and urinary cortisol:creatinine ratio may provide useful alternatives to plasma cortisol measurements to monitor replacement doses in hypoadrenal patients.
PMCID: PMC4280712  PMID: 25425285
Adrenal Cortex; HPA axis (hypothalamic-pituitary-adrenal); Cortisol; Hydrocortisone
9.  Factors associated with postprandial lipemia and apolipoprotein A-V levels in individuals with familial combined hyperlipidemia 
BMC Endocrine Disorders  2014;14(1):90.
Alterations in postprandial metabolism have been described in familial combined hyperlipidemia (FCH); however, their underlying mechanisms are not well characterized. We aimed to identify factors related to the magnitude of postprandial lipemia and apolipoprotein (apo) A-V levels in subjects with FCH.
FCH cases (n = 99) were studied using a standardized meal test. Abdominal obesity was assessed using the waist to hip ratio (WHR). A linear regression model was performed to investigate the variables associated with the triglycerides incremental area under the curve (iAUC). Independent associations between metabolic variables and apo A-V iAUC were also investigated in a randomly selected subgroup (n = 44). The study sample was classified according to the presence of fasting hypertriglyceridemia (≥150 mg/dL) and abdominal obesity (WHR ≥0.92 in men and ≥0.85 in women) to explore differences in parameters.
The fasting apo B-48 levels (r = 0.404), and the WHR (r = 0.359) were independent factors contributing to the triglycerides iAUC (r2 = 0.29, P < 0.001). The triglycerides iAUC was independently associated with the apo A-V iAUC (r2 = 0.54, P < 0.01). Patients with both hypertriglyceridemia and abdominal obesity showed the most robust triglycerides and apo A-V postprandial responses.
In patients with FCH the fasting apo B-48 level is the main factor associated with postprandial lipemia. Abdominal obesity also contributes to the magnitude of the postprandial response.
The triglycerides postprandial increment is the principal factor associated with the apo A-V postprandial response.
PMCID: PMC4253986  PMID: 25425215
Postprandial lipemia; Triglycerides; Apo B-48; Apo A-V; Abdominal obesity; Waist to hip ratio
10.  Insufficient early detection of peripheral neurovasculopathy and associated factors in rural diabetes residents of Taiwan: a cross-sectional study 
BMC Endocrine Disorders  2014;14(1):89.
Diabetic peripheral neuropathy (PN) and peripheral vasculopathy (PV) are major causes of foot ulcers in patients with diabetes. The early detection of PN/PV with appropriate health counseling is the best strategy for preventing foot lesions. The objective of this study is to examine the prevalence and associated risk factors of PN/PV among rural community residents with type 2 diabetes mellitus (T2DM).
This cross-sectional descriptive study was conducted in Taiwan from February to October 2012. Type 2 diabetes mellitus and health promotion scale, Michigan neuropathy screening instrument, and ankle-brachial pressure index values were measured.
A total of 404 (55% women) participated in and completed the program. The overall prevalence of PN and PV was 34.5 and 17.1%, respectively. The majority of the participants (90%) did not receive early PN/PV detection by health care providers. After adjustment for the potential confounding factors, multivariate analysis indicated that the factors determining PN/PV were age (P <0.001), living around sea coastal regions (P <0.001), high HbA1C level (P <0.01), and fewer regular health-promoting behaviors (P <0.01).
There was a high prevalence of PN/PV among rural T2DM residents who received insufficient early detection. The early detection of PN/PV and provision of health education with customized health-promoting behaviors of people with diabetes in the rural community are important issues.
PMCID: PMC4255455  PMID: 25421066
Type 2 diabetes mellitus; Diabetic foot ulcer; Peripheral neuropathy; Peripheral vasculopathy
11.  The use of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of thyroid lesions 
BMC Endocrine Disorders  2014;14(1):88.
Non-palpable thyroid nodules can be difficult to access by conventional ultrasound-guided fine needle aspiration, particularly when they are intrathoracic. Many of these patients are subject to multiple follow up scans or invasive diagnostic procedures such as mediastinoscopy or surgical resection. We aim to describe the feasibility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis of thyroid lesions.
All EBUS-TBNA performed at our institutions from February 2010 to February 2013 were screened, and those in which a thyroid biopsy was performed were reviewed.
