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1.  Increased waist circumference is independently associated with hypothyroidism in Mexican Americans: replicative evidence from two large, population-based studies 
Background
Mexican Americans are at an increased risk of both thyroid dysfunction and metabolic syndrome (MS). Thus it is conceivable that some components of the MS may be associated with the risk of thyroid dysfunction in these individuals. Our objective was to investigate and replicate the potential association of MS traits with thyroid dysfunction in Mexican Americans.
Methods
We conducted association testing for 18 MS traits in two large studies on Mexican Americans – the San Antonio Family Heart Study (SAFHS) and the National Health and Nutrition Examination Survey (NHANES) 2007–10. A total of 907 participants from 42 families in SAFHS and 1633 unrelated participants from NHANES 2007–10 were included in this study. The outcome measures were prevalence of clinical and subclinical hypothyroidism and thyroid function index (TFI) – a measure of thyroid function. For the SAFHS, we used polygenic regression analyses with multiple covariates to test associations in setting of family studies. For the NHANES 2007–10, we corrected for the survey design variables as needed for association analyses in survey data. In both datasets, we corrected for age, sex and their linear and quadratic interactions.
Results
TFI was an accurate indicator of clinical thyroid status (area under the receiver-operating-characteristic curve to detect clinical hypothyroidism, 0.98) in both SAFHS and NHANES 2007–10. Of the 18 MS traits, waist circumference (WC) showed the most consistent association with TFI in both studies independently of age, sex and body mass index (BMI). In the SAFHS and NHANES 2007–10 datasets, each standard deviation increase in WC was associated with 0.13 (p < 0.001) and 0.11 (p < 0.001) unit increase in the TFI, respectively. In a series of polygenic and linear regression models, central obesity (defined as WC ≥ 102 cm in men and ≥88 cm in women) was associated with clinical and subclinical hypothyroidism independent of age, sex, BMI and type 2 diabetes in both datasets. Estimated prevalence of hypothyroidism was consistently high in those with central obesity, especially below 45y of age.
Conclusions
WC independently associates with increased risk of thyroid dysfunction. Use of WC to identify Mexican American subjects at high risk of thyroid dysfunction should be investigated in future studies.
doi:10.1186/1472-6823-14-46
PMCID: PMC4057819  PMID: 24913450
Waist circumference; Central obesity; Thyroid dysfunction; Mexican Americans
2.  Epidemiology and costs of diabetes mellitus in Switzerland: an analysis of health care claims data, 2006 and 2011 
Background
Quantifying the burden of diabetes mellitus is fundamental for managing patients in health service delivery systems and improves the understanding of the importance of prevention and early intervention of diabetes. In Switzerland, epidemiological data on diabetes are very scarce. In this study we provide a first national overview of the current situation of diabetes mellitus in Switzerland as well as the development of the prevalence, incidence, mortality and costs between 2006 and 2011.
Methods
Using health care claims data of a large health insurance group, current epidemiology and costs were determined from a sample of adult enrollees in 2011. The identification of patients with diabetes was based on prescription data of diabetes related drugs using the Anatomical Therapeutic Chemical Classification as proxy for clinical diagnosis. We further evaluated changes in epidemiology and costs between 2006 and 2011. All results were weighted with census data to achieve an extrapolation to the Swiss general population level.
Results
A total of 920’402 patients were enrolled in 2011 and 49’757 (5.4%) were identified as diabetes cases. The extrapolated overall prevalence of diabetes in Switzerland was 4.9% (2006, 3.9%). The incidence was 0.58% in 2011 (2007, 0.63%). The extrapolated mortality rate was 2.6% with no significant change over time. Annual diabetes costs to the mandatory health insurance increased from EUR 5,036 per patient in 2006 to EUR 5’331 per patient in 2011.
Conclusions
This study shows a high medical and economic burden of diabetes. The prevalence and costs of diabetes in Switzerland increased substantially over time. Findings stress the need for public health strategies to manage patients with chronic conditions and optimize resource allocation in health service delivery systems.
doi:10.1186/1472-6823-14-44
PMCID: PMC4048540  PMID: 24894889
Diabetes; Prevalence; Incidence; Mortality; Costs
3.  Testicular histological and immunohistochemical aspects in a post-pubertal patient with 5 alpha-reductase type 2 deficiency: case report and review of the literature in a perspective of evaluation of potential fertility of these patients 
Background
Testicular morphology and immunohistochemical studies have never been reported in genetically documented adult patients with 5 alpha-reductase type 2 deficiency (5α-R2 deficiency).
Case presentation
We describe the testicular histopathology of a 17-year-old XY subject with 5α-R2 deficiency caused by the recurrent homozygous Gly115Asp loss of function mutation of the SRD5A2 gene.We also performed an immunohistochemical analysis in order to further study the relationship between seminiferous tubules structure, Sertoli cell differentiation and androgenic signaling impairment in this case. We thus evaluated the testicular expression of the anti-Müllerian hormone (AMH), androgen receptor (AR) and 3β-hydroxysteroid dehydrogenase (3βHSD). Histological analysis revealed a heterogeneous aspect with a majority (92%) of seminiferous tubules (ST) presenting a mature aspect but containing only Sertoli cells and devoid of germ cells and spermatogenesis. Focal areas of immature ST (8%) were also found. Testicular AR and 3βHSD expression were detected in adult male control, 5α-R2 deficiency and CAIS subjects. However, AMH expression was heterogeneous (detectable only in few AR negative prepubertal ST, but otherwise repressed) in the 5α-R2 deficiency, conversely to normal adult testis in which AMH was uniformly repressed and to an adult CAIS testis in which AMH was uniformly and strongly expressed.
