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1.  Comparison of Optimised MDI versus Pumps with or without Sensors in Severe Hypoglycaemia (the Hypo COMPaSS trial) 
Background
Severe hypoglycaemia (SH) is one of the most feared complications of type 1 diabetes (T1DM) with a reported prevalence of nearly 40%. In randomized trials of Multiple Daily Injections (MDI) and Continuous Subcutaneous Insulin Infusion (CSII) therapy there is a possible benefit of CSII in reducing SH. However few trials have used basal insulin analogues as the basal insulin in the MDI group and individuals with established SH have often been excluded from prospective studies. In published studies investigating the effect of Real Time Continuous Glucose Monitoring (RT-CGM) benefit in terms of reduced SH has not yet been demonstrated. The primary objective of this study is to elucidate whether in people with T1DM complicated by impaired awareness of hypoglycaemia (IAH), rigorous prevention of biochemical hypoglycaemia using optimized existing self-management technology and educational support will restore awareness and reduce risk of recurrent SH.
Methods/design
This is a multicentre prospective RCT comparing hypoglycaemia avoidance with optimized MDI and CSII with or without RT-CGM in a 2×2 factorial design in people with type 1 diabetes who have IAH. The primary outcome measure for this study is the difference in IAH (Gold score) at 24 weeks. Secondary outcomes include biomedical measures such as HbA1c, SH incidence, blinded CGM analysis, self monitored blood glucose (SMBG) and response to hypoglycaemia in gold standard clamp studies. Psychosocial measures including well-being and quality of life will also be assessed using several validated and novel measures. Analysis will be on an intention-to-treat basis.
Discussion
Most existing RCTs using this study’s interventions have been powered for change in HbA1c rather than IAH or SH. This trial will demonstrate whether IAH can be reversed and SH prevented in people with T1DM in even those at highest risk by using optimized conventional management and existing technology.
Trial Registration
ISRCTN52164803 Eudract No: 2009-015396-27
doi:10.1186/1472-6823-12-33
PMCID: PMC3556156  PMID: 23237320
2.  A case report: Familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis 
Background
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency in the presence of normal plasma renin and aldosterone level. Focal segmental glomerulosclerosis (FSGS) is a form of glomerular disease associated with proteinuria and nephritic syndrome. This is the first case of familial glucocorticoid deficiency associated with familial focal segmental glomerulosclerosis.
Case presentation
An eight month old boy presented with increased genital pigmentation. Initial investigation revealed that he was glucocorticoid deficient and was started on hydrocortisone and fludrocortisone with a diagnosis of primary adrenal insufficiency. Later fludrocortisone was withdrawn and he was diagnosed to have isolated glucocorticoid deficiency. He later developed focal segmental glomerulosclerosis for which he underwent renal transplantation at the age of five years. Now at the age of twelve years, this boy is doing well on hydrocortisone treatment. His two siblings and a first degree cousin also had isolated glucocorticoid deficiency. One of the above two siblings died due to renal failure secondary to focal segmental glomerulosclerosis.
Conclusion
Patients with familial glucocorticoid deficiency should be carefully followed for development of features of nephrotic syndrome.
doi:10.1186/1472-6823-12-32
PMCID: PMC3538046  PMID: 23232022
Familial glucocorticoid deficiency; Familial focal segmental glomerulosclerosis; ACTH resistance
3.  Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity 
Background
The use of chromium supplements is widespread for the prevention and treatment of diabetes mellitus but there are conflicting reports on efficacy, possibly reflecting discrepant effects across different populations. In the present studies, we test the hypothesis that chromium supplementation raises serum chromium levels and correspondingly improves insulin sensitivity.
Methods
A double blind placebo-controlled randomized trial was conducted on 31 non-obese, normoglycemic subjects. After baseline studies, the subjects were randomized to placebo or chromium picolinate 500 μg twice a day. The primary endpoint was change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. Pre-specified secondary endpoints included fasting lipids, blood pressure, weight, body composition measured by DXA scan.
Results
After 16 weeks of chromium picolinate therapy there was no significant change in insulin sensitivity between groups (p=0.83). There was, however, a strong association between serum chromium and change in insulin resistance (β = -0.83, p=0.01), where subjects with the highest serum chromium had a worsening of insulin sensitivity. This effect could not be explained by changes in physiological parameters such as body weight, truncal fat and serum lipids with chromium therapy.
Conclusions
Chromium therapy did not improve insulin sensitivity in non-obese normoglycemic individuals. Further, subjects who have high serum chromium levels paradoxically had a decline in insulin sensitivity. Caution therefore should be exercised in recommending the use of this supplement.
Trial registration
The study was registered on the NIH registry (clinicaltrials.gov) and the identifier is NCT00846248
doi:10.1186/1472-6823-12-31
PMCID: PMC3537689  PMID: 23194380
4.  Relationship between clinical characteristics and survival of gastroenteropancreatic neuroendocrine neoplasms: A single-institution analysis (1995–2012) in South China 
Background
Gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) is the most common type of neuroendocrine tumors accounting for 65–75% of neuroendocrine neoplasms (NENs). Given the fact that there are few studies on GEP-NENs among Chinese patients, we performed a retrospective study in South China.
Methods
Totally 178 patients with GEP-NENs treated at the First Affiliated Hospital of Sun Yat-sen University between January 1995 and May 2012 were analyzed retrospectively.
