Uric Acid in Primary Hyperparathyroidism: Assessment of Surgical versus Conservative Approach.

Introduction: Although suggested in early papers, the association between primary hyperparathyroidism (PHPT) and hyperuricemia is still debated, as is the potential benefit of parathyroidectomy compared to conservative treatment in serum uric acid (SUA) metabolism. Material and Methods: Our retrospective study of 125 Caucasian PHPT patients with surgical criteria evaluated between 2017 and 2021 at Elias Emergency and University Hospital, Bucharest, Romania aims to describe the characteristics of hyperuricemia in PHPT patients and to assess the differences in SUA levels between 38 surgically cured and 41 conservatively managed patients. Results: Our hyperuricemic PHPT patients (N=34) had significantly higher levels of calcium (11.55[11.05;12.42] vs. 11.2[10.8;11.96], p=.039) than the normouricemic subjects (N=91). At baseline, SUA correlated with age, serum total calcium (p=.004, r=.328), creatinine, triglycerides, and magnesium levels. A linear regression model identified calcium as a covariate with unique contribution for SUA variability. After successful parathyroidectomy, the 38 cured patients showed significantly lower serum calcium (9.3[8.7;9.75] vs. 11.55[11;12.12], p .001) and SUA (4.95[3.52;6.3] vs. 5.65[4.49;7.45], p=.011) levels compared to baseline. Conclusions: Hyperuricemic PHPT patients have significantly higher levels of serum calcium, which is also an independent determinant of SUA variability. Patients who undergo successful parathyroidectomies show a significant decrease in SUA during 1 year of follow-up.

Degraded Bone Microarchitecture in Women with PHPT-Significant Predictor of Fracture Probability.

Introduction: Patients with primary hyperparathyroidism (PHPT) experience bone mineral density (BMD) loss and trabecular bone score (TBS) alteration, which current guidelines recommend assessing. Considering TBS alongside BMD for a 10-year fracture risk assessment (FRAX) may improve PHPT management. Design: Retrospective, cross-sectional study composed of 49 Caucasian females (62 ± 10.6 years, 27.7 ± 0.87 kg/m2) with PHPT and 132 matched control subjects (61.3 ± 10.5 years, 27.5 ± 0.49 kg/m2) evaluated in 3 years. We assessed lumbar spine (LS) and femoral neck (FN) BMD, T and Z scores (GE Healthcare Lunar Osteodensitometer) and TBS (iNsight 1.8), major osteoporotic fracture (MOF), and hip FRAX. Results: Patients with PHPT had statistically lower mean values for lumbar spine bone mineral density (LS BMD) (0.95 ± 0.25 vs 1.01 ± 0.14 g/cm2, P = .01), LS T-scores (-2 ± 0.2 vs -1.4 ± 0.1 SD, P = .009), LS Z scores (-0.9 ± 0.19 vs -0.1 ± 0.11 SD, P = .009), femoral neck bone mineral density (FN BMD) (0.79 ± 0.02 vs 0.83 ± 0.01 g/cm2, P = .02), FN T-scores (-1.8 ± 0.13 vs -1.5 ± 0.07 SD, P = .017), FN Z scores (-0.51 ± 0.87 vs -0.1 ± 0.82 SD, P = .006), and TBS (0.95 ± 0.25 vs 1.01 ± 0.14 g/cm2, P = .01) compared with control subjects. 22.4% of patients with PHPT had degraded microarchitecture (TBS < 1.2) vs. 7.6% in control group (χ2 = 0.008). PHPT proved to be a covariate with unique contribution (P = .031) alongside LS BMD (P = .040) in a linear regression model [R 2 = 0.532, F(4,16) = 4.543] for TBS < 1.2. TBS adjustment elevated MOF FRAX both for PHPT (4.35 ± 0.6% vs 5.25% ± 0.73%, P < .001) and control groups (4.5 ± 0.24% vs 4.7% ± 0.26%, P < .001) compared with BMD-bases FRAX, but also increased differently between the 2 study groups (1.1-folds for PHPT patients and 1.04 for control subjects, P = .034). Conclusion: Compared with control, TBS-adjusted FRAX provides significantly higher MOF risk than BMD-based FRAX in PHPT women.

