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1.  Endogenous melatonin and oxidatively damaged guanine in DNA 
Background
A significant body of literature indicates that melatonin, a hormone primarily produced nocturnally by the pineal gland, is an important scavenger of hydroxyl radicals and other reactive oxygen species. Melatonin may also lower the rate of DNA base damage resulting from hydroxyl radical attack and increase the rate of repair of that damage. This paper reports the results of a study relating the level of overnight melatonin production to the overnight excretion of the two primary urinary metabolites of the repair of oxidatively damaged guanine in DNA.
Methods
Mother-father-daughter(s) families (n = 55) were recruited and provided complete overnight urine samples. Total overnight creatinine-adjusted 6-sulphatoxymelatonin (aMT6s/Cr) has been shown to be highly correlated with total overnight melatonin production. Urinary 8-oxo-7,8-dihydro-guanine (8-oxoGua) results from the repair of DNA or RNA guanine via the nucleobase excision repair pathway, while urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) may possibly result from the repair of DNA guanine via the nucleotide excision repair pathway. Total overnight urinary levels of 8-oxodG and 8-oxoGua are therefore a measure of total overnight guanine DNA damage. 8-oxodG and 8-oxoGua were measured using a high-performance liquid chromatography-electrospray ionization tandem mass spectrometry assay. The mother, father, and oldest sampled daughter were used for these analyses. Comparisons between the mothers, fathers, and daughters were calculated for aMT6s/Cr, 8-oxodG, and 8-oxoGua. Regression analyses of 8-oxodG and 8-oxoGua on aMT6s/Cr were conducted for mothers, fathers, and daughters separately, adjusting for age and BMI (or weight).
Results
Among the mothers, age range 42-80, lower melatonin production (as measured by aMT6s/CR) was associated with significantly higher levels of 8-oxodG (p < 0.05), but not with 8-oxoGua. Among the fathers, age range 46-80, lower melatonin production was associated with marginally higher levels of 8-oxoGua (p < 0.07), but not with 8-oxodG. Among the daughters, no relationship was found between melatonin levels and either 8-oxodG or 8-oxoGua levels. When the mother and father data were further analyzed using only subjects older than the oldest daughter, the associations became somewhat stronger.
Conclusion
Low levels of endogenous melatonin production among older individuals may lead to higher levels of oxidatively damaged guanine in DNA, thereby possibly increasing the risk of developing cancer. The possible different effects of melatonin in the rates of utilization of pathways for repair of oxidatively damaged guanine in DNA identified between older women and older men are intriguing.
doi:10.1186/1472-6823-9-22
PMCID: PMC2771025  PMID: 19835624
2.  Age-related increases in parathyroid hormone may be antecedent to both osteoporosis and dementia 
Background
Numerous studies have reported that age-induced increased parathyroid hormone plasma levels are associated with cognitive decline and dementia. Little is known about the correlation that may exist between neurological processing speed, cognition and bone density in cases of hyperparathyroidism. Thus, we decided to determine if parathyroid hormone levels correlate to processing speed and/or bone density.
Methods
The recruited subjects that met the inclusion criteria (n = 92, age-matched, age 18-90 years, mean = 58.85, SD = 15.47) were evaluated for plasma parathyroid hormone levels and these levels were statistically correlated with event-related P300 potentials. Groups were compared for age, bone density and P300 latency. One-tailed tests were used to ascertain the statistical significance of the correlations. The study groups were categorized and analyzed for differences of parathyroid hormone levels: parathyroid hormone levels <30 (n = 30, mean = 22.7 ± 5.6 SD) and PTH levels >30 (n = 62, mean = 62.4 ± 28.3 SD, p ≤ 02).
Results
Patients with parathyroid hormone levels <30 showed statistically significantly less P300 latency (P300 = 332.7 ± 4.8 SE) relative to those with parathyroid hormone levels >30, which demonstrated greater P300 latency (P300 = 345.7 ± 3.6 SE, p = .02). Participants with parathyroid hormone values <30 (n = 26) were found to have statistically significantly higher bone density (M = -1.25 ± .31 SE) than those with parathyroid hormone values >30 (n = 48, M = -1.85 ± .19 SE, p = .04).
Conclusion
Our findings of a statistically lower bone density and prolonged P300 in patients with high parathyroid hormone levels may suggest that increased parathyroid hormone levels coupled with prolonged P300 latency may become putative biological markers of both dementia and osteoporosis and warrant intensive investigation.
doi:10.1186/1472-6823-9-21
PMCID: PMC2768728  PMID: 19825157
3.  Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation 
Background
Acromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels.