Results
Pancreas was found the most common site of involvement (34.8%). 149 patients (83.7%) presented as non-functional tumors with non-specific symptoms such as abdominal pain (33.7%); carcinoid syndrome was not found in this study. Several methods are useful for localization of GEP-NENs, yielding varied detection rates from 77.8% to 98.7%. Positive rates of chromogranin A (CgA) and synaptophysin (Syn) immunhistochemically were 69.1% and 90.2%, respectively. 87 patients (51.5%) had G1 tumors, 31(18.3%) G2 tumors and 51 (30.2%) G3 tumors. Neuroendocrine tumor (NET), neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) were 69.8%, 27.2% and 3.0%, respectively. 28.1% of patients presented with distant disease. Surgery was performed in 152 (85.4%) patients, and overall 5-year survival rate was 54.5%. Functionality, G1 grading and NET classification were associated with favorable prognosis in univariate analysis. Distant metastasis contributed to unfavorable prognosis of these tumors.
Conclusions
Nonfunctional tumors with non-specific symptoms account for the majority of GEP-NENs. Diagnosis depends on pathological classification. Multidisciplinary treatments could help improve the outcome.
doi:10.1186/1472-6823-12-30
PMCID: PMC3526557  PMID: 23194346
Gastroenteropancreatic neuroendocrine neoplasms; Clinical pathological characteristics; Survival
5.  Right thyroid hemiagenesis with adenoma and hyperplasia of parathyroid glands -case report 
Background
Thyroid hemiagenesis is a rare anomaly, more commonly seen on the left side (ratio 4:1) and in females (ratio 3:1). The first to describe this anomaly was Handfield Jones in 1852.
Case presentation
We present a 66 year old female patient with right thyroid hemiagenesis, parathyroid adenoma on the side of hemiagenesis and parathyroid hyperplasia on the contralateral side. The patient had neck pain and was diagnosed as Hashimto thyroiditis with hyperparathyroidism. Parathyroid hormone, thyroglobulin antibodies (Tg-Ab) and thyroid peroxidase antibodies (TPO-Ab) were elevated. Neck ultrasound and technetium 99mTc-methoxyisobutyl isonitrile (MIBI) scintigraphy confirmed the right thyroid hemiagenesis, but not adenoma of parathyroid glands. Intraoperatively, right thyroid hemiagenesis was confirmed and left loboistmectomy was performed with removal of left inferior hyperplastic parathyroid gland. Postoperative PTH (parathyroid hormone) levels were within normal range. Five months after the operation PTH level was elevated again with calcium values at the upper limit. MIBI scintigraphy was performed again which showed increased accumulation of MIBI in the projection of the right parathyroid gland. Surgical reexploration of the neck and excision of the right upper parathyroid adenoma was performed which was located behind cricoid laryngeal cartilage. After surgery a normalization of calcium and PTH occured.
Conclusion
From available literature we have not found the case that described parathyroid adenoma on the side of thyroid hemiagenesis,with parathyroid hyperplasia on the contralateral side.
doi:10.1186/1472-6823-12-29
PMCID: PMC3534513  PMID: 23148717
Right thyroid hemiagenesis; Parathyroid adenoma; Parathyroid hyperplasia; Hyperparathyroidism
6.  The 5x1 DAFNE study protocol: a cluster randomised trial comparing a standard 5 day DAFNE course delivered over 1 week against DAFNE training delivered over 1 day a week for 5 consecutive weeks 
Background
Structured education programmes are now established as an essential component to assist effective self-management of diabetes. In the case of Type 1 diabetes, the Dose Adjustment For Normal Eating (DAFNE) programme improves both glycaemic control and quality of life. Traditionally delivered over five consecutive days, this format has been cited as a barrier to participation by some patients, such as those who work full-time. Some centres in the UK have organised structured education programmes to be delivered one day a week over several consecutive weeks. This type of format may add benefit by allowing more time in which to practice skills between sessions, but may suffer as a result of weaker peer support being generated compared to that formed over five consecutive days.
Methods/design
We aim to compare DAFNE delivered over five consecutive days (1 week course) with DAFNE delivered one day a week over five weeks (5 week course) in a randomised controlled trial. A total of 213 patients were randomised to attend either a 1 week or a 5 week course delivered in seven participating centres. Study outcomes (measured at baseline, 6 and 12 months post-course) include HbA1c, weight, self-reported rates of severe hypoglycaemia, psychosocial measures of quality of life, and cost-effectiveness. Generalisability was optimised by recruiting patients from DAFNE waiting lists at each centre, and by mailing eligible patients from hospital clinic lists. The inclusion and exclusion criteria were identical to those used to recruit to a standard DAFNE course (e.g., HbA1c <12%, with no lower limit). Qualitative interviews were undertaken with a sub-sample of n=30 patients and their course educators (n=11) to help understand and interpret differences and similarities in outcomes between the two arms, and to identify logistical problems and unanticipated issues arising from the adaptation and delivery of a 5 week course.
Discussion
This trial has been designed to test the hypothesis that the benefits of delivering a structured education programme over 5 weeks are comparable to those observed after a 1 week course. The results of the trial and the qualitative sub-study will both inform the design and delivery of future DAFNE courses, and the development of structured education programmes in other fields of medicine.