Insights into Epigenetic Changes Related to Genetic Variants and Cells-of-Origin of Pancreatic Neuroendocrine Tumors: An Algorithm for Practical Workup.

Current knowledge on the molecular landscape of pancreatic neuroendocrine tumors (PanNETs) has advanced significantly. Still, the cellular origin of PanNETs is uncertain and the associated mechanisms remain largely unknown. DAXX/ATRX and MEN1 are the three most frequently altered genes that drive PanNETs. They are recognized as a link between genetics and epigenetics. Moreover, the acknowledged impact on DNA methylation by somatic mutations in MEN1 is a valid hallmark of epigenetic mechanism. DAXX/ATRX and MEN1 can be studied at the immunohistochemical level as a reliable surrogate for sequencing. DAXX/ATRX mutations promote alternative lengthening of telomeres (ALT) activation, determined by specific fluorescence in situ hybridization (FISH) analysis. ALT phenotype is considered a significant predictor of worse prognosis and a marker of pancreatic origin. Additionally, ARX/PDX1 expression is linked to important epigenomic alterations and can be used as lineage associated immunohistochemical marker. Herein, ARX/PDX1 association with DAXX/ATRX/MEN1 and ALT can be studied through pathological assessment, as these biomarkers may provide important clues to the mechanism underlying disease pathogenesis. In this review, we present an overview of a new approach to tumor stratification based on genetic and epigenetic characteristics as well as cellular origin, with prognostic consequences.

Assessment of peripheral blood cells parameters as a valuable tool in patients with neuroendocrine neoplasms.

OBJECTIVES: Neuroendocrine neoplasms (NENs) are an extremely heterogeneous medical entity, representing a diagnostic and therapeutic challenge. Chronic inflammation, as is the case with other malignancies, plays a crucial role in NEN carcinogenesis. DESIGN: The complete blood count (CBC) is a reliable tool for monitoring patients with cancer. Quantifying the absolute count of neutrophils (N), lymphocytes (L), platelets (P), and the ratios that derive from these parameters (neutrophil-to-lymphocyte ratio - NLR, platelet-to-lymphocyte ratio - PLR, and inflammatory systemic index - SII calculated as N×P/L) proved their prognostic and predictive value in numerous malignancies. MATERIALS AND METHODS: We aimed to investigate the utility of these hematological parameters in 31 patients with NENs of various locations. Our study included the comparative analysis of pre-treatment hematological markers in NEN patients versus 21 age and gender matched healthy individuals. Additionally, for 26 out of the 31 patients included we analyzed and compared the inflammatory markers before and after treatment initiation. RESULTS: The results revealed a statistically significant higher median value of N, NLR, PLR and SII in the NENs group in comparison with the values obtained in the control group and higher values of N, NLR and SII in the pretreatment group. Furthermore, we observed a higher mean value of the post-treatment P in the pancreatic NENs as opposed to the values obtained for other tumor locations. CONCLUSIONS: The current study emphasizes the importance of the evaluation of CBC in the NENs setting thus adding value to prognostic models that can be useful for risk stratification and medical decision-making.

Radiomics Analysis of [18F]FDG PET/CT Thyroid Incidentalomas: How Can It Improve Patients' Clinical Management? A Systematic Review from the Literature.