Methods
Evidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG.
Results
One RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was £81,000/QALY and £212,000/LYG. To reduce this to £30K/QALY would require a reduction in drug cost by about one third.
Conclusion
PEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money.
doi:10.1186/1472-6823-9-20
PMCID: PMC2768727  PMID: 19814797
4.  The consequences of delaying insulin initiation in UK type 2 diabetes patients failing oral hyperglycaemic agents: a modelling study 
Background
Recent data have shown that type 2 diabetes patients in the UK delay initiating insulin on average for over 11 years after first being prescribed an oral medication. Using a published computer simulation model of diabetes we used UK-specific data to estimate the clinical consequences of immediately initiating insulin versus delaying initiation for periods in line with published estimates.
Methods
In the base case scenario simulated patients, with characteristics based on published UK data, were modelled as either initiating insulin immediately or delaying for 8 years. Clinical outcomes in terms of both life expectancy and quality-adjusted life expectancy and also diabetes-related complications (cumulative incidence and time to onset) were projected over a 35 year time horizon. Treatment effects associated with insulin use were taken from published studies and sensitivity analyses were performed around time to initiation of insulin, insulin efficacies and hypoglycaemia utilities.
Results
For patients immediately initiating insulin there were increases in (undiscounted) life expectancy of 0.61 years and quality-adjusted life expectancy of 0.34 quality-adjusted life years versus delaying initiation for 8 years. There were also substantial reductions in cumulative incidence and time to onset of all diabetes-related complications with immediate versus delayed insulin initiation. Sensitivity analyses showed that a reduced delay in insulin initiation or change in insulin efficacy still demonstrated clinical benefits for immediate versus delayed initiation.
Conclusion
UK type 2 diabetes patients are at increased risk of a large number of diabetes-related complications due to an unnecessary delay in insulin initiation. Despite clear guidelines recommending tight glycaemic control this failure to begin insulin therapy promptly is likely to result in needlessly reduced life expectancy and compromised quality of life.
doi:10.1186/1472-6823-9-19
PMCID: PMC2761913  PMID: 19804622
5.  The association between history of diabetic foot ulcer, perceived health and psychological distress: the Nord-Trøndelag Health Study 
Background
While the adverse impact of a history of a foot ulcer on physical health among persons with diabetes is well known, little is known about the association between foot ulcer, perceived health and psychological distress. Results from various studies are difficult to compare as different study designs, samples and/or different questionnaires have been used. The aim of this study was to compare levels of anxiety and depression, psychological well-being and perceived health between persons with diabetes, with or without a history of foot ulcer, and persons without diabetes in a large study of community-dwelling individuals.
Methods
This study included 65,126 persons, of whom 63,632 did not have diabetes, 1,339 had diabetes without a history of foot ulcer and 155 had diabetes and a history of foot ulcer. Levels of anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). Psychological well-being was measured on a four-item scale, and perceived health was measured with a one-item question. We investigated whether levels of anxiety, depression, psychological well-being and perceived health were different in the three study groups using multiple regression models controlling for demographic factors, body mass index, smoking and cardiovascular conditions. Separate multivariate analyses comparing the two diabetes samples were additionally adjusted for diabetes-specific variables.
Results
A history of foot ulcer was significantly associated with more depressive symptoms, poorer psychological well-being and poorer perceived health compared to participants without diabetes. In multivariate analyses, perceived health and psychological well-being were significantly poorer among those with a history of foot ulcer compared to those without diabetes. Among persons with diabetes, perceived health was significantly worse among those with a history of foot ulcer. After multivariate adjustment, levels of anxiety and depression and psychological well-being did not differ between the two diabetes groups.
Conclusion
Perceived health and psychological well-being were significantly poorer among participants with diabetes and a history of foot ulcer compared to those without diabetes. Among people with diabetes, a history of foot ulcer had significant negative impact on perceived health but did not independently contribute to psychological distress.
doi:10.1186/1472-6823-9-18
PMCID: PMC2737541  PMID: 19706152
6.  Actos Now for the prevention of diabetes (ACT NOW) study 
Background
Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.
Methods/Design
602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.
Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance.
Conclusion
ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM.
Trial Registration
clinical trials.gov identifier: NCT00220961
doi:10.1186/1472-6823-9-17
PMCID: PMC2725044  PMID: 19640291
7.  Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study 
Background
Most studies on cortisol have focused on smaller, selected samples. We therefore aimed to sex-specifically study the diurnal cortisol pattern and explore its association with abdominal obesity in a large unselected population.