Trial Registration
Clinicaltrials.gov NCT01069393
doi:10.1186/1472-6823-12-28
PMCID: PMC3515469  PMID: 23136929
Type 1 diabetes; Education; Teaching; Training programs
7.  Correction of vitamin D deficiency in critically ill patients - VITdAL@ICU study protocol of a double-blind, placebo-controlled randomized clinical trial 
Background
Vitamin D deficiency is associated with multiple adverse health outcomes including increased morbidity and mortality in the general population and in critically ill patients. However, no randomized controlled trial has evaluated so far whether treatment with sufficiently large doses of vitamin D can improve clinical outcome of patients in an intensive care setting.
Methods/design
The VITdAL@ICU trial is an investigator-initiated, non-commercial, double-blind, placebo-controlled randomized clinical trial. This study compares high-dose oral cholecalciferol (vitamin D3) versus placebo treatment in a mixed population of 480 critically ill patients with low 25-hydroxyvitamin-D levels at study enrollment (≤ 20ng/ml). Following an initial loading dose of 540,000 IU of vitamin D3, patients receive 90,000 IU of vitamin D3 on a monthly basis for 5 months. The study is designed to compare clinical outcome in the two study arms with the primary endpoint being length of hospital stay. Secondary endpoints include among others length of ICU stay, the percentage of patients with 25(OH)D levels > 30 ng/ml at day 7, ICU and hospital mortality and duration of mechanical ventilation. We describe here the VITdAL@ICU study protocol for the primary report.
Discussion
This trial is designed to evaluate whether high-dose vitamin D3 is able to improve morbidity and mortality in a mixed population of adult critically ill patients and correct vitamin D deficiency safely.
Trial registration
ClinicalTrials: NCT01130181
doi:10.1186/1472-6823-12-27
PMCID: PMC3534412  PMID: 23134762
Critical Illness; Vitamin D deficiency; Cholecalciferol; Vitamin D; Critical care; Intensive care; Vitamin D3
8.  Different thresholds of tissue-specific dose-responses to growth hormone in short prepubertal children 
Background
In addition to stimulating linear growth in children, growth hormone (GH) influences metabolism and body composition. These effects should be considered when individualizing GH treatment as dose-dependent changes in metabolic markers have been reported. Hypothesis: There are different dose-dependent thresholds for metabolic effects in response to GH treatment.
Method
A randomized, prospective, multicentre trial TRN 98-0198-003 was performed for a 2-year catch-up growth period, with two treatment regimens (a) individualized GH dose including six different dose groups ranging from 17–100 μg/kg/day (n=87) and (b) fixed GH dose of 43 μg/kg/day (n=41). The individualized GH dose group was used for finding dose–response effects, where the effective GH dose (ED 50%) required to achieve 50% Δ effect was calculated with piecewise linear regressions.
Results
Different thresholds for the GH dose were found for the metabolic effects. The GH dose to achieve half of a given effect (ED 50%, with 90% confidence interval) was calculated as 33(±24.4) μg/kg/day for Δ left ventricular diastolic diameter (cm), 39(±24.5) μg/kg/day for Δ alkaline phosphatase (μkat/L), 47(±43.5) μg/kg/day for Δ lean soft tissue (SDS), 48(±35.7) μg/kg/day for Δ insulin (mU/L), 51(±47.6) μg/kg/day for Δ height (SDS), and 57(±52.7) μg/kg/day for Δ insulin-like growth factor I (IGF-I) SDS. Even though lipolysis was seen in all subjects, there was no dose–response effect for Δ fat mass (SDS) or Δ leptin ng/ml in the dose range studied. None of the metabolic effects presented here were related to the dose selection procedure in the trial.
Conclusions
Dose-dependent thresholds were observed for different GH effects, with cardiac tissue being the most responsive and level of IGF-I the least responsive. The level of insulin was more responsive than that of IGF-I, with the threshold effect for height in the interval between.
doi:10.1186/1472-6823-12-26
PMCID: PMC3583138  PMID: 23116291
GH deficiency; GH sensitivity, GH responsiveness; Idiopathic short stature; GH dose-effect; Metabolic effects; Lipolysis
9.  Prevalence of the metabolic syndrome in a rural population in Ghana 
Background
The Metabolic syndrome (MS) which is a constellation of cardiometabolic risk factors including dyslipidaemia, hypertension, hyperglycaemia, central obesity, and endothelial dysfunction was hitherto relatively uncommon among Africans south of the Sahara. This study seeks to determine the prevalence of MS, its components and risk factors among a rural population in Ghana based on two popular international algorithms.
Methods
This was a cross-sectional survey of a rural population in Ghana conducted between November and December, 2007. Two hundred and twenty-eight (228) settler farmers, families and staff associated with the GOPDC Ltd, between the ages of 35 and 64 years, were randomly selected for the study; pregnant women were excluded. The prevalence of MS was estimated using the IDF and ATPIII criteria.
Results
The final subject pool included 102 males, and 104 females. The mean age of all subjects was 44.4 ± 6.9 years. The overall prevalence of MS by the IDF and ATPIII criteria were 35.9% and 15.0%, respectively, but there was an alarming female preponderance by both criteria {IDF: males = 15.7%, females =55.8%; ATPIII: males = 5.9%, females = 24.0%; sex differences p<0.001 for both criteria}. The most important determinants for IDF-defined MS were central obesity (55.3%), low High Density Lipoprotein (42.7%) and high Blood Pressure (39.5%).