BACKGROUND: We performed a systematic review of the literature to provide an overview of the application of PET-based radiomics of [18F]FDG-avid thyroid incidentalomas and to discuss the additional value of PET volumetric parameters and radiomic features over clinical data. METHODS: The most relevant databases were explored using an algorithm constructed based on a combination of terms related to our subject and English-language articles published until October 2021 were considered. Among the 247 identified articles, 19 studies were screened for eligibility and 11 met the criteria, with 4 studies including radiomics analyses. RESULTS: We summarized the available literature based on a study of PET volumetric parameters and radiomics. Ten articles provided accurate details about volumetric parameters and their prospective value in tumour assessment. We included the data provided by these articles in a sub-analysis, but could not obtain statistically relevant results. Four publications analyzed the diagnostic potential of radiomics and the possibility of creating precise predictive models, their corresponding quality score being assessed. CONCLUSIONS: The use of PET volumetric parameters and radiomics analysis in patients with [18F]FDG-avid thyroid incidentalomas outlines a great prospect in diagnosis and stratification of patients with malignant nodules and may represent a way of limiting the need for unnecessary invasive procedures; however, further studies need to be performed for a standardization of the method.

Body Composition as a Modulator of Bone Health Changes in Patients with Inflammatory Bowel Disease.

BACKGROUND: Bone impairment of multifactorial etiology is a common feature in inflammatory bowel disease (IBD). Body composition parameters, which might be selectively modified in these patients, are important determinants of bone strength. Our aim was to investigate the relationship between components of body composition and bone parameters in IBD patients. METHODS: This is a cross-sectional, retrospective study including 80 IBD patients (43 women, 37 men). Lumbar spine (LS), femoral neck (FN) and whole body DXA scans were performed to analyze regional bone mineral density (BMD), as well as body composition, including appendicular skeletal muscle mass index (ASMI), total and visceral fat mass (VAT). Trabecular bone score (TBS) was assessed using iNsight Software. RESULTS: Twenty (25%) IBD patients had inadequate LS-BMD z scores (<=-2DS). Lean mass (LM) was a significant determinant of LS-BMD, after adjusting for age, gender, BMI and fat mass (p < 0.01), while fat mass% remained associated with FN-BMD (p < 0.01). TBS correlated positively with BMI (r = 0.24, p < 0.05), LS-BMD (r = 0.56, p < 0.001), ASMI (r = 0.34, p < 0.001) and negatively with VAT/total fat% (r = -0.27, p < 0.05). Multivariate analysis showed that ASMI, LS-BMD (positively) and VAT/total fat% (negatively) were independently associated with TBS. CONCLUSIONS: In IBD patients, skeletal muscle mass and fat percentage and distribution are important factors associated with bone health.

Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review).

Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in 'liquid' biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.

Platelet Activation and Inflammation in Patients with Papillary Thyroid Cancer.

BACKGROUND: The primary endpoint was to analyze the preoperatory inflammatory markers and platelet indices in papillary thyroid cancer (PTC) patients compared with patients with benign thyroid pathology. The secondary endpoints were to analyze the relationship between these markers and the pathological features of PTC and to compare their pre- and postoperative levels in PTC patients. METHODS: In this retrospective case-control study, we analyzed the files of 1183 patients submitted to thyroidectomy between January 2012 and December 2018. A total of 234 patients with PTC (mean age 51.54 ± 13.10 years, 84.6% females) were compared with an age-, gender- and BMI-matched control group of 108 patients with histologic benign thyroid disorders. RESULTS: PTC patients had higher platelet count (PLT) (p = 0.011), plateletcrit (PCT) (p = 0.006), neutrophil (p = 0.022) and fibrinogen (p = 0.005) levels. Subgroup analysis showed that PTC females had higher PLT (p = 0.006), PCT (p < 0.001) and erythrocyte sedimentation rate (ESR) (p = 0.005), while males had higher neutrophil (p = 0.040) levels. Papillary thyroid cancer patients under 55 years had higher PLT (p < 0.001) and PCT (p = 0.010), while patients over 55 years had higher mean platelet volume (p = 0.032), neutrophil-to-lymphocyte ratio (p = 0.013), ESR (p = 0.005) and fibrinogen (p = 0.019) levels. Preoperative values for platelet indices and inflammatory markers were similar to the postoperative determinations in PTC patients. Fibrinogen (AUROC = 0.602, p = 0.02; cut-off = 327.5 mg/dL, Se = 53.8%, Sp = 62.9%) and PLT (AUROC = 0.584, p = 0.012; cut-off = 223.5 × 103/mm3, Se = 73.1%, Sp = 42.6%) were independent predictors of the presence of PTC. CONCLUSIONS: Our data show that fibrinogen and platelet count could be promising, inexpensive, independent predictors for the presence of PTC when compared with benign thyroid disorders.

