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1.  Study Protocol: insulin and its role in cancer 
Background
Studies have shown that metabolic syndrome and its consequent biochemical derangements in the various phases of diabetes may contribute to carcinogenesis. A part of this carcinogenic effect could be attributed to hyperinsulinism. High levels of insulin decrease the production of IGF-1 binding proteins and hence increase levels of free IGF-1. It is well established that bioactivity of free insulin growth factor 1 (IGF-1) increases tumor turnover rate. The objective is to investigate the role of insulin resistance/sensitivity in carcinogenesis by studying the relation between insulin resistance/sensitivity and IGF-1 levels in cancer patients. We postulate that hyperinsulinaemia which prevails during initial phases of insulin resistance (condition prior to overt diabetes) increases bioactivity of free IGF-1, which may contribute to process of carcinogenesis.
Methods/Design
Based on our pilot study results and power analysis of the same, we have designed a two group case-control study. 800 proven untreated cancer patients (solid epithelial cell tumors) under age of 50 shall be recruited with 200 healthy subjects serving as controls. Insulin resistance/sensitivity and free IGF-1 levels shall be determined in all subjects. Association between the two parameters shall be tested using suitable statistical methods.
Discussion
Well controlled studies in humans are essential to study the link between insulin resistance, hyperinsulinaemia, IGF-1 and carcinogenesis. This study could provide insights to the role of insulin, insulin resistance, IGF-1 in carcinogenesis although a precise role and the extent of influence cannot be determined. In future, cancer prevention and treatment strategies could revolve around insulin and insulin resistance.
doi:10.1186/1472-6823-7-10
PMCID: PMC2151943  PMID: 17953765
2.  Pakistanis living in Oslo have lower serum 1,25-dihydroxyvitamin D levels but higher serum ionized calcium levels compared with ethnic Norwegians. The Oslo Health Study 
Background
Persons of Pakistani origin living in Oslo have a much higher prevalence of vitamin D deficiency and secondary hyperparathyroidism but similar bone mineral density compared with ethnic Norwegians. Our objective was to investigate whether Pakistani immigrants living in Oslo have an altered vitamin D metabolism by means of compensatory higher serum levels of 1,25-dihydroxyvitamin D (s-1,25(OH)2D) compared with ethnic Norwegians; and whether serum levels of ionized calcium (s-Ca2+) differ between Pakistanis and Norwegians.
Methods
In a cross-sectional, population-based study venous serum samples were drawn from 94 Pakistani men and 67 Pakistani women aged 30–60 years, and 290 Norwegian men and 270 Norwegian women aged 45–60 years; in total 721 subjects.
Results
Pakistanis had lower s-1,25(OH)2D compared with Norwegians (p < 0.001). Age- and gender adjusted mean (95% CI) levels were 93 (86, 99) pmol/l in Pakistanis and 123 (120, 126) pmol/l in Norwegians, p < 0.001. The difference persisted after controlling for body mass index. There was a positive relation between serum 25-hydroxyvitamin D (s-25(OH)D) and s-1,25(OH)2D in both groups. S-Ca2+ was higher in Pakistanis; age-adjusted mean (95% CI) levels were 1.28 (1.27, 1.28) mmol/l in Pakistanis and 1.26 (1.26, 1.26) mmol/l in Norwegians, p < 0.001. In both groups, s-Ca2+ was inversely correlated to serum intact parathyroid hormone levels (s-iPTH). For any s-iPTH, s-Ca2+ was higher in Pakistanis, also when controlling for age.
Conclusion
Community-dwelling Pakistanis in Oslo with low vitamin D status and secondary hyperparathyroidism have lower s-1,25(OH)2D compared with ethnic Norwegians. However, the Pakistanis have higher s-Ca2+. The cause of the higher s-Ca2+ in Pakistanis in spite of their higher iPTH remains unclear.
doi:10.1186/1472-6823-7-9
PMCID: PMC2235861  PMID: 17945003
3.  Mitochondrial DNA mutations in oxyphilic and chief cell parathyroid adenomas 
Background
The potential pathogenetic significance of mitochondrial DNA (mtDNA) mutations in tumorigenesis is controversial. We hypothesized that benign tumorigenesis of a slowly replicating tissue like the human parathyroid might constitute an especially fertile ground on which a selective advantage conferred by mtDNA mutation could be manifested and might contribute to the oxyphilic phenotype observed in a subset of parathyroid tumors.