Conclusion
Intratesticular testosterone can repress AMH by itself, independently of its metabolism into dihydrotestosterone. We also compare our results to the few post pubertal cases of 5α-R2 deficiency with available histological testicular description, reported in the literature. We will discuss these histological findings, in the more general context of evaluating the fertility potential of these patients if they were raised as males and were azoospermic.
doi:10.1186/1472-6823-14-43
PMCID: PMC4041634  PMID: 24885102
5α-reductase type 2 deficiency; Testicular histology; Sertoli cell; Anti-Müllerian hormone; Androgen receptor
4.  Prevalence and correlates of diabetes mellitus in Malawi: population-based national NCD STEPS survey 
Background
Previously considered as a disease of the affluent, west or urban people and not of public health importance, diabetes mellitus is increasingly becoming a significant cause of morbidity and mortality in sub-Saharan Africa. However, population-based data to inform prevention, treatment and control are lacking.
Methods
Using the WHO STEPwise approach to chronic disease risk factor surveillance, a population-based, nationwide cross-sectional survey was conducted between July and September 2009 on participants aged 25–64 years. A multi-stage cluster sample design and weighting were used to produce a national representative data for that age range. Detailed findings on the magnitude of diabetes mellitus and impaired fasting blood glucose are presented in this paper.
Results
Fasting blood glucose measurement was conducted on 3056 participants (70.2% females, 87.9% from rural areas). The age- sex standardised population-based mean fasting blood glucose was 4.3 mmol/L (95% CI 4.1-4.4 mmol/L) with no significant differences by age, sex and location (urban/rural). The overall prevalence of impaired fasting blood glucose was 4.2% (95% CI 3.0%-5.4%). Prevalence of impaired blood glucose was higher in men than in women, 5.7% (95% CI 3.9%-7.5%) vs 2.7% (95% CI 1.6%- 3.8%), p < 0.01. In both men and women, prevalence of raised fasting blood glucose or currently on medication for diabetes was 5.6% (95% CI 2.6%- 8.5%). Although the prevalence of diabetes was higher in men than women, 6.5% (95% CI 2.6%-10.3%) vs 4.7% (95% CI 2.4%-7.0%), in rural than urban, 5.4% (95% CI 2.4%-8.4%) vs 4.4% (95% CI 2.8%-5.9%) and in males in rural than males in urban, 6.9% (95% CI 2.8%-11.0%) vs 3.2% (95% CI 0.1%-6.3%), the differences were not statistically significant, p > 0.05. Compared to previous estimates, prevalence of diabetes increased from <1.0% in 1960s to 5.6% in 2009 (this study).
Conclusion
High prevalence of impaired fasting blood glucose and diabetes mellitus call for the implementation of primary healthcare approaches such as the WHO package for essential non-communicable diseases to promote healthy lifestyles, early detection, treatment and control.
doi:10.1186/1472-6823-14-41
PMCID: PMC4018960  PMID: 24884894
Diabetes; Non-communicable diseases; Sub-Saharan Africa; Malawi
5.  Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia 
Background
Although chronic adrenocorticotropic hormone (ACTH) and androgen hyperstimulation are assumed to be involved in the pathogenesis of adrenal myelolipomas associated with poor-compliance patients with congenital adrenal hyperplasia (CAH), the expression of their receptors has not yet been demonstrated in these tumors so far.
Methods
We analyzed Melanocortin 2 receptor (MC2R), Androgen Receptor (AR), Leptin (LEP), and Steroidogenic factor 1 (SF1) expression using real-time qRT-PCR in two giant bilateral adrenal myelolipomas from two untreated simple virilizing CAH cases and in two sporadic adrenal myelolipomas. In addition, the X-chromosome inactivation pattern and CAG repeat numbers in AR exon 1 gene were evaluated in the 4 cases.
Results
The MC2R gene was overexpressed in myelolipomas from 3 out of 4 patients. AR overexpression was detected in 2 tumors: a giant bilateral myelolipoma in a CAH patient and a sporadic case. Simultaneous overexpression of AR and MC2R genes was found in two of the cases. Interestingly, the bilateral giant myelolipoma associated with CAH that had high androgen and ACTH levels but lacked MC2R and AR overexpression presented a significantly shorter AR allele compared with other tumors. In addition, X-chromosome inactivation pattern analysis showed a polyclonal origin in all tumors, suggesting a stimulatory effect as the trigger for tumor development.
Conclusion
These findings are the first evidence for MC2R or AR overexpression in giant bilateral myelolipomas from poor-compliance CAH patients.
doi:10.1186/1472-6823-14-42
PMCID: PMC4024625  PMID: 24884994
Adrenal myelolipoma; Congenital adrenal hyperplasia; ACTH; MC2R; Androgen receptor; Clonality analysis
6.  Service usage and vascular complications in young adults with type 1 diabetes 
Background
Few studies have examined young adults with type 1 diabetes use of health services and the development of vascular complications. As part of the Youth Outreach for Diabetes (YOuR-Diabetes) project, this study identified health service usage, the prevalence and factors predictive of development of vascular complications (hypertension, retinopathy and nephropathy) in a cohort of young adults (aged 16–30 years) with type 1 diabetes in Hunter New England and the Lower Mid-North Coast area of New South Wales, Australia.