Assessment of bone quality with trabecular bone score in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) patients have a significant risk of developing bone loss. The trabecular bone score (TBS) is a relatively new parameter used to provide information on bone quality. The study cohort included 81 patients with IBD and 81 healthy controls. Blood tests, dual-energy x-ray absorptiometry (DXA), including TBS, were assessed. Harvey-Bradshaw Index (HBI) for Crohn's disease (CD) and the Partial Mayo Score for ulcerative colitis (UC) were used for evaluation of clinical disease activity. Compared with the healthy controls, the IBD patients had lower lumbar spine (LS) bone mineral density (BMD) (1.06 ± 0.18 vs. 1.16 ± 0.15 g/cm2, p < 0.005), hip BMD (0.88 ± 0.13 vs. 0.97 ± 0.13 g/cm2, p < 0.005) and TBS (1.38 ± 0.1 vs. 1.43 ± 0.1, p < 0.005) values. The patients with stricturing CD had lower TBS (1.32 ± 0.13 vs. 1.40 ± 0.9, p = 0.03) and LS BMD (0.92 ± 0.19 vs. 1.07 ± 0.1, p = 0.01) values compared with those with non-stricturing CD. Multivariate regression model analysis identified HBI as independent factor associated with TBS. Our results support that all DXA parameters are lower in patients with IBD than in healthy patients. Moreover, TBS is a valuable tool for assessment of bone impairment in active CD.

Lean mass, magnesium, faecal calprotectin and glucocorticoid exposure as risk factors for low bone mineral density in inflammatory bowel disease patients.

BACKGROUND AND AIM: Low bone mineral density (BMD) is a common complication in patients with inflammatory bowel disease (IBD). However, debates are ongoing with regard to the other involved factors, especially in younger patients. This study aimed to evaluate the parameters that contribute to decreased BMD, focusing on premenopausal women and men aged <50 years. METHODS: This study included 81 patients with IBD and 81 age-, sex- and BMI-matched controls. Blood tests were conducted on IBD patients, and a dual-energy X-ray absorptiometry (DXA) scan was performed on both groups. RESULTS: Low BMD and fragility fracture were found to be more prevalent in IBD patients than in healthy subjects (49.3% vs 23.4%, P = 0.001 and 9.8% vs 1.2%, P = 0.01, respectively). Patients with low BMD were older, with a longer disease duration, higher faecal calprotectin (FC) levels and lower magnesium and lean mass (appreciated as appendicular skeletal muscle index (ASMI)). Multiple regression analysis revealed that ASMI, age and use of glucocorticoids were the independent parameters for decreased BMD. Although 91.3% of the patients had a 25-hydroxy vitamin D level of <30 ng/mL, it was not a statistically significant factor for decreased BMD. CONCLUSION: In our study, the levels of vitamin D did not seem to have an important impact on BMD. Conversely, FC, magnesium and lean mass are important factors, suggesting that good control of disease, adequate magnesium intake and increased lean mass can have a good impact on bone metabolism in patients with IBD.

Somatostatinoma and Neurofibromatosis Type 1-A Case Report and Review of the Literature.