Methods
We sought acquired mitochondrial DNA mutations by sequencing the entire 16.6 kb mitochondrial genome of each of thirty sporadic parathyroid adenomas (18 chief cell and 12 oxyphil cell), eight independent, polyclonal, parathyroid primary chief cell hyperplasias plus corresponding normal control samples, five normal parathyroid glands, and one normal thyroid gland.
Results
Twenty-seven somatic mutations were identified in 15 of 30 (9 of 12 oxyphil adenomas, 6 of 18 chief cell) parathyroid adenomas studied. No somatic mutations were observed in the hyperplastic parathyroid glands.
Conclusion
Features of the somatic mutations suggest that they may confer a selective advantage and contribute to the molecular pathogenesis of parathyroid adenomas. Importantly, the statistically significant differences in mutation prevalence in oxyphil vs. chief cell adenomas also suggest that mtDNA mutations may contribute to the oxyphil phenotype.
doi:10.1186/1472-6823-7-8
PMCID: PMC2099428  PMID: 17916247
4.  Association between erythrocyte Na+K+-ATPase activity and some blood lipids in type 1 diabetic patients from Lagos, Nigeria 
Background
Altered levels of erythrocyte Na+K+-ATPase, atherogenic and anti-atherogenic lipid metabolites have been implicated in diabetic complications but their pattern of interactions remains poorly understood.
This study evaluated this relationship in Nigerian patients with Type 1 diabetes mellitus.
Methods
A total of 34 consented Type 1 diabetic patients and age -matched 27 non-diabetic controls were enrolled. Fasting plasma levels of total cholesterol, triglycerides and HDL-cholesterol were determined spectrophotometrically and LDL-cholesterol estimated using Friedewald formula. Total protein content and Na+K+-ATPase activity were also determined spectrophotometrically from ghost erythrocyte membrane prepared by osmotic lysis.
Results
Results indicate significant (P < 0.05) reduction in Na+K+-ATPase activity in the Type 1 diabetic patients (0.38 ± 0.08 vs. 0.59 ± 0.07 uM Pi/mgprotein/h) compared to the control but with greater reduction in the diabetic subgroup with poor glycemic control (n = 20) and in whom cases of hypercholesterolemia (8.8%), hypertriglyceridemia (2.9%) and elevated LDL-cholesterol (5.9% each) were found. Correlation analyses further revealed significant (P < 0.05) inverse correlations [r = -(0.708-0.797] between all the atherogenic lipid metabolites measured and Na+K+-ATPase in this subgroup contrary to group with good glycemic control or non-diabetic subjects in which significant (P < 0.05) Na+K+-ATPase and HDL-C association were found (r = 0.427 - 0.489). The Na+K+-ATPase from the diabetic patients also exhibited increased sensitivity to digoxin and alterations in kinetic constants Vmax and Km determined by glycemic status of the patients.
Conclusion
It can be concluded that poor glycemic control evokes greater reduction in erythrocyte Na+K+-ATPase activity and promote enzyme-blood atherogenic lipid relationships in Type 1 diabetic Nigerian patients.
doi:10.1186/1472-6823-7-7
PMCID: PMC2045651  PMID: 17908327
5.  Brief Intervention in Type 1 diabetes – Education for Self-efficacy (BITES): Protocol for a randomised control trial to assess biophysical and psychological effectiveness 
Background
Self management is the cornerstone of effective preventive care in diabetes. Educational interventions that provide self-management skills for people with diabetes have been shown to reduce blood glucose concentrations. This in turn has the potential to reduce rates of complications. However, evidence to support type, quantity, setting and mode of delivery of self-management education is sparse.
Objectives: To study the biophysical and psychological effectiveness of a brief psycho-educational intervention for type 1 diabetes in adults.
Methods/Design
Design: Randomised controlled clinical trial.
Setting: Multidisciplinary specialist diabetes centre.
Hypothesis: Our hypothesis was that the brief (2.5-day) intervention would be biophysically and psychologically effective for people with type 1 diabetes.
Intervention: A brief psycho-educational intervention for type 1 diabetes developed by a multi-professional team comprising of a consultant diabetologist, a diabetes specialist nurse, a specialist diabetes dietician and a clinical health psychologist and delivered in 20 hours over 2.5 days.