We identified 12 cases of EBUS-TBNA thyroid biopsy. Nine patients had an indication for EBUS in addition to their thyroid lesions. The median age was 64 years (range 44 to 84 years), and 10 patients were male. Median lesion size was 22.5 mm (range, 10 to 43 mm). Five lesions were strictly intrathoracic. All cases were sampled with a 22G needle and rapid on-site cytologic examination. Adequate samples were obtained in all 12 cases. Malignancy was identified in 3 of the 12 patients (metastatic breast adenocarcinoma, large B-cell lymphoma, and metastatic lung adenocarcinoma). The remaining 9 samples were deemed to be benign nodules. Seven of these were confirmed by clinical follow-up (n = 3), biopsies (n = 3), or surgery (n = 1).
There were no EBUS-related complications.
EBUS-TBNA might be a safe and effective alternative for sampling thyroid lesions, particularly useful for those located below the thoracic inlet. Further prospective studies are required to compare its diagnostic yield and safety profile with standard techniques.
PMCID: PMC4247684  PMID: 25416021
EBUS-TBNA; Thyroid; Intrathoracic goiter
12.  A pattern of unspecific somatic symptoms as long-term premonitory signs of type 2 diabetes: findings from the population-based MONICA/KORA cohort study, 1984-2009 
BMC Endocrine Disorders  2014;14(1):87.
Unspecific symptoms often proceed a serious chronic disease condition long before the onset of the disease. The role of an unspecific premonitory symptom (UPMS) pattern as premonitory signs of subsequent type 2 diabetes mellitus (T2DM) diagnosis independent of established cardio-metabolic risk factors is unclear and therefore was examined in the present study.
The study population consisted of 10,566 participants aged 25–74 years at baseline drawn from the population-based MONICA/KORA Cohort Study conducted in 1984-2009 in the Augsburg region (Germany). Unspecific premonitory symptoms were assessed following the Somatic Symptom Scale-8 (SSS-8). The impact of the score on T2DM risk within a mean follow-up time of 16 years was estimated by Cox regression.
Within follow-up, 974 newly diagnosed T2DM cases were observed. The risk for T2DM increased by a hazard ratio (HR) of 1.03 (95% CI 1.01-1.04, p value < 0.001) for a one unit increase of the UPMS score in a Cox model adjusted for age, sex and survey. Additional adjustment for cardio-metabolic risk factors attenuated this effect (HR = 1.02) but significance remained (p value = 0.01).
Suffering from an elevated burden of unspecific somatic symptoms is associated with T2DM long before the onset and independent of established cardio-metabolic risk factors. Further research is needed to obtain insight in potential underlying pathophysiological mechanisms.
PMCID: PMC4247721  PMID: 25416641
Cohort study; General population; Type 2 diabetes mellitus; Unspecific premonitory symptom pattern
13.  Exploring the potential association between brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated compounds, phthalates, and bisphenol a in polycystic ovary syndrome: a case–control study 
BMC Endocrine Disorders  2014;14(1):86.
Polycystic Ovary Syndrome (PCOS) is an endocrine-metabolic disorder that affects approximately 6-10% of women of child-bearing age. Although preliminary studies suggest that certain pollutants may act as endocrine disruptors in animals, little is known about their potential association with PCOS. The objective of this case-control pilot study is to determine whether women with PCOS have higher concentrations of specific environmental contaminants compared to women who have not developed PCOS.
Fifty-two PCOS case-patients (diagnosed using the National Institutes of Health 1990 definition) and 50 controls were recruited in 2007–2008, from an urban academic medical center in Los Angeles, CA. Brominated diphenyl ethers, polychlorinated biphenyls (PCBs), organochlorine pesticides, and perfluorinated compounds (PFCs) were measured in serum, and phthalates metabolites and bisphenol A (BPA) in urine.
PCOS case-patients had significantly higher geometric mean (GM) serum concentrations of two PFCs: perfluorooctanoate (PFOA) (GMcases = 4.1 μg/L, GMcontrols = 2.3 μg/L; p = 0.001) and perfluorooctane sulfonate (PFOS) (GMcases = 8.2 μg/L, GMcontrols = 4.9 μg/L; p = 0.01), and lower urinary concentrations of monobenzyl phthalate (mBzP) (GMcases = 7.5 μg/g creatinine, GMcontrols = 11.7 μg/g creatinine; p = 0.02). Logistic regression, controlling for body mass index, age and race, identified an increased likelihood of PCOS in subjects with higher serum concentrations of PFOA and PFOS (adjusted-ORs = 5.8–6.9, p < 0.05), and with lower urine concentrations of mBzP and mono-n-butyl phthalate (mBP) (aORs = 0.14–0.25, p < 0.05).