Methods
A cross-sectional retrospective documentation survey was undertaken of case notes of young adults with type 1 diabetes accessing Hunter New England Local Health District public health services in 2010 and 2011, identified through ambulatory care clinic records, hospital attendances and other clinical records. Details of service usage, complications screening and evidence of vascular complications were extracted. Independent predictors were modelled using linear and logistic regression analyses.
Results
A cohort of 707 patients were reviewed; mean (SD) age was 23.0 (3.7) years, with mean diabetes duration of 10.2 (5.8, range 0.2 - 28.3) years; 42.4% lived/ 23.1% accessed services in non-metropolitan areas.
Routine preventative service usage was low and unplanned contacts high; both deteriorated with increasing age. Low levels of complications screening were found. Where documented, hypertension, particularly, was common, affecting 48.4% across the study period. Diabetes duration was a strong predictor of vascular complications along with glycaemic control; hypertension was linked with renal dysfunction.
Conclusion
Findings indicate a need to better understand young people’s drivers and achievements when accessing services, and how services can be reconfigured or delivered differently to better meet their needs and achieve better outcomes. Regular screening is required using current best practice guidelines as this affords the greatest chance for early complication detection, treatment initiation and secondary prevention.
doi:10.1186/1472-6823-14-39
PMCID: PMC4017963  PMID: 24884679
‘Service usage’; Health services; ‘Vascular complications’; ‘Prevalence’; ‘Prediction’; ‘Retinopathy’; ‘Nephropathy’; ‘Hypertension’; ‘Blood pressure’; ‘Young adults’; ‘Type 1 diabetes’
7.  European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy 
Background
Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93–140/million), secondary AI (estimated prevalence, 150–280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387).
Methods
Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy.
Results
Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands.
Conclusions
EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.
doi:10.1186/1472-6823-14-40
PMCID: PMC4049497  PMID: 24884782
8.  Central precocious puberty in a 3 year-old girl with Phenylketonuria: a rare association? 
Background
Central precocious puberty (CPP) and phenylketonuria (PKU) are two rare conditions, the latter being the rarer. To date, only one case featuring both these conditions has been reported, and hyperphenylalaninemia was assumed triggering CPP.
Case presentation
We present a 3.2 years old girl referred with a 12 months history of breast and pubic hair development, and vaginal discharge. Hyperphenylalaninemia had been identified by newborn screening and PKU subsequently confirmed by plasma amino acid and genetic analysis. Early dietary control of plasma phenylalanine had been excellent afterwards, resulting in phenylalanine concentrations consistently within the recommended range. Clinical scenario, hormonal assessment and imaging were in keeping with true idiopathic central precocious puberty. Treatment with long lasting gonadotropin-releasing hormone analogue led to regression of secondary sexual characteristics.
Conclusion
We describe for the first time CPP in a girl affected with PKU but with persistently well controlled blood phenylalanine concentrations. This finding is in contrast to a previous report which suggested persistently high phenylalaninemia levels as potential trigger for CPP in PKU patients. Our report, together with the lack of evidence in published cohort studies of children with PKU, strongly suggests this rare association is coincidental and independent of the presence of severe hyperphenylalaninemia.
doi:10.1186/1472-6823-14-38
PMCID: PMC4013055  PMID: 24773629
Precocious puberty; Phenylketonuria; Hyperphenylalaninaemia; Gonadotropin-realising hormone agonist treatment
9.  Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies 
Background
Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ≥65 years of age.
Methods
Pooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N = 2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n = 1,868; mean age, 52.8 years) or ≥65 years (n = 445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids.
Results
Canagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ≥65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ≥65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ≥65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ≥65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ≥65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ≥65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets.
Conclusions
Canagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM.
Trial registration
ClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.
doi:10.1186/1472-6823-14-37
PMCID: PMC4021426  PMID: 24742013
Canagliflozin; Type 2 diabetes mellitus; Sodium glucose co-transporter 2 (SGLT2) inhibitor; Antihyperglycaemic agent; Older patients
10.  Ectopic insulin secreting neuroendocrine tumor of kidney with recurrent hypoglycemia: a diagnostic dilemma 
Background
Hypoglycemia secondary to ectopic insulin secretion of non-pancreatic tumors is rare.
Case presentation
We describe a middle aged woman with recurrent hypoglycemia. On evaluation, she was detected to have hyperinsulinemic hypoglycemia and right sided renal mass lesion. 68Ga-Dotanoc and 99mTc-HYNICTOC scans confirmed the intrarenal mass to be of neuroendocrine origin. Right nephrectomy was done and it turned out to be an insulin secreting neuroendocrine tumour. Neuroendocrine nature of this tumour was further confirmed by ultra-structural examination. Her hypoglycemia did not recur after resection of this tumour.
Conclusion
Few cases of ectopic insulin secretion have been reported though some are not proven convincingly. This case addresses all the issues raised in previous case reports and proves by clinical, laboratory, functional imaging and immunohistochemical analysis that ectopic origin of insulin by non-pancreatic tumors does occur. To our knowledge, this is the first reported case of ectopic insulinoma arising from the kidney.
doi:10.1186/1472-6823-14-36
PMCID: PMC4046058  PMID: 24741994
Hyperinsulinemic hypoglycemia; Neuroendocrine tumour; Insulinoma; Carcinoid tumor; Renal tumour; 68Ga-Dotanoc scan; 99mTc-HYNICTOC scan
11.  Effects of human insulin and insulin aspart preparations on levels of IGF-I, IGFBPs and IGF bioactivity in patients with type 1 diabetes 
Background
Insulin aspart (IAsp) and its biphasic preparations BIAsp50 and BIAsp70 (containing 50% and 70% IAsp, respectively) have distinct glucose-lowering properties as compared to human insulin (HI). We investigated whether this affected the circulating IGF-system which depends on the hepatic insulin exposure.
