(18)F-sodium fluoride PET/CT for the in vivo visualization of Mönckeberg's sclerosis in a diabetic patient.

Diabetes is a major frequent cause of atherosclerosis vascular disease. Arterial calcification in diabetic patients is responsible for peripheral vascular involvement. Molecular imaging using (18)F-sodium fluoride ((18)F-NaF) positron emission tomography (PET)/computed tomography (CT) has been recently proposed as a marker to study the in vivo mineralization process in the atheroma plaque. A 69-year-old man with a history of type 2 diabetes and no clinical evidence of peripheral arterial disease underwent an (18)F-NaF PET/CT scan. A linear, well-defined (18)F-NaF uptake was detected along the femoral arteries. In addition, the CT component of the PET/CT identified an unsuspected "tram-track" calcification in his femoral arteries, suggestive of medial calcification (Mönckeberg's sclerosis). In other vascular territories, focal (18)F-NaF uptake was also detected in carotid and aorta atheroma plaques. Molecular imaging with (18)F-NaF PET/CT might provide new functional information about the in vivo vascular calcification process in diabetic patients.

Results from a national survey on the management of primary hyperparathyroidism.

BACKGROUND: Management of primary hyperparathyroidism (PHPT) continues to be challenging. At the Third International Workshop on PHPT, recent data on this disease were reviewed and new clinical recommendations were developed. There are few data on the influence of new guidelines in clinical practice. AIM: We designed an online survey that was sent to all Spanish hospital endocrinology services. METHODS: The questionnaire included 28 questions about diagnosis and management of PHPT. Ninety-nine of 131 sites (76%), giving health coverage to 70% of Spanish population, completed the survey. RESULTS: The reported incidence of PHPT was 9.95/100,000 person-years. Heighty percent of patients were asymptomatic. Each center performed a median (Q1, Q3) of 12 (6, 20) parathyroidectomies/year. The median (Q1, Q3) percentage of curative interventions (at first trial) was 90% (80, 95). The main reasons for not performing surgery were, by decreasing frequency: surgery contraindication, patient's refusal, loss of monitoring, limited surgery experience. Localization techniques were used in 83% of cases. The main criteria for parathyroidectomy in asymptomatic patients were Ca≥2.875 mmol/l (79%), Tscore ≤-2.5 SD at any site (91%), age <50 yr (80%) and glomerular filtration rate <60 ml/min/1.73 m 2 (82%). Minimally invasive surgery was performed in 42% of centers. Frequency of biochemistry and bone density determinations for non-surgically managed patients was in accordance with international guidelines. CONCLUSIONS: The clinical practice of Spanish endocrinologists is consistent with the recommendations of the guidelines from the Third International Workshop for the management of PHPT.

Association of ACACB polymorphisms with obesity and diabetes.

Acetyl-CoA carboxylase beta, encoded by the ACAB gene, plays an important role in the oxidation of fatty acids. The aim of this study was to check the hypothesis that allelic variants of ACACB influence the risk of obesity and type 2 diabetes mellitus. Twenty five tagging single nucleotide polymorphisms (SNPs) capturing common variants of the ACACB gene were selected and analyzed in two cohorts including 1695 postmenopausal women of the general population and in 161 women with severe obesity (BMI>35). In vitro binding of transcription factors was explored by electrophoretic mobility shift assays (EMSA). T alleles at the rs2268388 locus were overrepresented in women with severe obesity (18% vs. 10% in controls; OR 1.74 [95% confidence interval 1.30-2.47]), which was statistically significant after multiple-test adjustment (p=0.0004). Likewise, T alleles at the rs2268388 locus and C alleles at the rs2239607 locus were associated with diabetes, in the discovery as well as in the replication cohorts, even after women with severe obesity were excluded (OR 3.6 and 2.8, for TT and CC homozygotes, respectively). Allelic differences in the binding affinity for nuclear proteins were revealed in vitro by EMSA and competition experiments were consistent with the binding of glucorticoid receptor and serum response factor. In conclusion, common polymorphisms of ACACB gene are associated with obesity and, independently, with type 2 diabetes in postmenopausal women, suggesting that the activity of acetyl-CoA carboxylase beta plays an important role in these disorders related to energy metabolism.

Association of the 163A/G and 1181G/C osteoprotegerin polymorphism with bone mineral density.