Our data suggest that PCOS case-patients may differ from controls in their environmental contaminant profile. PCOS subjects had higher serum concentrations of two PFCs, PFOA and PFOS, and lower urine concentrations of mBP and mBzP. Future studies are needed to confirm these preliminary findings and determine if these chemicals or their precursors may have a role in the pathogenesis of PCOS.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6823-14-86) contains supplementary material, which is available to authorized users.
PMCID: PMC4287339  PMID: 25348326
14.  Health-related quality of life 5 years after carpal tunnel release among patients with diabetes: a prospective study with matched controls 
BMC Endocrine Disorders  2014;14(1):85.
Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy encountered in diabetes. The short-term improvement after carpal tunnel release has previously been demonstrated not to differ between patients with and without diabetes, despite a marked impairment in health-related quality of life (HRQL) among the former. In this study, we compare HRQL 5 years after carpal tunnel release between these two groups of patients.
In a prospective series, 35 patients with diabetes and CTS were matched with 31 control patients with idiopathic CTS but no diabetes. At the 5-year follow-up patients completed the Medical Outcomes Short-Form 36 (SF-36) and Antonovsky’s sense of coherence (SOC) questionnaire. Differences in changes over time were compared between patients with and without diabetes using mixed model analysis.
Although patients with diabetes reported a significant decrease in physical functioning (p =0.004) as compared to patients without diabetes, postoperative improvement was maintained in the physical domains, role physical and bodily pain. A more pronounced decline in the mental health domain, social function (p =0.03), was demonstrated among patients with diabetes. There was no evidence of any difference in SOC between the patient groups.
Patients with diabetes retained their improvement in physical domains sensitive to changes after carpal tunnel release in the long-term, despite a decline in other domains of both physical and mental HRQL. This differed from patients without diabetes. Differences in SOC could not explain the sharper decline in these domains among patients with diabetes.
PMCID: PMC4203934  PMID: 25326166
Carpal tunnel syndrome; Diabetes; Health-related quality of life; Sense of coherence; SF-36
15.  Testicular and inguinal lymph node metastases of medullary thyroid cancer: a case report and review of the literature 
BMC Endocrine Disorders  2014;14(1):84.
The involvement of the testis by metastatic medullary thyroid carcinoma has never been described before. We describe the first case of metastatic medullary thyroid carcinoma affecting testis and inguinal lymph nodes.
Case presentation
A 73-year-old Caucasian man was referred to undergo urologic surgery due to a painless nodule in the right testis and an homolateral inguinal lymphoadenomegaly. The patient had a history of medullary thyroid carcinoma with relapsing disease to the spine and lung nodules. Serum calcitonin and CEA levels were 175 pg/ml and 22 ng/ml, respectively. With suspected testicular cancer, the patient underwent radical right orchiectomy with the excision biopsy of the right inguinal lymph node. Histopathology and immunohistochemistry revealed that both the lesions were due to metastases from medullary thyroid carcinoma.
Metastases to the testis and inguinal lymph nodes may be due to various solid and hematological tumors. This case, despite its rarity, suggests that testis and inguinal lymph nodes should be considered as potential secondary sites of medullary thyroid carcinoma as well.
PMCID: PMC4271442  PMID: 25306429
Medullary thyroid cancer; Testicular metastasis; Inguinal lymph node metastasis
16.  Mental health in adolescents with Type 1 diabetes: results from a large population-based study 
BMC Endocrine Disorders  2014;14(1):83.
Diabetes has previously been linked to mental health problems in adolescents, but more recent studies have yielded mixed findings. The aim of the current study was to compare symptoms of mental health problems, sleep and eating disturbances in adolescents with and without Type 1 diabetes in a population based sample.
Data were taken from the youth@hordaland study, a large population based study in Hordaland County in Norway conducted in 2012. In all, 9883 adolescents aged 16–19 years (53% girls) provided self-reported data on both diabetes and a range of instruments assessing mental health symptoms, including depression, anxiety, obsessive-compulsive behaviours, hyperactivity, impulsivity, inattention, perfectionism, resilience, sleep problems and eating behaviour.