Primary outcomes: HbA1c and severe hypoglycaemia.
Secondary outcomes: Blood pressure, weight, height, lipid profile and composite psychometric scales.
Participants: We shall consent and recruit 120 subjects with postal invitations sent to eligible participants. Volunteers are to be seen at randomisation clinics where independent researcher verify eligibility and obtain consent. We shall randomise 60 to BITES and 60 to standard care.
Eligibility Criteria: Type 1 diabetes for longer than 12 months, multiple injection therapy for at least two months, minimum age of 18 and ability to read and write.
Randomisation: An independent evaluator to block randomise (block-size = 6), to intervention or control groups using sealed envelopes in strict ascendant order. Control group will receive standard care.
Assessment: Participants in both groups would attend unblinded assessments at baseline, 3, 6 and 12 months, in addition to their usual care. After the intervention, usual care would be provided.
Ethics approval: York Research Ethics Committee (Ref: 01/08/016) approved the study protocol.
Discussion
We hope the trial will demonstrate feasibility of a pragmatic randomised trial of BITES and help quantify therapeutic effect. A follow up multi-centre trial powered to detect this effect could provide further evidence.
Trial registration
Current Controlled Trials ISRCTN75807800
doi:10.1186/1472-6823-7-6
PMCID: PMC2048964  PMID: 17868462
6.  Diagnostic accuracy of basal TSH determinations based on the intravenous TRH stimulation test: An evaluation of 2570 tests and comparison with the literature 
Background
Basal TSH levels reflect the metabolic status of thyroid function, however the definition and interpretation of the basal levels of TSH is a matter of controversial debate. The aim of this study was to evaluate basal TSH levels in relation to the physiological response to i.v. TRH stimulation.
Methods
A series of 2570 women attending a specialized endocrine unit were evaluated. A standardized i.v. TRH stimulation test was carried out by applying 200 μg of TRH. TSH levels were measured both in the basal and the 30 minute blood sample. The normal response to TRH stimulation had been previously determined to be an absolute value lying between 2.5 and 20 mIU/l. Both TSH values were analyzed by cross tabulation. In addition the results were compared to reference values taken from the literature.
Results
Basal TSH values were within the normal range (0.3 to 3.5 mIU/l) in 91,5% of cases, diminished in 3,8% and elevated in 4.7%. Based on the response to TRH, 82.4% were considered euthyroid, 3.3% were latent hyperthyroid, and 14.3% were latent hypothyroid. Combining the data on basal and stimulated TSH levels, latent hypothyroidism was found in the following proportions for different TSH levels: 5.4% for TSH < 2.0 mIU/l, 30.2% for TSH between 2.0 and 3.0 mIU/l, 65,5% for TSH between 3.0 and 3.50 mIU/l, 87.5% for TSH between 3.5 and 4.0 mIU/l, and 88.2% for TSH between 4 and 5 mIU/l. The use of an upper normal range for TSH of 2.5 mIU/l, as recommended in the literature, misclassified 7.7% of euthyroid cases.
Conclusion
Our analysis strategy allows us to delineate the predictive value of basal TSH levels in relation to latent hypothyroidism. A grey area can be identified for values between 3.0 and 3.5 mIU/l.
doi:10.1186/1472-6823-7-5
PMCID: PMC1950865  PMID: 17678551
7.  Is annual surveillance of all treated hypothyroid patients necessary? 
Background
Annual surveillance (with thyroid function testing) is widely recommended for the long-term follow-up of treated hypothyroid patients. It is based largely on consensus opinion and there is limited evidence to support the frequency of monitoring. The majority of patients in our hospital based thyroid register are on 18 monthly follow-up.
Methods
We carried out a retrospective analysis to see if there is evidence to support more frequent testing. We used a logistic regression model to assess whether any baseline characteristics could be applied to predict an abnormal test.
Results
We identified 2,125 patients with a minimum of 10 years follow-up (89% female, 65% autoimmune hypothyroidism, and mean age at registration 51 years). There were 2 groups: 1182 (56%) had been allocated to 18 monthly follow-up and the rest had annual surveillance. The groups were well matched at baseline. Overall, during follow-up the 12 monthly group had more abnormal tests requiring dose adjustment. However, on logistic regression analysis, people aged less than 60 years, individuals taking < 150 μg thyroxine per day and people on 18 monthly follow-up had less abnormal tests.