Somatostatinomas are rare neuroendocrine tumors (NET) that arise in the gastrointestinal (GI) tract. Because of their insidious growth, they are usually asymptomatic until late stages, presenting as malignant disease. We report the case of a 50-year-old woman who presented with epigastric abdominal pain, diarrhea and significant weight loss in the last two years. On clinical examination the patient met the criteria for neurofibromatosis type 1 (NF1). Abdominal CT and MRI revealed an infiltrative duodenal mass, with pancreatic invasion, locoregional enlarged lymph nodes and disseminated hepatic nodules. Microscopy and immunohistochemistry uncovered a neuroendocrine tumor, staining positive for chromogranin A (CgA), synaptophysin and somatostatin, with a Ki67 = 1%. Somatostatin receptors (SSTRs) type 2 were negative and SSTRs type 5 were positive in less than 50% of tumoral cells. Our patient was classified as a T3N1M1 stage IV metastatic duodenal grade 1 somatostatinoma and treatment with somatostatin analogues and chemotherapy with capecitabine and temozolomide was started, with so far abdominal imaging follow-up showing stable disease. When a patient is diagnosed with a rare NET, such as a somatostatinoma, it is of utmost importance to determine if it is a sporadic tumor or just a feature of a genetic disorder.

Postoperative Hypoparathyroidism in Patients After Total Thyroidectomy - Experience of a Tertiary Center in Romania.

Background: Post-surgical hypoparathyroidism (PoSH) is a common long-term complication after thyroid surgery. The reported median (range) incidence rates of temporary and permanent PoSH was 27% (19 - 38%) and 1% (0 - 3%) respectively. Material and Methods: We retrospectively analyzed the files of 552 patients who underwent thyroidectomy in our surgery department between 2015- 2017 with the aim to assess the prevalence of PoSH and to identify patient and disease related factors associated with postoperative hypocalcemia. Results: 171 (30.97%) patients developed PoSH, 88.37% transient, 11.63% permanent. The median (IQR) duration of postoperative hypocalcemia was 60 (67.5) days. Preoperative biological parameters were similar in PoSH and the control group, except median (IQR) serum magnesium level that was significantly higher in PoSH group [2.04 (0.17) vs. 1.89 (0.28) mg/dl, p=0.005]. In the subgroup of patients with thyroid carcinoma the surgery duration was longer in PoSH patients compared to the control group [135 (60) vs. 110 (43) minutes, p=0.020]. In patients with PoSH, median post-operative serum calcium was significantly higher in patients with reported difficult surgery [8.2 (0.2) vs. 7.9 (0.6) mg/dl, p=0.043] and the mean serum calcium decrease was higher in patients with cervical neck dissection and lymphadenectomy (1.94 +-0.59 vs. 1.68 +-0.56 mg/dl, p=0.033). Conclusions: Our data show a high prevalence of PoSH that is likely to increase given the rising number of thyroid surgeries being performed. Further research is needed in order to better define this condition, to establish appropriate treatment and preventive measures.

Stroke Mortality Rates and Trends in Romania, 1994-2017.

BACKGROUND AND AIM: Romanian national level stroke mortality data is relatively scarce. The current study investigated stroke mortality rates and trends in Romania. METHODS: All individual deaths registered in Romania during 1994-2017 were analyzed using an anonymized database, based on death certificates. Stroke crude mortality rates (CMR) and age-standardized mortality rates (ASMR) were calculated and expressed per 100,000 persons-year. RESULTS: Between 1994 and 2017, 6,281,873 persons died in Romania, stroke being registered as the underlying cause of death in 959,319 cases. The overall stroke CMR was 188.2 (199.3 for women and 176.5 for men). The CMR for hemorrhagic stroke (HEMS) was 32.4 and for ischemic stroke (ISCS) 10.9. There was a significant decrease in stroke ASMR from 344.4 (95% confidence interval [CI] 343.4-345.4) in 1994 to 192.1 (95% CI 191.5-192.7) in 2017, with an annual percent change (APC) of 2.53% per year (95% CI 2.50-2.55, P < .001). Although compared with men, women had higher CMRs, when those rates were age-standardized men had higher ASMR as compared with women. The decline in HEMS ASMR had an APC of 4.65% per year (95% CI 4.59-4.70, P < .001). ISCS ASMR showed an initial increase in ASMR during 1994-2005, with APC 6.39% per year (95% CI 6.09-6.70, P < .001), followed by a significant decrease until 2017, with APC 2.83% per year (95% CI 2.59-3.07, P < .001). CONCLUSION: There was a significant reduction in stroke ASMR during 1994-2017. The decline was slow until 2002 and became steeper after that, with significant differences in gender analysis.