40 adolescents were classified as having Type 1 diabetes (prevalence 0.4%). We found that adolescents with Type 1 diabetes did not differ from their peers on any of the mental health measures.
This is one of the first population-based studies to examine mental health of adolescents with Type 1 diabetes. There was no evidence of increased psychopathology across a wide range of mental health measures. These findings contradict previous studies, and suggest that Type 1 diabetes is not associated with an increased risk of psychosocial problems.
PMCID: PMC4197324  PMID: 25303963
Type 1 diabetes; Mental health; Eating disturbances; Sleep; Correlates; Epidemiology
17.  Relationship between social determinants of health and processes and outcomes in adults with type 2 diabetes: validation of a conceptual framework 
BMC Endocrine Disorders  2014;14(1):82.
The aim of this study was to empirically validate a conceptual framework and elucidate the pathways linking social determinants of health to outcomes in individuals with type 2 diabetes.
615 adults were recruited from adult primary care clinics in the southeastern United States. The model was estimated using path analysis to determine if socioeconomic (education, employment, income) and psychosocial (fatalism, self-efficacy, depression, diabetes distress, serious psychological distress, social support, and perceived stress) factors would independently predict glycemic control or be associated with mediator/moderators of self-care, access to care, and processes of care. Covariates were gender, age, race and health literacy.
The final model (chi2 (15) = 17.68, p = 0.28; RMSEA = 0.02, CFI = 0.99) showed lower glycemic control was directly associated with less hours worked (r = 0.13, p = 0.002), more fatalistic attitudes (r = −0.09, p = 0.03), more self-efficacy (r = −0.30, p < 0.001), and less diabetes distress (r = 0.12, p = 0.03), with the majority of total effects being direct. Significant paths associated self-care with diabetes distress (r = −0.14, p = 0.01) and perceived stress (r = −0.15, p = .001); access to care with income (r = 0.08, p = 0.03), diabetes distress (r = −0.21, p < 0.001) and social support (r = 0.08, p = 0.03); and processes of care with income (r = −0.11, p = 0.03), social support (r = 0.10, p = 0.04), and perceived stress (r = 0.10, p = 0.04). The paths explained 76% of the variance in the model.
Consistent with the conceptual framework, social determinants were associated with glycemic control through a direct association and mediators/moderators of self-care, access to care and processes of care. This study provides the first validation of a conceptual framework for the relationship between socioeconomic and psychological components of social determinants of health and diabetes outcomes.
PMCID: PMC4203970  PMID: 25298071
Diabetes; Social determinants; Socioeconomic; Psychological; Glycemic control; Conceptual framework
18.  A novel mutation in calcium-sensing receptor gene associated to hypercalcemia and hypercalciuria 
BMC Endocrine Disorders  2014;14(1):81.
Familial Hyperparathyroidism (HPT) and Familial benign Hypocalciuric Hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. FHH has been demonstrated to be caused by inactivating mutations of calcium-sensing receptor (CaSR) gene, involved in PTH regulation as well as in renal calcium excretion.
Case presentation
In two individuals, father and son, we found a novel heterozygous mutation in CaSR gene. The hypercalcemia was present only in father, which, by contrast to the classic form of FHH showed hypercalciuria (from 300 to 600 mg/24 h in different evaluations) and a Calcium/Creatinine ratio of 0.031, instead of low or normal calciuria (<0.01 typical finding in FHH). His son showed the same mutation in CaSR gene, but no clinical signs or hypercalcemia although serum ionized calcium levels were close to the upper limit of normal values (1.30 mmol/L: normal range: 1.12-1.31 mmol/L). Sequence analysis revealed a point mutation at codon 972 of CaSR gene (chromosome 3q), located within cytoplasmic domain of the CaSR, that changes Threonine with Methionine. The father was treated with Cinacalcet 90 mg/day, with a decrease of total serum calcemia from an average value of 12.2 mg/dl to 10.9 mg/dl.
This is a case of a novel inactivating point mutation of CaSR gene that determines an atypical clinical presentation of FHH, characterized by hypercalcemia, hypercalciuria and inadequate normal PTH levels. Functional assay demonstrated that the 972 M variant influenced the maturation of the protein, in terms of the post-translational glycosylation. The impairment of the receptor activity is in keeping with the specific localization of the 972 residue in the C-terminal tail, assigned to the intracellular signalling, that on the basis of the our findings appears to be differently modulated in parathyroid gland and in kidney.