Conclusion
The triad of central obesity, high blood pressure and low HDL were most responsible for the syndrome in this rural population.
doi:10.1186/1472-6823-12-25
PMCID: PMC3534326  PMID: 23110418
Metabolic syndrome; Rural Ghana; Determinants; ATPIII; IDF
10.  No effect modification of serum bilirubin or coffee consumption on the association of gamma-glutamyltransferase with glycated hemoglobin in a cross-sectional study of Japanese men and women 
Background
Oxidative stress has been implicated in the development of type 2 diabetes mellitus. Bilirubin is a potent endogenous antioxidant, and coffee is a major source of exogenous antioxidants. Serum gamma-glutamyltransferase (GGT), a marker of oxidative stress, is a strong predictor of the risk of type 2 diabetes mellitus. This study evaluated the effect modification of bilirubin and coffee consumption on the association of serum GGT with glycated hemoglobin (HbA1c) and the combined effect of bilirubin and coffee on HbA1c concentrations.
Methods
The subjects were 4492 men and 6242 women aged 49–76 years who participated in the baseline survey of an on-going cohort study on lifestyle-related diseases in Fukuoka, Japan. Geometric means of HbA1c were examined according to quartile categories of GGT, with stratification by serum total bilirubin (≥ 0.6 mg/dL versus less in men and ≥ 0.5 mg/dL versus less in women) and coffee consumption (< 1, 1–3 and ≥ 4 cups of per day). Statistical adjustment was made for age, smoking, alcohol use and body mass index by using analysis of covariance.
Results
HbA1 concentrations increased progressively with increasing levels of GGT in both men and women. The increasing trend of HbA1c concentrations associated with GGT did not differ by either bilirubin status or coffee consumption. Both men and women with high bilirubin had consistently lower concentrations of HbA1c across the GGT quartiles. Higher coffee consumption was associated with lower concentrations of HbA1c in women with low bilirubin (trend P = 0.04), but not with high bilirubin (trend P = 0.37). There was no such association between coffee and HbA1c in men with either low or high bilirubin levels.
Conclusions
Bilirubin is possibly protective against deterioration of glucose metabolism. Further studies are needed regarding the combined effect of bilirubin and coffee on glucose metabolism.
doi:10.1186/1472-6823-12-24
PMCID: PMC3509408  PMID: 23092212
11.  Incidence and predictors of hypoglycaemia in type 2 diabetes – an analysis of the prospective DiaRegis registry 
Background
Hypoglycaemia is a serious adverse effect of antidiabetic drug therapy. We aimed to determine incidence rates of hypoglycaemia in type-2 diabetic patients and identify predictors of hypoglycaemia when treatment is intensified.
Methods
DiaRegis is a prospective German registry that follows 3810 patients with type-2 diabetes referred for treatment intensification because of insufficient glycaemic control on one or two oral antidiabetic drugs.
Results
Out of a total of 3347 patients with data available for the present analysis 473 (14.1%) presented any severity hypoglycaemia over a follow-up of 12 months. 0.4% were hospitalized (mean of 1.3±0.6 episodes), 0.1% needed medical assistance (1.0±0.0), 0.8% needed any help (1.1±0.5) and 10.1% no help (3.4±3.7), and 8.0% had no specific symptoms (3.6±3.5). Patients with incident hypoglycaemia had longer diabetes duration, higher HbA1c and a more frequent smoking history; more had co-morbid disease conditions such as coronary artery disease, peripheral arterial disease, amputation, heart failure, peripheral neuropathy, diabetic retinopathy and clinically relevant depression at baseline. Multivariable adjusted positive predictors of incident hypoglycaemia over the follow-up were prior anamnestic hypoglycaemia, retinopathy, depression, insulin use and blood glucose self-measurement, but not sulfonylurea use as previously reported for anamnestic or recalled hypogylcaemia. On the contrary, glitazones, DPP-4 inhibitors and GLP-1 analogues were associated with a reduced risk of hypoglycaemia.
Conclusions
Hypoglycaemia is a frequent adverse effect in ambulatory patients when antidiabetic treatment is intensified. Particular attention is warranted in patients with prior episodes of hypoglycaemia, microvascular disease such as retinopathy and in patients receiving insulin. On the other hand glitazones, DPP-4 inhibitors and GLP-1 analogues are associated with a reduced risk.
doi:10.1186/1472-6823-12-23
PMCID: PMC3515411  PMID: 23075070
12.  Leptin, insulin and thyroid hormones in a cohort of Egyptian obese Down syndrome children: a comparative study 
Background
Obesity is a major worldwide health problem. It is commonly observed in Down syndrome individuals than in the general population. The reason for increased risk of obesity in DS is unclear.
The current study was designed to clarify differences in some obesity- related hormones in a group of prepubertal Down syndrome children.
Methods
Thirty six Egyptian children with Down syndrome were enrolled in this study, divided according to their body mass index (BMI) into 23 obese and13 non obese. Another group of 43 non Down children were recruited, they were divided according to their BMI into 20 patients having simple obesity and 23 non obese, as control groups. Fasting blood samples were collected for estimation of fasting blood glucose (FBG), insulin, leptin, free thyroxin (FT4), thyroid stimulating hormones (TSH) and creatine kinase (CK). Insulin resistance was assessed by Homeostasis Model Assessment method (HOMA-IR). The ratio of leptin to BMI (LEP/BMI) was used as an index of leptin resistance.