Rates and Causes of Death among Adult Diabetes Patients in Romania.

Aims: To study the age and sex-dependent mortality rates and causes of death in a large Romanian diabetes cohort as compared with the general population. Methods: All adult patients aged 20-64 years, receiving a free diabetes prescription in a major urban area during 2001-2008 were included and followed-up for death until December 31, 2011. Crude mortality rates and standardized mortality rate ratios (SMR) against general population (data from the National Institute of Statistics) were calculated. Years lost due to diabetes were computed assuming the general population mortality rates for ages below 20 and above 64 years. Results: During the 11 years study period, 49,328 diabetes patients (mean age at baseline 53.0 ± 8.8 years) contributed 297,370 person-years and 5,053 deaths. All cause mortality rates (per 1000 person years) increased with age and was 3.4 in 20-24 years age group and 25.7 in 60-64 year age group, while the corresponding SMR decreased from 6.0 to 1.5. Diabetes patients aged 20-24 years had a life expectancy of 48.6 years, which was 6.6 years less compared with the corresponding general population (55.2 years). The gap was 7.0 years in women and 5.8 years in men. Diabetes patients aged 20-24 years lost 196 minutes of life daily due to diabetes in women and 182 minutes in men. Conclusions: Mortality rates increased, while mortality rate ratios against general population decreased with age. Men had higher mortality rates, but women had higher mortality rate ratios in the gender analysis.

Long-term thyroid disorders in pediatric survivors of hematopoietic stem cell transplantation after chemotherapy-only conditioning.

BACKGROUND: Thyroid dysfunction (TD) was usually described in hematopoietic stem cell transplantation (HSCT) recipients who were given total body irradiation (TBI) in the conditioning regimen. Because previous studies have reported discrepant results regarding the presence of long-term thyroid complications in HSCT survivors following chemotherapy-only conditioning, we investigated the frequency of thyroid abnormalities in a series of children treated with HSCT for different disorders without TBI as part of the conditioning protocol. METHODS: We compared thyroid-stimulating hormone, free thyroxine, total triiodothyronine (TT3), anti-peroxidase (TPO Ab) and anti-thyroglobulin antibodies and thyroid volume z-score in 28 HSCT survivors and 16 healthy subjects matched for age and sex. RESULTS: HSCT recipients had a higher frequency of TD and thyroid complications in total, including TD and euthyroid Hashimoto thyroiditis, compared to the control group. Patients transplanted for Hodgkin lymphoma (HL) were more likely to develop a thyroid complication compared to patients with non-malignant hematologic diseases and leukemia patients. BEAM (carmustine, etoposide, citarabin and melphalan) conditioning compared to busulfan (Bu) and fludarabine (Flu)-based regimens and autologous compared to allogenic grafting were associated with a higher prevalence of TD in our study. HSCT survivors had higher mean serum TT3 levels. A multivariate analysis revealed that autologous (auto)-HSCT recipients had higher mean serum titers of TPO Ab compared to allogenic (allo)-HSCT recipients and controls and the mean thyroid volume z-score was significantly higher in controls compared to auto-/allo-HSCT survivors. CONCLUSIONS: We identified a 35.7% prevalence of thyroid abnormalities, emphasizing the need for a long-term surveillance of thyroid function and morphology even in this group of patients who were not exposed to TBI.

Adiponectin expression in visceral adiposity is an important determinant of insulin resistance in morbid obesity.