Methods
In 2001–2004, 1811 men and women (30–75 years) were randomly selected from the Vara population, south-western Sweden (81% participation rate). Of these, 1671 subjects with full information on basal morning and evening salivary cortisol and anthropometric measurements were included in this cross-sectional study. Differences between groups were examined by general linear model and by logistic and linear regression analyses.
Results
Morning and Δ-cortisol (morning – evening cortisol) were significantly higher in women than men. In both genders older age was significantly associated with higher levels of all cortisol measures, however, most consistently with evening cortisol. In women only, age-adjusted means of WHR were significantly lower in the highest compared to the lowest quartile of morning cortisol (p = 0.036) and Δ-cortisol (p < 0.001), respectively. Furthermore, when comparing WHR above and below the mean, the age-adjusted OR in women for the lowest quartile of cortisol compared to the highest was 1.5 (1.0–2.2, p = 0.058) for morning cortisol and 1.9 (1.3–2.8) for Δ-cortisol. All findings for Δ-cortisol remained after adjustments for multiple covariates and were also seen in a linear regression analysis (p = 0.003).
Conclusion
In summary, our findings of generally higher cortisol levels in women than men of all ages are novel and the stronger results seen for Δ-cortisol as opposed to morning cortisol in the association with WHR emphasise the need of studying cortisol variation intra-individually. To our knowledge, the associations in this study have never before been investigated in such a large population sample of both men and women. Our results therefore offer important knowledge on the descriptive characteristics of cortisol in relation to age and gender, and on the impact that associations previously seen between cortisol and abdominal obesity in smaller, selected samples have on a population level.
doi:10.1186/1472-6823-9-16
PMCID: PMC2711063  PMID: 19545400
8.  Randomized controlled trial of the efficacy of aerobic exercise in reducing metabolic risk in healthy older people: The Hertfordshire Physical Activity Trial 
Background
While there are compelling observational data confirming that individuals who exercise are healthier, the efficacy of aerobic exercise interventions to reduce metabolic risk and improve insulin sensitivity in older people has not been fully elucidated. Furthermore, while low birth weight has been shown to predict adverse health outcomes later in life, its influence on the response to aerobic exercise is unknown. Our primary objective is to assess the efficacy of a fully supervised twelve week aerobic exercise intervention in reducing clustered metabolic risk in healthy older adults. A secondary objective is to determine the influence of low birth weight on the response to exercise in this group.
Methods/Design
We aim to recruit 100 participants born between 1931–1939, from the Hertfordshire Cohort Study and randomly assign them to no intervention or to 36 fully supervised one hour sessions on a cycle ergometer, over twelve weeks. Each participant will undergo detailed anthropometric and metabolic assessment pre- and post-intervention, including muscle biopsy, magnetic resonance imaging and spectroscopy, objective measurement of physical activity and sub-maximal fitness testing.
Discussion
Given the extensive phenotypic characterization, this study will provide valuable insights into the mechanisms underlying the beneficial effects of aerobic exercise as well as the efficacy, feasibility and safety of such interventions in this age group.
Trial Registration
Current Controlled Trials: ISRCTN60986572
doi:10.1186/1472-6823-9-15
PMCID: PMC2708167  PMID: 19545359
9.  Cost-effectiveness comparison between palpation- and ultrasound-guided thyroid fine-needle aspiration biopsies 
Background
The aim of this study is to perform a cost-effectiveness comparison between palpation-guided thyroid fine-needle aspiration biopsies (P-FNA) and ultrasound-guided thyroid FNA biopsies (USG-FNA).
Methods
Each nodule was considered as a case. Diagnostic steps were history and physical examination, TSH measurement, Tc99m thyroid scintigraphy for nodules with a low TSH level, initial P-FNA versus initial USG-FNA, repeat USG-FNA for nodules with initial inadequate P-FNA or USG-FNA, hemithyroidectomy for inadequate repeat USG-FNA. American Thyroid Association thyroid nodule management guidelines were simulated in estimating the cost of P-FNA strategy. American Association of Clinical Endocrinologists guidelines were simulated for USG-FNA strategy. Total costs were estimated by adding the cost of each diagnostic step to reach a diagnosis for 100 nodules. Strategy cost was found by dividing the total cost to 100. Incremental cost-effectiveness ratio (ICER) was calculated by dividing the difference between strategy cost of USG-FNA and P-FNA to the difference between accuracy of USG-FNA and P-FNA. A positive ICER indicates more and a negative ICER indicates less expense to achieve one more additional accurate diagnosis of thyroid cancer for USG-FNA.