Methods
In a randomized, four-period crossover study, 19 patients with type 1 diabetes received identical doses (0.2 U/kg sc) of IAsp, BIAsp70, BIAsp50 and HI together with a standardized meal. Serum total IGF-I and IGFBP-1 to -3 were measured by immunoassays for nine hours post-prandially. Bioactive IGF was determined by an in-house, cell-based IGF-I receptor kinase activation (KIRA) assay.
Results
Despite marked differences in peripheral insulin concentrations and plasma glucose, the four insulin preparations resulted in parallel decreases in IGFBP-1 levels during the first 3 hours, and parallel increases during the last part of the study (3–9 hours). Thus, only minor significances were seen. Insulin aspart and human insulin resulted in a lower area under the curve (AUC) during the first 3 hours as compared to BIAsp70 (p = 0.009), and overall, human insulin resulted in a lower IGFBP-1 AUC than BIAsp70 (p = 0.025). Nevertheless, responses and AUCs of bioactive IGF were similar for all four insulin preparations. Changes in levels of bioactive IGF were inversely correlated to those of IGFBP-1, increasing during the first 3 hours, whereafter levels declined (-0.83 ≤ r ≤ -0.30; all p-values <0.05).
Total IGF-I and IGFBP-3 remained stable during the 9 hours, whereas IGFBP-2 changed opposite of IGFBP-1, increasing after 3–4 hours whereafter levels gradually declined. The four insulin preparations resulted in similar profiles and AUCs of total IGF-I, IGFBP-2 and IGFBP-3.
Conclusions
Despite distinct glucose-lowering properties, the tested insulin preparations had similar effects on IGF-I concentration and IGF bioactivity, IGFBP-2 and IGFBP-3 as compared to HI; only small differences in IGFBP-1 were seen and they did not affect bioactive IGF. Thus, insulin aspart containing preparation behaves as HI in regards to the circulating IGF-system. However, bioactive IGF appeared to be more sensitive to insulin exposure than total IGF-I. The physiological significance of this finding remains to be determined.
Trial registration
NCT00888732
doi:10.1186/1472-6823-14-35
PMCID: PMC3986432  PMID: 24725803
Insulin; Insulin analogue; IGF; IGFBP
12.  A case of osmotic demyelination syndrome occurred after the correction of severe hyponatraemia in hyperemesis gravidarum 
Background
Osmotic demyelination syndrome (ODS) may be observed as a result of a rapid change in serum osmolarity, such as that induced by an overly rapid correction of serum sodium levels in hyponatraemic patients.
Case presentation
We describe the case of a 21-year-old woman who was hospitalized at week 10 of gestation because of severe hyperemesis. At admission the patient appeared restless and confused and severe hyponatraemia (serum sodium 107 mmol/L) and hypokalemia (serum potassium 1.1 mmol/L) were detected. Active and simultaneous correction of these imbalances led to an overly rapid increase of serum sodium levels (17 mmol/L in the first 24 hours). Isotonic saline solution was stopped and replaced by 5% dextrose solution infusion. However, the neurological alterations worsened and the radiological features were consistent with the diagnosis of extra-pontine ODS. Steroids were administered intravenously with progressive improvement of biochemical and clinical abnormalities. At the time of discharge, 20 days later, the patient was able to walk and eat autonomously with only minimal external support.
Conclusions
This report illustrates an unusual case of ODS, occurred after an excessive rate of correction of hyponatraemia obtained with isotonic saline infusion. Hypokaliemia and its active correction very likely played a crucial role in facilitating the onset of ODS. This interesting aspect will be explained in detail in the article. A more cautious and thoughtful correction of electrolyte alterations, would have probably prevented the onset of ODS in this patient. Physicians should be aware of the possibly fatal consequences that an exceedingly rapid change of serum osmolarity may have and should strictly follow the known safety measures in order to prevent it to occur.
doi:10.1186/1472-6823-14-34
PMCID: PMC3989779  PMID: 24725751
Osmotic demyelination syndrome; Hyponatraemia; Pregnancy
13.  Prevalence and determinants of osteoporosis in patients with type 1 and type 2 diabetes mellitus 
Background
Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in patients with type 1 and 2 diabetes.
Methods
Three hundred and ninety-eight consecutive diabetic patients from a single outpatient clinic received a standardized questionnaire on osteoporosis risk factors, and were evaluated for diabetes-related complications, HbA1c levels, and lumbar spine (LS) and femoral neck (FN) BMD. Of these, 139 (71 men, 68 women) type 1 and 243 (115 men, 128 women) type 2 diabetes patients were included in the study. BMD (T-scores and values adjusted for age, BMI and duration of disease) was compared between patient groups and between patients with type 2 diabetes and population-based controls (255 men, 249 women).
Results
For both genders, adjusted BMD was not different between the type 1 and type 2 diabetes groups but was higher in the type 2 group compared with controls (p < 0.0001). Osteoporosis prevalence (BMD T-score < −2.5 SD) at FN and LS was equivalent in the type 1 and type 2 diabetes groups, but lower in type 2 patients compared with controls (FN: 13.0% vs 21.2%, LS: 6.1% vs 14.9% men; FN: 21.9% vs 32.1%, LS: 9.4% vs 26.9% women). Osteoporosis prevalence was higher at FN-BMD than at LS-BMD. BMD was positively correlated with BMI and negatively correlated with age, but not correlated with diabetes-specific parameters (therapy, HbBA1c, micro- and macrovascular complications) in all subgroups. Fragility fracture prevalence was low (5.2%) and not different between diabetes groups. Fracture patients had lower BMDs compared with those without fractures; however, BMD T-score was above −2.5 SD in most patients.