Results
Median values of FBG, insulin, and HOMA-IR were significantly higher in Down versus non Down groups, while median values of leptin and leptin resistance were non-significantly different among Down versus non Down groups. Median TSH values were non- significantly different between obese Down and obese non Down. Although the median values of TSH and FT4 were within normal range in Down groups, four cases of subclinical hypothyroidism were encountered. Leptin levels were correlated with insulin and IR but not with TSH in Down groups.
Conclusion
Increased circulating leptin, a marker of leptin resistance in obese children with Down syndrome seems to be similar to that in children with simple obesity. Elevated FBG and insulin in obese Down children highlights the presence of early IR. Associated myopathy evidenced by mildly elevated CK levels could be an added factor for obesity in such group of patients.
doi:10.1186/1472-6823-12-22
PMCID: PMC3528445  PMID: 23067442
Down syndrome; Obesity; Leptin; Leptin resistance; Insulin resistance
13.  Insulin analogues dosing and costs - comparing real-life daily doses of insulin detemir and insulin glargine in type 2 diabetes patients 
Background
The uncertainties regarding dose similarities between basal long-acting insulin analogues remain. Recent real-world studies indicate dose similarities between insulin detemir and insulin glargine, but further studies are still warranted.
The aim of this study was to compare real-life daily doses of insulin detemir and insulin glargine in type 2 diabetes patients when administered once daily.
Methods
We analysed 536 patient cases from general practice (63%) and endocrinological outpatient clinics (37%). A self-administered questionnaire completed by the treating physician was used to obtain data on patient characteristics (gender, age, weight, height, latest HbA1c-value), daily doses, administration of and number of years treated with insulin detemir and insulin glargine, concomitant insulin use and use of non-insulin anti-diabetic medication. Both bivariate analyses and multivariate regression analyses were applied to examine whether there were differences in the daily doses of insulin detemir and insulin glargine.
Results
There was no significant difference in the mean daily doses of insulin detemir (0.414 U/kg) and insulin glargine (0.416 U/kg) (p = 0.4341). In multivariate regression analyses, age and BMI had a significant influence on daily insulin dose with the dose increasing 0.003 U/kg (p = 0.0375) and 0.008 U/kg (p = 0.0003) with every 1 increment in age and BMI, respectively.
Conclusions
Dose similarities between insulin detemir and insulin glargine were seen in type 2 diabetes patients when administered once daily. Thus, the use of insulin detemir and insulin glargine is not associated with different medical costs if the price and treating algorithm are similar.
doi:10.1186/1472-6823-12-21
PMCID: PMC3512463  PMID: 23009558
Insulin detemir; Insulin glargine; Type 2 diabetes; Dose; Health care costs
14.  Rationale and design of the multinational observational study assessing insulin use: the MOSAIc study 
Background
Although consensus guidelines recommend insulin progression among patients with type 2 diabetes (T2DM) who fail to meet glycemic targets over time, many fewer patients are progressed than may benefit. We describe the rationale and design of the MOSAIc (Multinational Observational Study Assessing Insulin use) study, a multinational observational cohort study to identify patient-, physician, and health care environment-based factors associated with insulin progression for patients with T2DM in real-world practice.
Methods/design
We will enroll 4,500 patients with T2DM taking initial insulin therapy for ≥3 months across 175 physician practice sites in 18 countries. Extensive demographic, clinical, and psychosocial data at the patient and physician level and practice site characteristics will be collected at baseline and regular intervals during a 24-month follow-up period. We will use a multivariable logistic regression model to identify predictors of insulin progression and highlight potential opportunities for health behavior intervention to improve insulin progression rates. Secondary outcomes include evaluating factors associated with glycemic control, hypoglycemia, and treatment adherence among patients who do and do not progress beyond their initial insulin therapy and exploring geographic heterogeneity in treatment.
Discussion
Practice site and patient recruitment began in 2011 and baseline data will be available in late 2012. The MOSAIC study’s longitudinal observational design as well as the breadth and depth of data will be used to explore and quantify predictors of insulin progression and to identify potential opportunities for health behavior intervention in order to improve T2DM treatment and clinical outcomes.
doi:10.1186/1472-6823-12-20
PMCID: PMC3545975  PMID: 22999494
Type 2 diabetes; Insulin; Treatment; Health outcomes; Epidemiology
15.  Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism: a randomized, double-blind, placebo-controlled trial 
Background
Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess.
Methods/design
Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease.
The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1–84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints.
Discussion
In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism.
Trial registration
ISRCTN33941607
doi:10.1186/1472-6823-12-19
PMCID: PMC3515510  PMID: 22974443
Aldosterone; Mineralocorticoid receptor blocker; Hyperparathyroidism
16.  Diabetes related knowledge among residents and nurses: a multicenter study in Karachi, Pakistan 
Background
Assessment of knowledge among resident trainees and nurses is very important since majority of patients admitted in hospital have underlying diabetes which could lead to adverse clinical outcomes if not managed efficiently. Therefore, the purpose of this study was to evaluate and compare the knowledge related to the management of diabetes among registered nurses (RN) and trainee residents of internal medicine (IMR), family medicine (FMR) and surgery (SR) at tertiary care hospitals of Karachi, Pakistan.
Methods
A validated questionnaire consisting of 21 open ended questions related to diabetes awareness was acquired through a study done at Thomas Jefferson University Hospital, Philadelphia with the permission of primary author.