Results
Seventy-eight P-FNAs and 190 USG-FNAs were performed between April 2003 and May 2008. There were no differences in age, gender, thyroid function, frequency of multinodular goiter, nodule location and diameter (median nodule diameter: 18.4 mm in P-FNA and 17.0 mm in USG-FNA) between groups. Cytology results in P-FNA versus USG-FNA groups were as follows: benign 49% versus 62% (p = 0.04), inadequate 42% versus 29% (p = 0.03), malignant 3% (p = 1.00) and indeterminate 6% (p = 0.78) for both. Eleven nodules from P-FNA and 18 from USG-FNA group underwent surgery. The accuracy of P-FNA was 0.64 and USG-FNA 0.72. Unit cost of P-FNA was 148 Euros and USG-FNA 226 Euros. The cost of P-FNA strategy was 534 Euros and USG-FNA strategy 523 Euros. Strategy cost includes the expense of repeat USG-FNA for initial inadequate FNAs and surgery for repeat inadequate USG-FNAs. ICER was -138 Euros.
Conclusion
Universal application of USG-FNA for all thyroid nodules is cost-effective and saves 138 Euros per additional accurate diagnosis of benign versus malignant thyroid nodular disease.
Trial registration
ClinicalTrials.gov, NCT00571090
doi:10.1186/1472-6823-9-14
PMCID: PMC2688006  PMID: 19445710
10.  DreamTel; Diabetes risk evaluation and management tele-monitoring study protocol 
Background
The rising prevalence of type 2 diabetes underlines the importance of secondary strategies for the prevention of target organ damage. While access to diabetes education centers and diabetes intensification management has been shown to improve blood glucose control, these services are not available to all that require them, particularly in rural and northern areas. The provision of these services through the Home Care team is an advance that can overcome these barriers. Transfer of blood glucose data electronically from the home to the health care provider may improve diabetes management.
Methods and design
The study population will consist of patients with type 2 diabetes with uncontrolled A1c levels living on reserve in the Battlefords region of Saskatchewan, Canada. This pilot study will take place over three phases. In the first phase over three months the impact of the introduction of the Bluetooth enabled glucose monitor will be assessed. In the second phase over three months, the development of guidelines based treatment algorithms for diabetes intensification will be completed. In the third phase lasting 18 months, study subjects will have diabetes intensification according to the algorithms developed.
Discussion
The first phase will determine if the use of the Bluetooth enabled blood glucose devices which can transmit results electronically will lead to changes in A1c levels. It will also determine the feasibility of recruiting subjects to use this technology. The rest of the Diabetes Risk Evaluation and Management Tele-monitoring (DreamTel) study will determine if the delivery of a diabetes intensification management program by the Home Care team supported by the Bluetooth enabled glucose meters leads to improvements in diabetes management.
Trial Registration
Protocol NCT00325624
doi:10.1186/1472-6823-9-13
PMCID: PMC2689225  PMID: 19426530
11.  Familial history of diabetes and clinical characteristics in Greek subjects with type 2 diabetes 
Background
A lot of studies have showed an excess maternal transmission of type 2 diabetes (T2D). The aim, therefore, of the present study was to estimate the prevalence of familial history of T2D in Greek patients, and to evaluate its potential effect on the patient's metabolic control and the presence of diabetic complications.
Methods
A total of 1,473 T2D patients were recruited. Those with diabetic mothers, diabetic fathers, diabetic relatives other than parents and no known diabetic relatives, were considered separately.
Results
The prevalence of diabetes in the mother, the father and relatives other than parents, was 27.7, 11.0 and 10.7%, respectively. Patients with paternal diabetes had a higher prevalence of hypertension (64.8 vs. 57.1%, P = 0.05) and lower LDL-cholesterol levels (115.12 ± 39.76 vs. 127.13 ± 46.53 mg/dl, P = 0.006) than patients with diabetes in the mother. Patients with familial diabetes were significantly younger (P < 0.001), with lower age at diabetes diagnosis (P < 0.001) than those without diabetic relatives. Patients with a diabetic parent had higher body mass index (BMI) (31.22 ± 5.87 vs. 30.67 ± 5.35 Kg/m2, P = 0.08), higher prevalence of dyslipidemia (49.8 vs. 44.6%, P = 0.06) and retinopathy (17.9 vs. 14.5%, P = 0.08) compared with patients with no diabetic relatives. No difference in the degree of metabolic control and the prevalence of chronic complications were observed.