Conclusions
Diabetes-specific parameters did not predict BMD. Fracture occurrence was similar in both diabetes groups and related to lower BMD, but seems unrelated to the threshold T-score, <−2.5 SD. These results suggest that osteoporosis, and related fractures, is a clinically significant and commonly underestimated problem in diabetes patients.
doi:10.1186/1472-6823-14-33
PMCID: PMC4021186  PMID: 24721668
Bone mineral density; Diabetes mellitus; Fractures; Osteoporosis; Vascular complications
14.  1,25-dihydroxyvitamin D and PTHrP mediated malignant hypercalcemia in a seminoma 
Background
Seminomas have been rarely associated with malignant hypercalcemia. The responsible mechanism of hypercalcemia in this setting has been described to be secondary to 1,25-dihydroxyvitamin D secretion. The relationship with PTHrP has not been determined or studied.
The aim of this study is to describe and discuss the case and the pathophysiological mechanisms involved in a malignant hypercalcemia mediated by 1,25-dihydroxyvitamin D and PTHrP cosecretion in a patient with seminoma.
Case presentation
A 35-year-old man was consulted for assessment and management of severe hypercalcemia related to an abdominal mass. Nausea, polyuria, polydipsia, lethargy and confusion led him to the emergency department. An abdominal and pelvic enhanced CT confirmed a calcified pelvic mass, along with multiple retroperitoneal lymphadenopathy. Chest x-ray revealed “cannon ball” pulmonary metastases. The histopathology result was consistent with a seminoma. Serum calcium was 14.7 mg/dl, PTH was undetectable, 25-dihydroxyvitamin D was within normal values and PTHrP and 1,25-dihydroxyvitamin were elevated (35.0 pg/ml, and 212 pg/ml, respectively). After the first cycle of chemotherapy with bleomycin, etoposide and cisplatin, normocalcemia was restored. Both PTHrP and 1,25-dihydroxyvitamin D, dropped dramatically to 9.0 pg/ml and 8.0 pg/ml, respectively.
Conclusion
The association of seminoma and malignant hypercalcemia is extremely rare. We describe a case of a patient with a seminoma and malignant hypercalcemia related to paraneoplastic cosecretion of 1,25-dihydroxyvitamin D and PTHrP. After successful chemotherapy, calcium, PTHrP and 1,25-Dihydroxyvitamin D returned to normal values.
doi:10.1186/1472-6823-14-32
PMCID: PMC3991903  PMID: 24721620
1,25-dihydroxyvitamin D; Calcitriol; PTHrP; Malignant hypercalcemia; Seminoma
15.  A pilot study: the development of a culturally tailored Malaysian Diabetes Education Module (MY-DEMO) based on the Health Belief Model 
Background
Diabetes education and self-care remains the cornerstone of diabetes management. There are many structured diabetes modules available in the United Kingdom, Europe and United States of America. Contrastingly, few structured and validated diabetes modules are available in Malaysia. This pilot study aims to develop and validate diabetes education material suitable and tailored for a multicultural society like Malaysia.
Methods
The theoretical framework of this module was founded from the Health Belief Model (HBM). The participants were assessed using 6-item pre- and post-test questionnaires that measured some of the known HBM constructs namely cues to action, perceived severity and perceived benefit. Data was analysed using PASW Statistics 18.0.
Results
The pre- and post-test questionnaires were administered to 88 participants (31 males). In general, there was a significant increase in the total score in post-test (97.34 ± 6.13%) compared to pre-test (92.80 ± 12.83%) (p < 0.05) and a significant increase in excellent score (>85%) at post-test (84.1%) compared to pre-test (70.5%) (p < 0.05). There was an improvement in post-test score in 4 of 6 items tested. The remaining 2 items which measured the perceived severity and cues to action had poorer post-test score.
Conclusions
The preliminary results from this pilot study suggest contextualised content material embedded within MY DEMO maybe suitable for integration with the existing diabetes education programmes. This was the first known validated diabetes education programme available in the Malay language.
doi:10.1186/1472-6823-14-31
PMCID: PMC4005520  PMID: 24708715
Self-efficacy; Validation; Education; Module; Knowledge; Health-belief model
16.  Continuous intraperitoneal insulin infusion in type 1 diabetes: a 6-year post-trial follow-up 
Background
Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a treatment option for patients with type 1 diabetes mellitus (T1DM). Aim of the present study was to describe the long-term course of glycaemic control, complications, health related quality of life (HRQOL) and treatment satisfaction among T1DM patients treated with CIPII.
Methods
Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) therapy in 2006 were followed until 2012. Laboratory, continuous glucose monitoring, HRQOL and treatment satisfaction measurements were performed at the start of the study, the end of the SC-, the end of the CIPII treatment phase in 2006 and during CIPII therapy in 2012. Linear mixed models were used to calculate estimated values and to test differences between the moments in time.