Results
169 IMR, 27 FMR, 86 SR and 99 RN completed a questionnaire that assessed the knowledge related to different aspects of management of diabetes. The results were further stratified by participant's specialty and level of training. The percentage of knowledge based questions answered correctly was found to be low. The overall mean correct percentage among all the participants was 50% +/- 21. There was no statistical difference in terms of knowledge between IMR & FMR residents (64% +/- 14 vs. 60% +/- 16, p = 0.47) respectively. The total scores of SR and RN were quite low (40% +/- 16 & 31% +/- 15 respectively).SR and RN were found to have profound deficit in both inpatient and outpatient knowledge of diabetes. We did not observe any improvement in level of knowledge of FMR & SR with increase in duration of their training (p = 0.47 & 0.80 respectively). In contrast, improvement in the level of knowledge of IMR was observed from first to second year of their training (p = 0.03) with no further improvement thereafter. RN's didn't respond correctly on most of the items related to in-patient management of diabetes (Mean score 40% +/- 20).
Conclusion
As there are no prior studies in our setting evaluating knowledge related to diabetes management among residents and nurses, this study is of paramount importance. Based on these results, considerable knowledge gaps were found among trainee residents and nurses pointing towards need of providing additional education to improve the delivery of diabetes care.
doi:10.1186/1472-6823-12-18
PMCID: PMC3515418  PMID: 22967029
17.  Unilateral adrenal hyperplasia is a usual cause of primary hyperaldosteronism. Results from a Swedish screening study 
Background
The existence of unilateral adrenal hyperplasia (AH) has been considered a rare cause of primary hyperaldosteronism (PA).
Methods
In a prospective study we screened for PA in a non-selected (NSP) and selected hypertensive population (SP), to define the cause of PA. We included 353 consecutive patients with hypertension; age 20 to 88 years, 165 women and 188 men, from a university-based Hypertension and Nephrology Outpatient clinics (123 SP) and two primary care centres, (230 NSP) from the same catch-up area. Serum aldosterone and plasma renin activity (PRA) were measured and the ARR calculated. Verifying diagnostic procedure was performed in patients with both elevated aldosterone and ARR. Patients diagnosed with PA were invited for adrenal venous sampling (AVS) and offered laparoscopic adrenalectomy when AVS found the disease to be unilateral.
Results
After screening, 46 patients, 13% of the whole population (22.8% SP and 7.8% NSP) had aldosterone and ARR above the locally defined cut-off limits (0.43 nmol/l and 1.28 respectively). After diagnostic verification, 20 patients (6%) had PA, (14.5% SP and 1.4% NSP). Imaging diagnostic procedures with CT-scans and scintigraphy were inconclusive. AVS, performed in 15 patients verified bilateral disease in 4 and unilateral in 10 patients. One AVS failed. After laparoscopic adrenalectomy, 4 patients were found to have adenoma and 5 unilateral AH. One patient denied operation.
Conclusion
The prevalence of PA was in agreement with previous studies. The study finds unilateral PA common and unilateral AH as half of those cases. As may be suspected PA is found in much higher frequency in specialised hypertensive units compared to primary care centers. AVS was mandatory in diagnosis of unilateral PA.
doi:10.1186/1472-6823-12-17
PMCID: PMC3515501  PMID: 22958674
Endocrine hypertension; Hyperaldosteronism; Aldosterone; Renin; Hypertension; Resistant hypertension; Adrenal hyperplasia
18.  Association of Alanine Aminotransferase Levels (ALT) with the Hepatic Insulin Resistance Index (HIRI): a cross-sectional study 
Background
The association between serum alanine aminotransferase (ALT) levels and hepatic insulin resistance (IR) has been evaluated with the hyperinsulinemic-euglycemic clamp. However, there is no information about the association of ALT with the Hepatic Insulin Resistance Index (HIRI). The aim of this study was to evaluate the association between serum ALT levels and HIRI in subjects with differing degrees of impaired glucose metabolism.
Methods
This cross-sectional study included subjects that had an indication for testing for type 2 diabetes mellitus (T2DM) with an oral glucose tolerance test (OGTT). Clinical and biochemical evaluations were carried out including serum ALT level quantification. HIRI was calculated for each participant. Correlation analyses and lineal regression models were used to evaluate the association between ALT levels and HIRI.
Results
A total of 324 subjects (37.6% male) were included. The mean age was 40.4 ± 14.3 years and the mean body mass index (BMI) was 32.0 ± 7.3 kg/m2. Individuals were divided into 1 of 5 groups: without metabolic abnormalities (n = 113, 34.8%); with the metabolic syndrome (MetS, n = 179, 55.2%), impaired fasting glucose (IFG, n = 85, 26.2%); impaired glucose tolerance (IGT, n = 91, 28.0%), and T2DM (n = 23, 7.0%). The ALT (p < 0.001) and HOMA2-IR (p < 0.001) values progressively increased with HIRI quartiles, while ISI-Matsuda (p < 0.001) progressively decreased. After adjustment for sex, age, and BMI, we identified a significant correlation between HIRI and ALT in persons with the MetS (r = 0.22, p = 0.003), IFG (r = 0.33, p < 0.001), IGT (r = 0.37, p < 0.001), and T2DM (r = 0.72, p < 0.001). Lineal regression analysis adjusting for age, HDL-C, TG and waist circumference (WC) showed an independent association between ALT and HIRI in subjects with the MetS (beta = 0.07, p = 0.01), IFG (beta = 0.10, p = 0.02), IGT (beta = 0.09, p = 0.007), and T2DM (beta = 0.31, p = 0.003). This association was not identified in subjects without metabolic abnormalities.