Conclusion
The present study showed an excess maternal transmission of T2D in a sample of Greek diabetic patients. However, no different influence was found between maternal and paternal diabetes on the clinical characteristics of diabetic patients except for LDL-cholesterol levels and presence of hypertension. The presence of a family history of diabetes resulted to an early onset of the disease to the offspring.
doi:10.1186/1472-6823-9-12
PMCID: PMC2680864  PMID: 19397813
12.  Graz Endocrine Causes of Hypertension (GECOH) study: a diagnostic accuracy study of aldosterone to active renin ratio in screening for primary aldosteronism 
Background
Primary aldosteronism (PA) affects approximately 5 to 10% of all patients with arterial hypertension and is associated with an excess rate of cardiovascular complications that can be significantly reduced by a targeted treatment. There exists a general consensus that the aldosterone to renin ratio should be used as a screening tool but valid data about the accuracy of the aldosterone to renin ratio in screening for PA are sparse. In the Graz endocrine causes of hypertension (GECOH) study we aim to prospectively evaluate diagnostic procedures for PA.
Methods and design
In this single center, diagnostic accuracy study we will enrol 400 patients that are routinely referred to our tertiary care center for screening for endocrine hypertension. We will determine the aldosterone to active renin ratio (AARR) as a screening test. In addition, all study participants will have a second determination of the AARR and will undergo a saline infusion test (SIT) as a confirmatory test. PA will be diagnosed in patients with at least one AARR of ≥ 5.7 ng/dL/ng/L (including an aldosterone concentration of ≥ 9 ng/dL) who have an aldosterone level of ≥ 10 ng/dL after the saline infusion test. As a primary outcome we will calculate the receiver operating characteristic curve of the AARR in diagnosing PA. Secondary outcomes include the test characteristics of the saline infusion test involving a comparison with 24 hours urine aldosterone levels and the accuracy of the aldosterone to renin activity ratio in diagnosing PA. In addition we will evaluate whether the use of beta-blockers significantly alters the accuracy of the AARR and we will validate our laboratory methods for aldosterone and renin.
Conclusion
Screening for PA with subsequent targeted treatment is of great potential benefit for hypertensive patients. In the GECOH study we will evaluate a standardised procedure for screening and diagnosing of this disease.
doi:10.1186/1472-6823-9-11
PMCID: PMC2671510  PMID: 19351411
13.  Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)α agonist fenofibrate and the PPARγ agonist pioglitazone 
Background
All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats.
Methods
Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied.
Results
The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1.
Conclusion
We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.
doi:10.1186/1472-6823-9-10
PMCID: PMC2678137  PMID: 19331671
14.  Clinical features, predictive factors and outcome of hyperglycaemic emergencies in a developing country 
Background
Hyperglycaemic emergencies are common acute complications of diabetes mellitus (DM) but unfortunately, there is a dearth of published data on this entity from Nigeria. This study attempts to describe the clinical and laboratory scenario associated with this complication of DM.
Methods
This study was carried out in DM patients who presented to an urban hospital in Nigeria with hyperglycaemic emergencies (HEs). The information extracted included biodata, laboratory data and hospitalization outcome. Outcome measures included mortality rates, case fatality rates and predictive factors for HEs mortality. Statistical tests used are χ2, Student's t test and logistic regression.
Results
A total of 111 subjects with HEs were recruited for the study. Diabetes ketoacidosis (DKA) and hyperosomolar hyperglycaemic state (HHS) accounted for 94 (85%) and 17 (15%) respectively of the HEs. The mean age (SD) of the subjects was 53.9 (14.4) years and their ages ranged from 22 to 86 years. DKA occurred in all subjects with type 1 DM and 73 (81%) of subjects with type 2 DM. The presence of HSS was noted in 17 (19%) of the subjects with type 2 DM.
Hypokalaemia (HK) was documented in 41 (37%) of the study subjects. Elevated urea levels and hyponatraemia were noted more in subjects with DKA than in those subjects with HHS (57.5%,19% vs 53%,18%). The mortality rate for HEs in this report is 20% and the case fatality rates for DKA and HHS are 18% and 35% respectively.
The predictive factors for HEs mortality include, sepsis, foot ulceration, previously undetected DM, hypokalaemia and being elderly.
Conclusion
HHS carry a higher case fatality rate than DKA and the predictive factors for hyperglycaemic emergencies' mortality in the Nigerian with DM include foot ulcers, hypokalaemia and being elderly.
doi:10.1186/1472-6823-9-9
PMCID: PMC2661082  PMID: 19272167
15.  Anti-inflammatory effect of rosiglitazone is not reflected in expression of NFκB-related genes in peripheral blood mononuclear cells of patients with type 2 diabetes mellitus 
Background
Rosiglitazone not only improves insulin-sensitivity, but also exerts anti-inflammatory effects. We have now examined in type 2 diabetic patients if these effects are reflected by changes in mRNA expression in peripheral blood mononuclear cells (PBMCs) to see if these cells can be used to study these anti-inflammatory effects at the molecular level in vivo.