Results
In 2012, more time was spent in hyperglycaemia than after the CIPII treatment phase in 2006: 37% (95% CI 29, 44) vs. 55% (95% CI 48, 63), mean difference 19.8% (95% CI 3.0, 36.6). HbA1c was 65 mmol/mol (95% CI 60, 71) at the end of the SC treatment phase in 2006, 58 mmol/mol (95% CI 53, 64) at the end of the CIPII treatment phase and 65 mmol/mol (95% CI 60, 71) in 2012, respectively (p > 0.05). In 2012, the median number of grade 2 hypoglycaemic events per week (1 (95% CI 0, 2)) was still significantly lower than during prior SC therapy (3 (95% CI 2, 4)): mean change -1.8 (95% CI -3.4, -0.4). Treatment satisfaction with CIPII was better than with SC insulin therapy and HRQOL remained stable. Pump or catheter dysfunction of the necessitated re-operation in 7 patients. No mortality was reported.
Conclusions
After 6 years of CIPII treatment, glycaemic regulation is stable and the number of hypoglycaemic events decreased compared to SC insulin therapy. Treatment satisfaction with CIPII is superior to SC insulin therapy, HRQOL is stable and complications are scarce. CIPII is a safe and effective treatment option for selected patients with T1DM, also on longer term.
doi:10.1186/1472-6823-14-30
PMCID: PMC4029992  PMID: 24708696
Type 1 diabetes mellitus; Intraperitoneal insulin; Insulin infusion devices; Quality of life; Treatment satisfaction; Complications; Subcutaneous insulin
17.  The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene 
Background
Aldosterone synthase (CYP11B2) deficiency is a rare autosomal recessive disorder, usually presenting with severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood. Neonatal screening for congenital adrenal hyperplasia, another cause of salt wasting, using 17-hydroxyprogesterone measurement would fail to detect aldosterone synthase deficiency, a diagnosis which may be missed until the patient presents with salt-wasting crisis. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation for suspected patients would facilitate clinical management of the patient and assessment of the genetic implication in their offspring.
Case presentation
We describe a 33-year old Chinese man who presented in infancy with life-threatening hyponatraemia and failure to thrive, but remained asymptomatic on fludrocortisone since. Chromosomal analysis confirmed a normal male karyotype of 46, XY. Plasma steroid profile showed high plasma renin activity, low aldosterone level, and elevated 18-hydroxycorticosterone, compatible with type 2 aldosterone synthase deficiency. The patient was heterozygous for a novel CYP11B2 mutation: c.977C > A (p.Thr326Lys) in exon 3. He also carried a heterozygous mutation c.523_525delAAG (p.Lys175del) in exon 6, a known pathogenic mutation causing aldosterone synthase deficiency. Sequencing of CYP11B2 in his parents demonstrated that the mother was heterozygous for c.977C > A, and the father was heterozygous for c.523_525delAAG.
Conclusion
Although a rare cause of hyperreninaemic hypoaldosteronism, aldosterone synthase deficiency should be suspected and the diagnosis sought in patients who present with life-threatening salt-wasting in infancy, as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted. To our knowledge, this is the first Chinese patient in which the molecular basis of aldosterone synthase deficiency has been identified.
doi:10.1186/1472-6823-14-29
PMCID: PMC3976226  PMID: 24694176
Aldosterone synthase deficiency; Salt-wasting; Hypoaldosteronism
18.  Menstruation associated hypocalcemic symptoms and serum calcium in patients with idiopathic hypoparathyroidism 
Background
Some of the patients with idiopathic hypoparathyroidism (IHP) report symptoms of hypocalcemia during menstruation. There is limited data on this observation.
Methods
Twenty six menstruating women with IHP and 26 healthy controls were questioned regarding symptoms suggestive of hypocalcemia during menstruation. Twelve patients and eight controls were asked to prospectively monitor symptoms suggestive of hypocalcemia and premenstrual syndrome (PMS) if any, over two consecutive menstrual cycles. Serum ionized calcium (SiCa++), total and albumin adjusted calcium and intact paratharmone (iPTH) were measured at eight points covering menstrual, immediate post-menstrual, mid-cycle and premenstrual phase.
Results
Twelve of the 26 (46.2%) patients with IHP reported hypocalcemic symptoms during menstruation as compared to none of the controls. During prospective monitoring, there was no specific trend of hypocalcemic symptoms with respect to the phase of menstrual cycle. The mean SiCa++, serum total and albumin-adjusted calcium, iPTH and inorganic-phosphorus measured over two menstrual cycles were not significantly different in either of the two study groups. None of the subjects had PMS.
Conclusion
Women with IHP do not show any trend of hypocalcemic symptoms or fluctuations in serum calcium over different phases of menstrual cycles. Therefore, patients with hypoparathyroidism linking hypocalcemic symptoms with menstruation should be reassured regarding lack of this association.
doi:10.1186/1472-6823-14-28
PMCID: PMC3994449  PMID: 24655472
Hypoparathyroidism; Hypocalcemic symptoms; Ionized calcium; Menstruation
19.  Levels of brain natriuretic peptide are associated with peripheral arterial disease in subjects with type-2 diabetes mellitus 
Background
The effects of brain natriuretic peptide (BNP) on the risk of cardiovascular disease and atherosclerosis have been studied. However, little information is available regarding peripheral arterial disease (PAD), particularly among subjects with type-2 diabetes mellitus (T2DM). The aim of our study was to assess the potential relationship between BNP levels and PAD among T2DM patients.
Methods
The study cohort was 507 T2DM outpatients in which BNP levels were measured. Cross-sectional associations between BNP levels (in tertiles) and PAD were examined.