INTRODUCTION: Visceral adiposity is associated with decreased serum adiponectin levels, peripheral resistance to insulin and an increased risk of cardio-metabolic complications. However, the link between adiponectin expression in visceral adipose tissue (VAT), its serum levels and metabolic protection is controversial. The aim of this study was to investigate the relationship between the adiponectin gene expression in VAT and clinical and metabolic parameters in patients with severe obesity. MATERIAL AND METHODS: This is a cross-sectional study that included 51 severely obese patients (age 43.24±11.29 years, BMI 45.13±8.67 kg/m2), extensively evaluated clinically and biologically (metabolic tests, serum adiponectin measurements, HOMA-IR) before bariatric surgery. Omental adipose tissue was sampled during the intervention and the relative quantification of adiponectin gene expression was performed by real-time PCR, using beta-actin as reference gene. RESULTS: Adiponectin mRNA in VAT was significantly higher in obese insulin-sensitive patients than in the rest of obese patients (p < 0.05) and negatively correlated with HOMA-IR (r =-0.354, p=0.016) and uric acid (r =-0.304, p=0.045). After adjustment for gender, TG/HDL ratio and uric acid, adiponectin expresion (ß= -0.439, p=0.001), waist circumference (ß=0.467, p=0.001) and serum adiponectin (ß =-0.339, p=0.011) remained significantly associated with HOMA-IR, together explaining more than 50% of its variation. CONCLUSIONS: In severely obese patients, adiponectin gene expression in VAT is negatively correlated with serum levels of uric acid and is an independent determinant, together with anthropometric parameters of visceral obesity and serum adiponectin levels, of insulin resistance.

All-cause and cardiovascular mortality associated with sulphonylurea and metformin therapy in type 2 diabetes.

PURPOSE: To test the hypothesis that cumulative exposure to sulphonylurea (SU) or metformin (MET) have different effects on mortality when taken as a replacement or add-on of one for the other. METHODS: All consecutive diabetes patients aged over 20 years were screened at their first diabetes outpatient visit between 2001 and 2008 (n = 79869). Only patients on MET (n = 11374) or SU (n = 18502) monotherapy were retained. All patients were followed up for death until December 31, 2011, but censored at first exposure to anything else besides MET/SU. Adjusted time-dependent Cox regression and competing risk regression analysis, with daily updates of treatment modalities were performed. RESULTS: Mean age was 62.1 ± 11.2 years and follow-up was 4.6 ± 3.2 years (138496 person-years). Adjusted all-cause and cardiovascular mortality rates were significantly higher in MET as compared with SU group. All-cause mortality hazard ratios (HR) for cumulative time exposure were as follows: HR 0.956 (95%CI 0.951-0.962, p < 0.001) for SU added to MET, HR 1.092 (95%CI 1.087-1.096, p < 0.001) for SU replacing MET, HR 0.979 (95%CI 0.975-0.983, p < 0.001) for MET added to SU, and HR 1.127 (95%CI 1.118-1.136, p < 0.001) for MET replacing SU. CONCLUSION(S): The effect on all-cause mortality was beneficial for MET+SU combined therapy, but deleterious for either SU replacing MET, or MET replacing SU. There were no major outcome differences when analyzing individual SU, or specific mortality.

Cardiovascular risk assessment in osteoporotic patients using osteoprotegerin as a reliable predictive biochemical marker.