Method
Eleven obese type 2 diabetic patients received rosiglitazone (2 × 4 mg/d) for 8 weeks. Fasting blood samples were obtained before and after treatment. Ten obese control subjects served as reference group. The expression of NFκB-related genes and PPARγ target genes in PBMCs, plasma TNFα, IL6, MCP1 and hsCRP concentrations were measured. In addition, blood samples were obtained after a hyperinsulinemic-euglycemic clamp.
Results
Rosiglitazone reduced plasma MCP1 and hsCRP concentrations in diabetic patients (-9.5 ± 5.3 pg/mL, p = 0.043 and -1.1 ± 0.3 mg/L p = 0.003), respectively). For hsCRP, the concentration became comparable with the non-diabetic reference group. However, of the 84 NFκB-related genes that were measured in PBMCs from type 2 diabetic subjects, only RELA, SLC20A1, INFγ and IL1R1 changed significantly (p < 0.05). In addition, PPARγ and its target genes (CD36 and LPL) did not change. During the clamp, insulin reduced plasma MCP1 concentration in the diabetic and reference groups (-9.1 ± 1.8%, p = 0.001 and -11.1 ± 4.1%, p = 0.023, respectively) and increased IL6 concentration in the reference group only (23.5 ± 9.0%, p = 0.028).
Conclusion
In type 2 diabetic patients, the anti-inflammatory effect of rosiglitazone is not reflected by changes in NFκB and PPARγ target genes in PBMCs in vivo. Furthermore, our results do not support that high insulin concentrations contribute to the pro-inflammatory profile in type 2 diabetic patients.
doi:10.1186/1472-6823-9-8
PMCID: PMC2653037  PMID: 19243600
16.  Zinc transporter gene expression is regulated by pro-inflammatory cytokines: a potential role for zinc transporters in beta-cell apoptosis? 
Background
β-cells are extremely rich in zinc and zinc homeostasis is regulated by zinc transporter proteins. β-cells are sensitive to cytokines, interleukin-1β (IL-1β) has been associated with β-cell dysfunction and -death in both type 1 and type 2 diabetes. This study explores the regulation of zinc transporters following cytokine exposure.
Methods
The effects of cytokines IL-1β, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on zinc transporter gene expression were measured in INS-1-cells and rat pancreatic islets. Being the more sensitive transporter, we further explored ZnT8 (Slc30A8): the effect of ZnT8 over expression on cytokine induced apoptosis was investigated as well as expression of the insulin gene and two apoptosis associated genes, BAX and BCL2.
Results
Our results showed a dynamic response of genes responsible for β-cell zinc homeostasis to cytokines: IL-1β down regulated a number of zinc-transporters, most strikingly ZnT8 in both islets and INS-1 cells. The effect was even more pronounced when mixing the cytokines. TNF-α had little effect on zinc transporter expression. IFN-γ down regulated a number of zinc transporters. Insulin expression was down regulated by all cytokines. ZnT8 over expressing cells were more sensitive to IL-1β induced apoptosis whereas no differences were observed with IFN-γ, TNF-α, or a mixture of cytokines.
Conclusion
The zinc transporting system in β-cells is influenced by the exposure to cytokines. Particularly ZnT8, which has been associated with the development of diabetes, seems to be cytokine sensitive.
doi:10.1186/1472-6823-9-7
PMCID: PMC2651882  PMID: 19243577
17.  Self-care coping strategies in people with diabetes: a qualitative exploratory study 
Background
The management of diabetes self-care is largely the responsibility of the patient. With more emphasis on the prevention of complications, adherence to diabetes self-care regimens can be difficult. Diabetes self-care requires the patient to make many dietary and lifestyle changes. This study will explore patient perceptions of diabetes self-care, with particular reference to the burden of self-care and coping strategies among patients.
Methods
A maximum variation sample of 17 patients was selected from GP practices and diabetes clinics in Ireland to include patients with types 1 and 2 diabetes, various self-care regimens, and a range of diabetes complications. Data were collected by in-depth interviews; which were tape-recorded and transcribed. The transcripts were analysed using open and axial coding procedures to identify main categories, and were reviewed by an independent corroborator. Discussion of the results is made in the theoretical context of the health belief, health value, self-efficacy, and locus of control frameworks.