PMCID: PMC4197257  PMID: 25292184
CaSR gene; Hyperparathyroidism; FHH; Hypercalcemia; Hypercalciuria; Hypocalciuria
19.  Evaluation of pituitary function after infectious meningitis in childhood 
BMC Endocrine Disorders  2014;14(1):80.
A number of studies of adults have shown that pituitary deficiencies can develop in a considerable proportion of subjects during the acute phase of meningitis or years after the infection has disappeared. The results of the very few studies of the impact of pediatric meningitis on hypothalamic-pituitary function are conflicting.
In order to determine the incidence of pituitary dysfunction in children with central nervous system infection, we evaluated pituitary function and anthropometric parameters in 19 children with meningitis of different etiologies (15 males; mean age ± standard deviation [SD] at pituitary evaluation, 5.9 ± 4.0 years; mean time from the acute event ± SD, 18 ± 10 months).
All of the subjects had a normal stature and growth velocity for their age and gender, and none of them was obese. On the basis of Tanner’s reference charts, 17 subjects (13 boys and all four girls) were pre-pubertal; two boys were in Tanner stage 2. None of the subjects had central hypothyroidism. All of the patients had normal serum of insulin growth factor (IGF)-I and prolactin. Their sex steroid and gonadotropin levels were concordant with their age and pubertal status. Early morning urine osmolality and serum electrolyte levels showed no signs of diabetes insipidus. All of the patients had normal plasma adrenocorticotropic hormone (ACTH) levels. Peak cortisol responses to the standard dose Synacthen test (SDST) were normal in all cases.
The results showed that hypopituitarism following infectious meningitis appears to be infrequent in childhood and children’s pituitary glands seem to be less vulnerable to damage than those of adults.
PMCID: PMC4196011  PMID: 25287789
Hypopituitarism; Meningitis; GH deficiency; Hypodrenalism; Pediatric infectious diseases
20.  A descriptive study of adrenal crises in adults with adrenal insufficiency: increased risk with age and in those with bacterial infections 
BMC Endocrine Disorders  2014;14(1):79.
An adrenal crisis (AC) is a major cause of morbidity in hypoadrenal patients. However, there is little information available on the incidence and underlying causes of AC.
The aim of the present study was to describe the incidence of AC in New South Wales (NSW), Australia. Using a health department database, we selected de-identified data on all adults aged 20 years and over who were treated in any hospital in NSW between July1, 2000-June 30, 2011, with either a principal or secondary diagnosis of an AC. AC admission rates were calculated overall and within age categories. Frequencies of co-morbid diagnoses were analysed by age and sex groups. Poisson regression was used to assess the significance of the observed change in AC related admissions with age, while controlling for any secular trends by including year in the model. Chi sq tests were used to assess the differences in frequencies of categorical variables between groups.
824 patients received treatment for an AC in hospital, corresponding to 74.9 admissions/year. The majority (62.5%) of the patients were women and 52.8% were aged 60 years and over. Admission rates were significantly associated with increasing age (p < 0.0001). Patients in the 60–69, 70–79 and 80+ age groups had the highest average admission rates (24.3, 35.2 and 45.8 per million/year). A principal or secondary diagnosis of an infection was reported in 317 (38.5%) patients and infection was significantly associated with age (p < 0.0001) with older patients having the highest proportion of cases. The most frequent infections were pneumonia/lower respiratory tract infection in 85 (10.3%) cases and urinary tract infection (UTI) in 82 (10.0%) patients. Women experienced 78.0% of the reported UTIs. There were 125 patients (15.2%) with an AC and a record of gastroenteritis. Twenty-six (3.2%) patients died in hospital but, of these, only 4 deaths (0.9%) were recorded among the 467 patients with a principal diagnosis of an AC.
The incidence of AC increases with age. Infections, especially bacterial infections, are associated with the incidence of ACs and this increases with age.
PMCID: PMC4200115  PMID: 25273066
Adrenal crisis; Hypoadrenalism; Infection
21.  Wasting syndrome with deep bradycardia as presenting manifestation of long-standing severe male hypogonadotropic hypogonadism: a case series 
Physiological functioning of the testes is important for cardiac health besides for virilisation, physical strength, behavior and reproduction; moreover, hypogonadism has been demonstrated as a significant risk marker of increased all-cause and cardiovascular mortality.