Osteoprotegerin (OPG), a member of the tumour necrosis factor receptor (TNFR) superfamily of proteins known to be involved in a large number of biological systems, plays a pivotal role in bone remodelling. In addition to the roles of OPG in bone metabolism, it has been reported to be associated with a high cardiovascular risk in patients with metabolic syndrome. In most cases, the exact functions of OPG remain to be established; however, the widespread expression of OPG suggests that this molecule may have multiple biological activities, mainly in the cardiometabolic environment. The aim of this study was to evaluate the value of OPG as a predictive marker for cardiovascular and metabolic risk in osteoporotic patients. The study group comprised patients with osteoporosis, in order to evaluate the association between OPG serum levels and cardiovascular pathology. Our results revealed significant correlations between classical biochemical bone and metabolic parameters, such as osteocalcin and parathyroid hormone with lipid and glucose biomarkers, sustaining the crosstalk between calcium and bone parameters and cardiovascular risk. The OPG serum level proved to have a significant and independent predictive value for metabolic syndrome (MetS) as a cardiovascular risk standard in osteoporotic patients. The OPG serum levels were increased in patients with MetS as a protective response against the atherosclerotic lesions. The serum levels of 25­hydroxy vitamin D had significant and independent predictive value for cardiovascular and metabolic risk in our subjects, sustaining the active role of vitamin D beyond the area of bone metabolism.

IGF-1 and Insulin Resistance Are Major Determinants of Common Carotid Artery Thickness in Morbidly Obese Young Patients.

We assessed the relationship between insulin resistance, serum insulin-like growth factor 1 (IGF-1) levels, and common carotid intima-media thickness (CC-IMT) in morbidly obese young patients. A total of 249 patients (aged 37.9 ± 9.8 years, body mass index [BMI] 45.6 ± 8.3 kg/m(2)) were evaluated (metabolic tests, serum IGF-1 measurements, homeostasis model assessment-insulin resistance [HOMA-IR], and ultrasonographically assessed CC-IMT) in a research program for bariatric surgery candidates. After adjusting for age, gender, BMI, systolic blood pressure, uric acid, antihypertensive and lipid-lowering treatment, metabolic syndrome, and metabolic class, both HOMA-IR and IGF-1 z-score were significantly associated with CC-IMT. These results were confirmed in logistic regression analysis, in which age (ß = 1.11, P = .001), gender (ß = 3.19, P = .001), HOMA-IR (ß = 1.221, P = .005), and IGF-1 z-score (ß = 1.734, P = .009) were the only independent determinants of abnormal CC-IMT, presumably modulating the effect of the other risk factors included in the regression. Area under the receiver-operating characteristic curve for the model was 0.841 (confidence interval: 0.776-0.907; P < .001). In conclusion, in morbidly obese young adults, insulin resistance and IGF-1 z-score are significantly associated with CC-IMT, independent of other major cardiovascular risk factors.

Cardiovascular Mortality in Type 2 Diabetes Patients with Incident Exposure to Insulin Glargine.

The study investigated the impact of insulin glargine exposure on cardiovascular mortality in type 2 diabetes patients with incident insulin initiation. All consecutive diabetes patients aged >40 years were screened at their first diabetes outpatient visit between 01/01/2001 and 12/31/2008 (n = 79869). Exclusion criteria restricted the cohort to 4990 incident insulin users, aged 40-79 years, who were followed up for death until 12/31/2011. Baseline was defined 6 months after insulin initiation. Adjusted time-dependent competing risk regression analysis was performed. Mean baseline age was 62 ± 9 years, with mean follow-up of 4.7 ± 1.9 years. During 23179 person-years of exposure time, there were 887 deaths (521 cardiovascular). Glargine cumulative time exposure significantly lowered overall cardiovascular, subhazard ratio (SHR) 0.963 (CI 95% 0.944-0.981, p < 0.001), and myocardial infarction mortality, SHR 0.945 (CI 95% 0.899-0.994, p = 0.028), but not stroke mortality. Glargine cumulative dose exposure (10,000 IU increments) significantly lowered cardiovascular mortality, SHR 0.977 (CI 95% 0.960-0.993, p = 0.006), but not for myocardial infarction and stroke. Both cumulative dose and time exposure to insulin glargine were associated with lower cardiovascular mortality. The effect was mostly driven by myocardial infarction end point, supporting the concept of macrovascular benefit for basal analogue insulin use in type 2 diabetes.