Conclusions
ALT levels are independently associated with HIRI in subjects with the MetS, IFG, IGT, and T2DM. The ALT value in these subjects may be an indirect parameter to evaluate hepatic IR.
doi:10.1186/1472-6823-12-16
PMCID: PMC3515498  PMID: 22947097
Alanine aminotransferase; ALT; Hepatic insulin resistance; HIRI
19.  Prevalence of diabetes mellitus among non institutionalized elderly in Monastir City 
Background
Diabetes is a major public health problem worldwide. This problem is particularly relevant to the elderly. The prevalence of each condition increase with age. The present study aimed to determine the prevalence of Diabetes Mellitus (DM) among elderly; we also examined socio-economic factors and life style that are likely to be associated with DM.
Methods
A cross-sectional study was conducted in 2008–2009, and used a multistage cluster sampling method to select a representative sample among non institutionalized elderly in Monastir City. A total of 598 elderly aged 65 to 95 years were included.
Results
The prevalence of DM was 27.4% (29.2% in males’ vs 26.5% in females). Elderly with DM showed higher prevalence of hypertension, obesity and abdominal obesity. DM prevalence decreased with advancing ages in both men and women. Urban residents had a higher prevalence than did their rural counterparts. In multivariate analysis, DM was associated with abdominal obesity (OR [95% CI], 2.6 [1.1-6]; p <0.01), co-existing diseases (3.8 [2.4-6]; p <0.01), and hypertension (2.7 [1.6-4.5] ; p <0.01).
Conclusion
The study highlights the DM problem in Tunisia. An ageing population together with social, economic and lifestyle changes have led to a dramatic increase in DM. These data emphasize the urgent need for a comprehensive integrated population-based intervention program to ameliorate the growing problem of DM.
doi:10.1186/1472-6823-12-15
PMCID: PMC3461464  PMID: 22898260
Diabetes; Elderly; Prevalence; Tunisia; Non institutionalized
20.  A case report: Giant cystic parathyroid adenoma presenting with parathyroid crisis after Vitamin D replacement 
Background
Parathyroid adenoma with cystic degeneration is a rare cause of primary hyperparathyroidism. The clinical and biochemical presentation may mimic parathyroid carcinoma.
Case presentation
We report the case of a 55 year old lady, who had longstanding history of depression and acid peptic disease. Serum calcium eight months prior to presentation was slightly high, but she was never worked up. She was found to be Vitamin D deficient while being investigated for generalized body aches. A month after she was replaced with Vitamin D, she presented to us with parathyroid crisis. Her corrected serum calcium was 23.0 mg/dL. She had severe gastrointestinal symptoms and acute kidney injury. She had unexplained consistent hypokalemia until surgery. Neck ultrasound and CT scan revealed giant parathyroid cyst extending into the mediastinum. After initial medical management for parathyroid crisis, parathyroid cystic adenoma was surgically excised. Her serum calcium, intact parathyroid hormone, creatinine and potassium levels normalized after surgery.
Conclusion
This case of parathyroid crisis, with very high serum calcium and parathyroid hormone levels, is a rare presentation of parathyroid adenoma with cystic degeneration. This case also highlights that Vitamin D replacement may unmask subclinical hyperparathyroidism. Consistent hypokalemia until surgery merits research into its association with hypercalcemia.
doi:10.1186/1472-6823-12-14
PMCID: PMC3462668  PMID: 22840059
Parathyroid; Adenoma; Cystic; Hypercalcemia; Hyperparathyroidism; Vitamin D; Crisis; Mediastinum; Hypokalemia; Sestamibi
21.  Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward 
Background
Mutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A) result in the commonest type of maturity onset diabetes of the young (MODY). HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein/regenerating (PSP/reg) gene in surviving neighbour cells, and that PSP/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis.
Methods
We analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed.
Results
PSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37) subjects compared to controls (n = 60) (median = 12.50 ng/ml, IQR = 10.61-17.87 ng/ml versus median = 10.72 ng/ml, IQR = 8.94-12.54 ng/ml, p = 0.0008). PSP/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02). Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02) with an age of 25 years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes.
Conclusion
Our data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and over. PSP/reg1A may be developed as a serum marker to detect increased beta-cell apoptosis, or its therapeutic response.
doi:10.1186/1472-6823-12-13
PMCID: PMC3433346  PMID: 22808921
Maturity onset diabetes of the young (MODY); Apoptosis; Serum biomarker; Beta-Cell; Type 1 diabetes; Pancreatic stone protein (PSP); Regenerating gene 1A (reg1A)
22.  Post-partum pituitary insufficiency and livedo reticularis presenting a diagnostic challenge in a resource limited setting in Tanzania: a case report, clinical discussion and brief review of existing literature 
Background
Pituitary disorders following pregnancy are an important yet under reported clinical entity in the developing world. Conversely, post partum panhypopituitarism has a more devastating impact on women in such settings due to high fertility rates, poor obstetric care and scarcity of diagnostic and therapeutic resources available.