Cases presentation
We reported two cases of long-standing hypogonadotropic hypogonadism presenting with wasting, bradycardia and heart failure. The two patients were admitted to emergency department for deep weakness, unresponsive anemia and severe bradycardia, requiring in one case the implanting of a monocameral pace-maker for treatment of heart failure. No previous cardiologic disorders were known and cardiac ischemia was ruled out in both patients. The first patient presented congenital hypogonadotropic hypogonadism combined with mild central hypothyroidism and growth hormone deficiency occurred in the peripubertal age, while the second one was diagnosed with isolated adult-onset severe central hypogonadism. Testosterone deficiency was the main feature in both patients as physical examination revealed clinical stigmata of hypogonadism and testosterone replacement induced a dramatic improvement of general condition. Genetic analysis of genes involved in hypogonadotropic hypogonadism failed to identify alterations.
Long-standing hypogonadism in males can be associated with life threatening body alterations including severe bradycardia and heart failure.
PMCID: PMC4179860  PMID: 25260871
Hypogonadism; Bradycardia; Hypopituitarism; Heart failure
22.  Metabolic syndrome among a middle-aged population in the Red River Delta region of Vietnam 
Metabolic syndrome (MetS) is a clustering of metabolic risk factors for cardiovascular diseases and type 2 diabetes. The study aimed to estimate the prevalence of MetS, its components, and their associations among rural middle-aged population in Vietnam.
A cross-sectional study with a representative sample (n = 2443) was conducted to collect data on demographic, socioeconomic, anthropometric, lifestyles, plasma glucose, and lipid profile. The age- and sex-adjusted prevalences of MetS and its components were calculated using the direct standardization. Associations of risk factors with MetS were evaluated using logistic regression, taken into account the confounding factors.
The total age- and sex-adjusted prevalence (95% CI) of MetS was 16.3% (14.0 - 18.6). The most frequent component of MetS was high triglycerides (43.2%), followed by low HDL-C (42.0%), elevated blood pressure (29.2%), high plasma glucose (14.3%), and central obesity (12.3%). Of the total population, only 17.6% did not have any component of MetS and more than 40% had at least two MetS components. The association of MetS with residence, age, body mass index, marital status, and siesta time per day was statistically significant in univariate analysis and replicated in multivariate analysis.
The MetS prevalence and its components are common and major public health burden in the middle-aged adults in Vietnam. Habitants living in urban, being never-married, having an increase in age, BMI, and siesta time per day are significantly associated with MetS, and they should be paid much more attention for screening and implementing preventive activities.
PMCID: PMC4179436  PMID: 25261978
Metabolic syndrome; Population–based study; Prevalence; Associated factors; Vietnamese
23.  Prevalence and predictors of metabolic abnormalities in Chinese women with PCOS: a cross- sectional study 
Polycystic ovary syndrome (PCOS) is a common condition estimated to affect 5.61% of Chinese women of reproductive age, but little is known about the prevalence and predictors in Chinese PCOS patients. This study aimed to determine the prevalence and predictors of the metabolic abnormalities in Chinese women with and without PCOS.
A large-scale national epidemiological investigation was conducted in reproductive age women (19 to 45 years) across China. 833 reproductive aged PCOS women, who participated in the healthcare screening, were recruited from ten provinces in China. Clinical history, ultrasonographic exam (ovarian follicle), hormonal and metabolic parameters were the main outcome measures.
The prevalence of metabolic syndrome (MetS) as compared in PCOS and non-PCOS women from community were 18.2% vs 14.7%, and IR (insulin resistance) were 14.2% vs 9.3% (p < 0.001) respectively. After adjusting for age, the indicators (central obesity, hypertension, fasting insulin, SHBG, dyslipinaemia) for metabolic disturbances were significantly higher in PCOS than in non-PCOS groups. Using multivariate logistic regression, central obesity and FAI were risk factors, while SHBG was a protective factor on the occurrence of Mets and IR in PCOS women (OR: 1.132, 1.105 and 0.995).
The risk factors of the metabolic syndrome and insulin resistance were BMI and FAI for PCOS women, respectively. The decrease of SHBG level was also a risk factor for insulin resistance in both PCOS and metabolic disturbance.