Results
Compared withT2DM patients without PAD, BNP levels were markedly higher in patients with PAD (p = 0.001). Correlation analyses showed that the BNP level was negatively correlated with the ankle–brachial index (r = −0.453, p = 0.033). At a cutoff value of 78.2 pg/ml, the BNP level showed a sensitivity of 71.9%, a specificity of 68.1%, and a positive predictive value of 84.3% for a diagnosis of PAD. The area under the receiver-operating characteristic curve increased significantly if BNP levels were incorporated into a predictive model of the potential risk factors for PAD (0.85 vs 0.81, p = 0.029).
Conclusions
BNP is a potential and promising biomarker for PAD screening in T2DM patients.
doi:10.1186/1472-6823-14-27
PMCID: PMC3998194  PMID: 24655436
Brain natriuretic peptide; Peripheral arterial disease; Type-2 diabetes mellitus
20.  Hand-foot syndrome associated with use of sorafenib in a patient with papillary thyroid cancer: a case report 
Background
Hand-foot syndrome (HFS), also known as palmar-plantar Erythrodysesthesia (PPE), acral erythema or Burgdorf reaction, is a dermatologic toxic reaction to certain chemotherapies, including sorafenib. A high incidence of adverse events is already described in dermatological clinical trials of this drug, but its use in medical practice, common in the patient with metastatic thyroid carcinoma has not yet been reported. Sorafenib (BAY 43-9006) is an orally administered multi-level kinase inhibitor, approved for treatment of solid tumors such as renal cell carcinoma, hepatocellular carcinoma and recently for metastatic thyroid carcinoma.
Case presentation
We report a case of a 29 year old Latin woman diagnosed with papillary thyroid carcinoma, who was initially given a total thyroidectomy, central and bilateral neck lymph node removal followed by a radioiodine therapy. Subsequent evaluation indicated locoregional progressive disease and metastatic involvement in both lungs. Following this, the patient was prescribed 200 mg of sorafenib administered every 12 hours, but after four days, she presented with a skin reaction compatible with hand-foot syndrome. After discontinuation of the therapy, this reaction ceased.
Conclusion
Sorafenib as a new therapeutic option for patients with radioactive iodine (RAI)-resistant metastatic differentiated thyroid cancer, it is important that clinicians are fully aware of the potential adverse effects. All patients on Sorafenib therapy should be educated to recognize the first symptoms to obtaining the maximal benefit from this anti-neoplastic rescue therapy.
doi:10.1186/1472-6823-14-26
PMCID: PMC3994654  PMID: 24641872
Hand-foot syndrome; Palmo-plantar Erythrodysesthesia; Sorafenib; Thyroid Cancer; Tyrosin kinase inhibitor; Targeted therapies
21.  Relationship between hyperglycemia, hormone disturbances, and clinical evolution in severely hyperglycemic post surgery critically ill children: an observational study 
Background
To study hormonal changes associated with severe hyperglycemia in critically ill children and the relationship with prognosis and length of stay in intensive care.
Methods
Observational study in twenty-nine critically ill children with severe hyperglycemia defined as 2 blood glucose measurements greater than 180 mg/dL. Severity of illness was assessed using pediatric index of mortality (PIM2), pediatric risk of mortality (PRISM) score, and pediatric logistic organ dysfunction (PELOD) scales. Blood glucose, glycosuria, insulin, C-peptide, cortisol, corticotropin, insulinlike growth factor-1, growth hormone, thyrotropin, thyroxine, and treatment with insulin were recorded. β-cell function and insulin sensitivity and resistance were determined on the basis of the homeostatic model assessment (HOMA), using blood glucose and C-peptide levels.
Results
The initial blood glucose level was 249 mg/dL and fell gradually to 125 mg/dL at 72 hours. Initial β-cell function (49.2%) and insulin sensitivity (13.2%) were low. At the time of diagnosis of hyperglycemia, 50% of the patients presented insulin resistance and β-cell dysfunction, 46% presented isolated insulin resistance, and 4% isolated β-cell dysfunction. β-cell function improved rapidly but insulin resistance persisted. Initial glycemia did not correlate with any other factor, and there was no relationship between glycemia and mortality. Patients who died had higher cortisol and growth hormone levels at diagnosis. Length of stay was correlated by univariate analysis, but not by multivariate analysis, with C-peptide and glycemic control at 24 hours, insulin resistance, and severity of illness scores.
Conclusions
Critically ill children with severe hyperglycemia initially present decreased β-cell function and insulin sensitivity. Nonsurvivors had higher cortisol and growth hormone levels and developed hyperglycemia later than survivors.
doi:10.1186/1472-6823-14-25
PMCID: PMC3995587  PMID: 24628829
Hyperglycemia; Critically ill children; Length of stay; Hormone disturbances
22.  Reviewer Acknowledgement 2013 
Contributing reviewers
The editors of BMC Endocrine Disorders would like to thank all our reviewers who have contributed to the journal in Volume 13 (2013).
doi:10.1186/1472-6823-14-15
PMCID: PMC3973827  PMID: 24606593
23.  Association of blood manganese level with diabetes and renal dysfunction: a cross-sectional study of the Korean general population 
Background
The purpose of this study was to evaluate the association between blood manganese levels and the prevalence of chronic diseases in the Korean population.
Methods
This was a cross-sectional study based on the Korean National Health and Nutrition Examination Survey (KNAHNES). The study included 3996 participants 20 years of age or older whose blood manganese levels had been measured. The participants were also evaluated for the presence of five chronic diseases: diabetes, renal dysfunction, hypertension, ischemic heart disease, and stroke.