Results
Patients' perceptions of their self-care varied on a spectrum, displaying differences in self-care responsibilities such as competence with dietary planning, testing blood sugar and regular exercise. Three patient types could be distinguished, which were labeled: "proactive manager," a patient who independently monitors blood glucose and adjusts his/her self-care regime to maintain metabolic control; "passive follower," a patient who follows his/her prescribed self-care regime, but does not react autonomously to changes in metabolic control; and "nonconformist," a patient who does not follow most of his/her prescribed self-care regimen.
Conclusion
Patients have different diabetes self-care coping strategies which are influenced by their self-care health value and consequently may affect their diet and exercise choices, frequency of blood glucose monitoring, and compliance with prescribed medication regimens. Particular attention should be paid to the patient's self-care coping strategy, and self-care protocols should be tailored to complement the different patient types.
doi:10.1186/1472-6823-9-6
PMCID: PMC2664817  PMID: 19232113
18.  Diabetes Mellitus: Indigenous naming, indigenous diagnosis and self-management in an African setting: the example from Cameroon 
Background
The objective was to examine how the indigenous naming, indigenous self-diagnosis and management of diabetes evolved with awareness in order to develop a socially oriented theoretical model for its care.
Methods
The data was collected through a one-year extended participant observation in Bafut, a rural health district of Cameroon. The sample consisted of 72 participants in a rural health district of Cameroon (men and women) with type 2 diabetes. We used participant observation to collect data through focus group discussions, in depth interviews and fieldwork conversations. The method of analysis entailed a thick description, thematic analysis entailing constant comparison within and across FGD and across individual participants and content analysis.
Results
The core concepts identified were the evolution of names for diabetes and the indigenous diagnostic and self-management procedures. Participants fell into one of two naming typologies: (a) Naming excluding any signs and symptoms of diabetes; (b) naming including signs and symptoms of diabetes. Participants fell into two typologies of diagnostic procedures: (a) those that use indigenous diagnostic procedures for monitoring and controlling diabetes outcomes and b) those that had initially used it only for diagnosis and continued to use them for self management. These typologies varied according to how participants' awareness evolved and the impact on self-diagnosis and management.
Conclusion
The evolution of names for diabetes was an important factor that influenced the subsequent self-diagnosis and management of diabetes in both traditional and modern biomedical settings.
doi:10.1186/1472-6823-9-5
PMCID: PMC2661081  PMID: 19224650
19.  Serum 25-hydroxyvitamin D is not related to cardiac natriuretic peptide in nulliparous and lactating women 
Background
Vitamin D deficiency is associated with heightened risk of cardiovascular disease. Potential mechanisms include involvement of vitamin D in regulation of renin-angiotensin system and manufacture and secretion of cardiac natriuretic peptides. Our aim was to document relationships between 25 hydroxyvitamin [25(OH)D] and N-terminal pro B-type natriuretic peptide (NT-proBNP) and plasma renin activity (PRA) levels and to document the effect of vitamin D administration on NT-proBNP and PRA levels in vitamin D deficient subjects.
Methods
Serum 25(OH)D, parathyroid hormone (PTH), plasma or serum NT-proBNP and PRA levels were measured at baseline in nulliparous and lactating women and after 2 months of oral vitamin D2 (2,000 IU/day or 60,000 IU/month) supplementation to lactating women.
Results
Baseline levels of 25(OH)D were low (<50 nmol/L) in most women whereas PRA and NT-proBNP levels were within the normal range. There were no significant correlations between baseline 25(OH)D or PTH with NT-proBNP and PRA. Vitamin D administration over a 2-month period in lactating women was associated with a decline in NT-proBNP (by 9.1 ± 2.0 pmol/L; p < 0.001) and PRA (by 0.32 ± 0.17 nmol/L/hr; p = 0.064). However, there were no significant correlations between the changes from baseline in 25(OH)D and either NT-proBNP (r = -0.04, p = 0.8) or PRA (r = -0.04, p = 0.8).
Conclusion
We found no significant correlations between 25(OH)D or PTH with NT-proBNP and PRA in vitamin D deficient women. Further information is required to clarify the effects of vitamin D administration on cardiac structure and function.
doi:10.1186/1472-6823-9-4
PMCID: PMC2646736  PMID: 19178708
20.  Extremely short duration high intensity interval training substantially improves insulin action in young healthy males 
Background
Traditional high volume aerobic exercise training reduces cardiovascular and metabolic disease risk but involves a substantial time commitment. Extremely low volume high-intensity interval training (HIT) has recently been demonstrated to produce improvements to aerobic function, but it is unknown whether HIT has the capacity to improve insulin action and hence glycemic control.