PMCID: PMC4171713  PMID: 25223276
Prevalence; Predictor; Metabolic abnormalities; PCOS; Community
24.  Depression, smoking, physical inactivity and season independently associated with midnight salivary cortisol in type 1 diabetes 
Disturbances of the circadian rhythm of cortisol secretion are associated with depression, coronary calcification, and higher all-cause and cardiovascular mortality.
The primary aim of this study was to test the associations between midnight salivary cortisol (MSC), depression and HbA1c, and control for behavioural, environmental and intra individual factors with possible impact on cortisol secretion, like smoking, physical inactivity, season, medication, diabetes duration, severe hypoglycemia episodes, age and gender in patients with type 1 diabetes. Secondary aims were to present MSC levels for a reference group of non-depressed type 1 diabetes patients with a healthy life style (physically active and non-smoking), and to explore seasonal variations.
A cross-sectional population based study of 196 patients (54% men and 46% women) aged 18–59 years that participated in a randomized controlled trial targeting depression in type 1 diabetes. Depression was assessed by the Hospital Anxiety and Depression Scale-depression subscale. MSC, HbA1c, serum-lipids, blood pressure, waist circumference and data from medical records and the Swedish National Diabetes Registry were collected.
Thirty four patients (17%) had MSC ≥9.3 nmol/L, which was associated with smoking (AOR 5.5), spring season (AOR 4.3), physical inactivity (AOR 3.9), self-reported depression (AOR 3.1), and older age (per year) (AOR 1.08). HbA1c >70 mmol/mol (>8.6%) (AOR 4.2) and MSC ≥9.3 nmol/L (AOR 4.4) were independently linked to self-reported depression. Season was strongly associated with MSC levels and no other variables studied showed seasonal variations. In a reference group of 137 non-depressed patients with a healthy life style (physically active, non-smoking) the median MSC level was 4.6 nmol/L (range 1.9–23.0).
In this study of patients with type 1 diabetes high MSC was linked to smoking, physical inactivity, depression, season and older age. Thus a high cortisol value identified three major targets for treatment in type 1 diabetes.
PMCID: PMC4236572  PMID: 25224993
Midnight salivary cortisol; Depression; Type 1 diabetes; Smoking; Physical activity; Season; HbA1c
25.  Lifestyle and clinical factors associated with elevated C-reactive protein among newly diagnosed Type 2 diabetes mellitus patients: a cross-sectional study from the nationwide DD2 cohort 
We aimed to examine the prevalence of and modifiable factors associated with elevated C-reactive Protein (CRP), a marker of inflammation, in men and women with newly diagnosed Type 2 Diabetes mellitus (DM) in a population-based setting.
CRP was measured in 1,037 patients (57% male) with newly diagnosed Type 2 DM included in the prospective nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. We assessed the prevalence of elevated CRP and calculated relative risks (RR) examining the association of CRP with lifestyle and clinical factors by Poisson regression, stratified by gender. We used linear regression to examine the association of CRP with other biomarkers.
The median CRP value was 2.1 mg/L (interquartile range, 1.0 – 4.8 mg/L). In total, 405 out of the 1,037 Type 2 DM patients (40%) had elevated CRP levels (>3.0 mg/L). More women (46%) than men (34%) had elevated CRP. Among women, a lower risk of elevated CRP was observed in patients receiving statins (adjusted RR (aRR) 0.7 (95% confidence interval (CI) 0.6-0.9)), whereas a higher risk was seen in patients with central obesity (aRR 2.3 (95% CI 1.0-5.3)). For men, CRP was primarily elevated among patients with no regular physical activity (aRR 1.5 (95% CI 1.1-1.9)), previous cardiovascular disease (aRR1.5 (95% CI 1.2-1.9) and other comorbidity. For both genders, elevated CRP was 1.4-fold increased in those with weight gain >30 kg since age 20 years. Sensitivity analyses showed consistent results with the full analysis. The linear regression analysis conveyed an association between high CRP and increased fasting blood glucose.
Among newly diagnosed Type 2 DM patients, 40% had elevated CRP levels. Important modifiable risk factors for elevated CRP may vary by gender, and include low physical activity for men and central obesity and absence of statin use for women.
PMCID: PMC4161271  PMID: 25163828
C-reactive protein; Lifestyle factors; Obesity; Physical activity

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