Results
Blood manganese levels were significantly lower in the diabetes group compared with the non-diabetes group (1.26 ± 0.02 vs. 1.35 ± 0.01 μg/dL; p = 0.001) and the renal dysfunction group compared with those with normal renal function (1.28 ± 0.03 vs. 1.35 ± 0.01 μg/dL; p = 0.04). There was no significant association between blood manganese levels and the presence of ischemic heart disease or stroke. A multivariate logistic regression analysis adjusted for age, sex, and body mass index was performed; the odds ratio was 0.652 (95% CI: 0.46–0.92) for diabetes and 0.589 (95% CI: 0.39–0.88) for renal dysfunction when comparing the higher quartiles (Q2-4) with the lowest quartile (Q1) of blood manganese level. The prevalence of diabetes was 7.6% in Q1 and 5.3% in Q2-4 (p = 0.02). Similarly, the prevalence of renal dysfunction was 6.8% in Q1, compared with 4.6% in Q2-4 (p = 0.02).
Conclusion
The prevalence of diabetes and renal dysfunction increased in participants with low blood manganese levels, suggesting that blood manganese may play a role in glucose homeostasis and renal function.
doi:10.1186/1472-6823-14-24
PMCID: PMC3973834  PMID: 24606630
Manganese; Diabetes; Renal dysfunction
24.  Management of type 2 diabetes and its prescription drug cost before and during the economic crisis in Greece: an observational study 
Background
The aim of the present study is to examine the clinical indices related to cardiovascular risk management of Greek patients with type 2 diabetes, before and after the major economic crisis that emerged in the country.
Methods
In this retrospective database study, the medical records of patients with type 2 diabetes treated at three diabetes outpatient centers of the national health system during 2006 and 2012 were examined. Only patients with at least six months of follow-up prior to the recorded examination were included. The prescription cost was calculated in Euros per patient-year (€PY).
Results
A total of 1953 medical records (938 from 2006 and 1015 from 2012) were included. There were no significant differences in adjusted HbA1c, systolic blood pressure and HDL-C, while significant reductions were observed in LDL-C and triglycerides. In 2012, a higher proportion of patients were prescribed glucose-lowering, lipid-lowering and antihypertensive medications. Almost 4 out of 10 patients were prescribed the new incretin-based medications, while the use of older drugs, except for metformin, decreased. A significant increase in the adjusted glucose-lowering prescription cost (612.4 [586.5-638.2] €PY vs 390.7 [363.5-418.0]; p < 0.001) and total prescription cost (1306.7 [1264.6-1348.7] €PY vs 1122.3[1078.1-1166.5]; p < 0.001) was observed. The cost of antihypertensive prescriptions declined, while no difference was observed for lipid-lowering and antiplatelet agents.
Conclusions
During the economic crisis, the cardiovascular risk indices of Greek patients with type 2 diabetes being followed in public outpatient diabetes clinics did not deteriorate and in the case of lipid profile improved. However, the total prescription cost increased, mainly due to the higher cost of glucose-lowering prescriptions.
doi:10.1186/1472-6823-14-23
PMCID: PMC3946132  PMID: 24593679
Type 2 diabetes; Prescription cost; Economic crisis; Cardiovascular risk
25.  Retinopathy among young adults with Diabetes Mellitus from a tertiary care setting in Sri Lanka 
Background
Diabetic retinopathy (DR) is one of the leading causes for complete loss of vision among working-aged adults around the world. The present study aims to evaluate the rate of DR and its risk factors among the adults with young-onset diabetes from a tertiary care setting in Sri Lanka.
Methods
A consecutive sample of 1,007 individuals referred from multiple centers, were invited for the study. Ophthalmological evaluation was done, with dilated indirect ophthalmoscopy by an Ophthalmologist. Retinopathy was classified according to the International Clinical DR Disease Severity Scale. An interviewer-administered questionnaire was used to collect socio-demographic and anthropometric details. Seated blood pressure, Fasting Blood Glucose (FBG), HbA1c and urine microalbumin were also measured. Data were analysed using SPSSv14. A binary logistic regression analysis was performed in all patients, with ‘presence of DR’ as the dichotomous dependent variable and other independent covariates.
Results
Sample size was 684 (response rate–67.9%), mean age was 37.1 ± 5.9 years and 36.0% were males. Mean duration of diabetes was 5.2 ± 4.0 years. Previous retinal screening had been done in 51.0% by a non-specialist doctor and in 41.5% by a consultant ophthalmologist. Rate of any degree of DR in the study population was 18.1% (Males 16.4%, Females 20.0%; P = NS). In patients with DR, majority had mild Non-Proliferative DR (NPDR) (57.2%), while 32.2% had moderate NPDR, 0.8% had severe NPDR and 9.7% had maculopathy. Mean age, duration of diabetes, systolic (SBP) and diastolic blood pressure (DBP), FBG, HbA1c and urine microalbumin levels were significantly higher amongst the patients with DR. The results of the binary logistic regression indicate that the duration of diabetes (OR:1.24), HbA1c (OR:1.19), age (OR:1.11), urine Microalbumin (OR:1.11) and DBP (OR:1.04) all were significantly associated with DR.
Conclusions
In this large multi center study, nearly one in five adults with young-onset diabetes was found to have retinopathy. Age, duration of diabetes, HbA1C and urine Microalbumin levels were significantly associated with the presence of retinopathy, while HbA1c was also a significant factor determining severity. Nearly 50% of the study population has never undergone retinal screening by an ophthalmologist, highlighting the need for well organized screening programs.
doi:10.1186/1472-6823-14-20
PMCID: PMC3943575  PMID: 24588941
Diabetic retinopathy; Diabetes mellitus; Rate; Young-onset diabetes; Sri Lanka

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