Conclusion
18 monthly surveillance may be adequate in the long term follow-up of hypothyroid patients less than 60 years of age on a stable thyroxine dose of 100–150 μg/day where there are robust follow-up mechanisms in place. Implementing this strategy has potential for cost saving.
doi:10.1186/1472-6823-7-4
PMCID: PMC1920515  PMID: 17605766
8.  A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo 
Background
Cycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points.
Methods/Design
3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids.
Discussion
This study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens.
Trial registration
clinical trials.gov NCT00377676
doi:10.1186/1472-6823-7-3
PMCID: PMC1924849  PMID: 17592632
9.  Accuracy of self-reported height measurements in parents and its effect on mid-parental target height calculation 
Background
Clinical determination of mid-parental height is an important part of the assessment of a child's growth, however our clinical impression has been that parents cannot be relied upon to accurately report their own heights. Therefore, we conducted this study to assess the accuracy of parental height self-reporting and its effect on calculated mid-parental target height for children presenting to a pediatric endocrinology office.
Methods
All parents bringing their children for an initial evaluation to a pediatric endocrinology clinic over a period of nine months were questioned and then measured by a pediatric endocrinologist. Parents were blinded to the study. Mid-parental target heights, based on reported and actual height were compared.
Results
There were 241 families: 98 fathers and 217 mothers in our study. Mean measured paternal height was 173.2 cm, self reported 174.9 cm (p < 0.0001), partner reported 177 cm (p = 0.0004). Only 50% of fathers and 58% of mothers reported their height within ± 2 cm of their measured height, while 15% of fathers and 12% of mothers were inaccurate by more than 4 cm. Mean measured maternal height was 160.6 cm, self-reported 161.1 cm (NS), partner reported 161.7 cm (NS). Inaccuracy of height self-report had a small but significant effect on the mean MPTH (0.4 cm, p = 0.045). Analysis showed that only 70% of MPTH calculated by reported heights fell within ± 2 cm of MPTH calculated using measured heights, 24% being in ± 2–4 cm range, and 6% were inaccurate by more than 4 cm.
Conclusion
There is a significant difference in paternal measured versus reported heights with an overall trend for fathers to overestimate their own height. A large subset of parents makes a substantial error in their height self-report, which leads to erroneous MPTH. Inaccuracy is even greater when one parent reports the other parent's height. When a child's growth is in question, measured rather than reported parental heights should be obtained.
doi:10.1186/1472-6823-7-2
PMCID: PMC1852563  PMID: 17407570
10.  The uncoupling protein 1 gene, UCP1, is expressed in mammalian islet cells and associated with acute insulin response to glucose in African American families from the IRAS Family Study 
Background
Variants of uncoupling protein genes UCP1 and UCP2 have been associated with a range of traits. We wished to evaluate contributions of known UCP1 and UCP2 variants to metabolic traits in the Insulin Resistance and Atherosclerosis (IRAS) Family Study.
Methods
We genotyped five promoter or coding single nucleotide polymorphisms (SNPs) in 239 African American (AA) participants and 583 Hispanic participants from San Antonio (SA) and San Luis Valley. Generalized estimating equations using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation were computed for the test of genotypic association, and dominant, additive and recessive models. Tests were adjusted for age, gender and BMI (glucose homeostasis and lipid traits), or age and gender (obesity traits), and empirical P-values estimated using a gene dropping approach.
Results
UCP1 A-3826G was associated with AIRg in AA (P = 0.006) and approached significance in Hispanic families (P = 0.054); and with HDL-C levels in SA families (P = 0.0004). Although UCP1 expression is reported to be restricted to adipose tissue, RT-PCR indicated that UCP1 is expressed in human pancreas and MIN-6 cells, and immunohistochemistry demonstrated co-localization of UCP1 protein with insulin in human islets. UCP2 A55V was associated with waist circumference (P = 0.045) in AA, and BMI in SA (P = 0.018); and UCP2 G-866A with waist-to-hip ratio in AA (P = 0.016).
Conclusion
This study suggests a functional variant of UCP1 contributes to the variance of AIRg in an AA population; the plausibility of this unexpected association is supported by the novel finding that UCP1 is expressed in islets.
doi:10.1186/1472-6823-7-1
PMCID: PMC1852562  PMID: 17397545

Results 1-10 (10)