Case presentation
A 37 year old African female presented ten years post partum with features of multiple endocrine deficiencies including hypothyroidism, hypoadrenalism, lactation failure and secondary amenorrhea. In addition she had clinical features of an underlying autoimmune condition. These included a history of post-partum thyroiditis, alopecia areata, livedo reticularis and deranged coagulation indices. A remarkable clinical response followed appropriate hormone replacement therapy including steroids. This constellation has never been reported before; we therefore present an interesting clinical discussion including a brief review of existing literature.
Conclusion
Post partum pituitary insufficiency is an under-reported condition of immense clinical importance especially in the developing world. A high clinical index of suspicion is vital to ensure an early and correct diagnosis which will have a direct bearing on management and patient outcome.
doi:10.1186/1472-6823-12-4
PMCID: PMC3393611  PMID: 22583510
Post partum panhypopituitarism; Lymphocytic hypophysitis; Sheehan’s syndrome; Livedo reticularis; Africa
23.  Evaluation of risk equations for prediction of short-term coronary heart disease events in patients with long-standing type 2 diabetes: the Translating Research into Action for Diabetes (TRIAD) study 
Background
To evaluate the U.K. Prospective Diabetes Study (UKPDS) and Framingham risk equations for predicting short-term risk of coronary heart disease (CHD) events among adults with long-standing type 2 diabetes, including those with and without preexisting CHD.
Methods
Prospective cohort of U.S. managed care enrollees aged ≥ 18 years and mean diabetes duration of more than 10 years, participating in the Translating Research into Action for Diabetes (TRIAD) study, was followed for the first occurrence of CHD events from 2000 to 2003. The UKPDS and Framingham risk equations were evaluated for discriminating power and calibration.
Results
A total of 8303 TRIAD participants, were identified to evaluate the UKPDS (n = 5914, 120 events), Framingham-initial (n = 5914, 218 events) and Framingham-secondary (n = 2389, 374 events) risk equations, according to their prior CHD history. All of these equations exhibited low discriminating power with Harrell’s c-index <0.65. All except the Framingham-initial equation for women and the Framingham-secondary equation for men had low levels of calibration. After adjsusting for the average values of predictors and event rates in the TRIAD population, the calibration of these equations greatly improved.
Conclusions
The UKPDS and Framingham risk equations may be inappropriate for predicting the short-term risk of CHD events in patients with long-standing type 2 diabetes, partly due to changes in medications used by patients with diabetes and other improvements in clinical care since the Frmaingham and UKPDS studies were conducted. Refinement of these equations to reflect contemporary CHD profiles, diagnostics and therapies are needed to provide reliable risk estimates to inform effective treatment.
doi:10.1186/1472-6823-12-12
PMCID: PMC3433369  PMID: 22776317
24.  Beta cell response to a mixed meal in nigerian patients with type 2 diabetes 
Background
The pathophysiology of type2 diabetes involves both insulin resistance and poor beta cell function. Studies have been done in several populations to assess the relative importance of these mechanisms in individual patients. In our environment studies to assess beta cell function have been done with glucagon stimulation or an oral glucose tolerance test. This study was done to assess the response of the beta cell to a standardized mixed meal and its relationship with glycaemic control in patients with type2 diabetes.
Methods
Ninety patients with type 2 diabetes were recruited into the study. Weight, height, body mass index and waist circumference were measured. Blood samples were analysed for fasting plasma glucose (FPG) and fasting C peptide (FCP) and glycated haemoglobin (HbA1c). Patients were given their usual drugs for management of their diabetes and then served with a standard meal calculated to contain 50 g of carbohydrate, made up of 53 % carbohydrate, 17 % of protein and 30 % of lipids, providing 500 kcal. Blood samples 2 hours after the start of the meal were analysed for postprandial glucose (PPG) and postprandial C peptide (PCP). Fasting (M0) and postprandial beta cell responsiveness (M1) were calculated.
Results
The mean FPG and PPG were 7.51+/− 3.39 mmol/l and 11.02+/−4.03 mmol/l respectively while the mean glycated haemoglobin (HbA1c) was 9.0+/−2.5 %. The mean fasting C peptide was 1.44+/−1.80ug/ml. Many of the patients (56.7 %) had low FCP levels. The mean postprandial C peptide was 4.0+/−2.8 ng/ml. There were significant correlations between M1, HbA1c and PPG (p = 0.015, 0.024, 0.001 respectively) and also between M0, HbA1c, PPG and FPG (p = 0.001, 0.002, 0.001). HbA1c decreased across increasing tertiles of M0 (p < 0.001) and also M1 (p = 0.002). In step-wise linear regression analysis, M0 and M1 significantly predicted HbA1c.
Conclusions
Many of the patients had low C peptide levels with poor beta cell response to the meal. The patients had poor glycaemic control and poor beta cell function. Both fasting and postprandial beta cell responsiveness were significant determinants of blood glucose and glycated haemoglobin levels. It is likely that putting these patients on insulin may have led to better glycaemic control in them.
doi:10.1186/1472-6823-12-11
PMCID: PMC3489861  PMID: 22738260
Beta cell; Type2 diabetes; Meal stimulation; Glycaemic control
25.  A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design 
Background
Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial.
Methods/design
The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year.
Discussion
In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996.
doi:10.1186/1472-6823-12-10
PMCID: PMC3433358  PMID: 22727048
Type 1 diabetes; Severe hypoglycaemia; Human insulin; Insulin analogues; PROBE

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