Methods
Sixteen young men (age: 21 ± 2 y; BMI: 23.7 ± 3.1 kg·m-2; VO2peak: 48 ± 9 ml·kg-1·min-1) performed 2 weeks of supervised HIT comprising of a total of 15 min of exercise (6 sessions; 4–6 × 30-s cycle sprints per session). Aerobic performance (250-kJ self-paced cycling time trial), and glucose, insulin and NEFA responses to a 75-g oral glucose load (oral glucose tolerance test; OGTT) were determined before and after training.
Results
Following 2 weeks of HIT, the area under the plasma glucose, insulin and NEFA concentration-time curves were all reduced (12%, 37%, 26% respectively, all P < 0.001). Fasting plasma insulin and glucose concentrations remained unchanged, but there was a tendency for reduced fasting plasma NEFA concentrations post-training (pre: 350 ± 36 v post: 290 ± 39 μmol·l-1, P = 0.058). Insulin sensitivity, as measured by the Cederholm index, was improved by 23% (P < 0.01), while aerobic cycling performance improved by ~6% (P < 0.01).
Conclusion
The efficacy of a high intensity exercise protocol, involving only ~250 kcal of work each week, to substantially improve insulin action in young sedentary subjects is remarkable. This novel time-efficient training paradigm can be used as a strategy to reduce metabolic risk factors in young and middle aged sedentary populations who otherwise would not adhere to time consuming traditional aerobic exercise regimes.
doi:10.1186/1472-6823-9-3
PMCID: PMC2640399  PMID: 19175906
21.  Alteration of renal respiratory Complex-III during experimental type-1 diabetes 
Background
Diabetes has become the single most common cause for end-stage renal disease in the United States. It has been established that mitochondrial damage occurs during diabetes; however, little is known about what initiates mitochondrial injury and oxidant production during the early stages of diabetes. Inactivation of mitochondrial respiratory complexes or alteration of their critical subunits can lead to generation of mitochondrial oxidants, mitochondrial damage, and organ injury. Thus, one goal of this study was to determine the status of mitochondrial respiratory complexes in the rat kidney during the early stages of diabetes (5-weeks post streptozotocin injection).
Methods
Mitochondrial complex activity assays, blue native gel electrophoresis (BN-PAGE), Complex III immunoprecipitation, and an ATP assay were performed to examine the effects of diabetes on the status of respiratory complexes and energy levels in renal mitochondria. Creatinine clearance and urine albumin excretion were measured to assess the status of renal function in our model.
Results
Interestingly, of all four respiratory complexes only cytochrome c reductase (Complex-III) activity was significantly decreased, whereas two Complex III subunits, Core 2 protein and Rieske protein, were up regulated in the diabetic renal mitochondria. The BN-PAGE data suggested that Complex III failed to assemble correctly, which could also explain the compensatory upregulation of specific Complex III subunits. In addition, the renal F0F1-ATPase activity and ATP levels were increased during diabetes.
Conclusion
In summary, these findings show for the first time that early (and selective) inactivation of Complex-III may contribute to the mitochondrial oxidant production which occurs in the early stages of diabetes.
doi:10.1186/1472-6823-9-2
PMCID: PMC2636815  PMID: 19166612
22.  Waist circumference and insulin resistance: a cross-sectional study of Japanese men 
Background
Visceral obesity is positively related to insulin resistance. The nature of the relationship between waist circumference and insulin resistance has not been known in Japanese populations. This study examined the relationship between waist circumference and insulin resistance and evaluated the optimal cutoff point for waist circumference in relation to insulin resistance in middle-aged Japanese men.
Methods
Study subjects included 4800 Japanese men aged 39 to 60 years. Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR). The relationship of waist circumference with HOMA-IR was assessed by use of adjusted means of HOMA-IR and odds ratios of elevated HOMA-IR defined as the highest quintile (≥2.00). Receiver operating characteristics (ROC) curve analysis using Youden index and the area under curve (AUC) was employed to determine optimal cutoffs of waist circumference in relation to HOMA-IR.
Results
Adjusted geometric means of HOMA-IR and prevalence odds of elevated HOMA-IR were progressively higher with increasing levels of waist circumference. In the ROC curve analysis, the highest value of Youden index was obtained for a cutoff point of 85 cm in waist circumference across different values of HOMA-IR. Multiple logistic regression analysis also indicated that the AUC was consistently the largest for a waist circumference of 85 cm.
Conclusion
Waist circumference is linearly related to insulin resistance, and 85 cm in waist circumference is an optimal cutoff in predicting insulin resistance in middle-aged Japanese men.
doi:10.1186/1472-6823-9-1
PMCID: PMC2635363  PMID: 19138424

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