The aim of the study was to investigate the distribution of 163 A/G osteoprotegerin gene promoter and 1181 G/C osteoprotegerin exon 1 polymorphisms in a group of women with different hormonal status and to analyze their relationship with BMD. Osteoprotegerin polymorphisms and BMD were analyzed in 332 women (69 premenopausal and 263 postmenopausal). BMD was quantified at the lumbar spine (L 2-4), femoral neck, and total hip. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman ((R)) SNP Genotyping assays. There were not significant differences in BMD according to 163 A/G genotype. However, significant differences in lumbar spine BMD were found according to 1181 G/C alleles. Thus, women with CC genotype had significant higher BMD at the lumbar spine than those with GC or GG genotype. No differences were found in femoral neck and total hip BMD. In age-adjusted models, the 1181 G/C OPG polymorphism explained 2.2% of BMD variance at the spine, 0.3% at the femoral neck, and 0.9% at the total hip in the whole group. In the subgroup of premenopausal women, the polymorphism was strongly related to spine BMD, and explained 11.5% of the variance, whereas body weight explained 7.9%. The 1181 G/C polymorphism was associated with lumbar spine BMD in Spanish women. Premenopausal women with the CC genotype had a higher BMD.

Value of soluble CD30 in liver transplantation.

INTRODUCTION: CD30 is a membrane glycoprotein that belongs to the tumor necrosis factor superfamily. It is expressed on activated T cells. After activation of CD30(+) T cells, a soluble form of CD30 (sCD30) released into the bloodstream, can be measured in the serum. The aim of our study was to investigate the time course of serum levels of sCD30 during hepatic allograft rejection. MATERIALS AND METHODS: Serum levels of sCD30 were determined in 30 healthy subjects and 50 hepatic transplant recipients. These patients were divided into two groups: group I, 35 patients without rejection; and group II, 15 patients with acute rejection. Samples were collected on day 1 and 7 after transplantation and on the day of liver biopsy. RESULTS: The concentrations of sCD30 were similar in the rejection (40.4 +/- 16.5 U/mL) and nonrejection groups (43.0 +/- 18.2 U/mL) on postoperative day 1. We observed a significant increase in sCD30 levels in the rejection group on postoperative day 7 (76.3 +/- 61.8 U/mL vs 46.8 +/- 20.5 U/mL; P = .01). The difference increased when a diagnosis of acute rejection had been established: namely 133.0 +/- 113.5 U/mL versus 40.1 +/- 22.0 U/mL; (P = .001). These levels were also significantly higher during the entire postoperative period in all the patients, with or without rejection, than those observed in healthy controls (26.6 +/- 5.3 U/mL; P = .005). CONCLUSIONS: The release of circulating sCD30 is a prominent feature coinciding with the first episode of hepatic allograft rejection. So, monitoring of sCD30 levels may be useful for the early diagnosis of an acute rejection episode.

Blood-soluble Fas levels are increased in type 2 diabetic patients with peripheral vascular disease.

AIM: To investigate the possible utility of plasma sFas (soluble Fas) levels as a marker of peripheral vascular disease (PVD) in type 2 diabetic patients, and the relationship between classical cardiovascular risk factors and sFas levels in these patients. MATERIALS AND METHODS: sFas levels were measured in 57 type 2 diabetic patients with and 60 without PVD matched for age and sex. Diagnosis of PVD was established in presence of at least one of the following criteria: leg or foot amputation of vascular cause, lower-extremity arterial angioplasty or surgical by-pass, or ankle-braquial index (ABI) less than 1 in at least one side of the body. ELISA was used to measure sFas levels. RESULTS: None of the risk factors assessed total cholesterol, HDL cholesterol, triglycerides, CRP, ACE, fibrinogen, Lp(a) and homocysteine was significantly different between both groups of patients. However, patients with PVD had higher plasma sFas levels than the group without PVD (10.25+/-3.7 ng/ml VS. 8.86+/-2.6 ng/ml; p=0.02). Levels of sFas were 1.45 ng/ml (95% CI: 0.32-2.58; p=0.013) higher in PVD patients when adjusting by age, total, HDL and LDL cholesterol, triglycerides, homocysteine, CRP, ACE, arterial hypertension and tobacco smoking. Using multiple logistic regression sFas is a predictor of PVD, although not potent. CONCLUSION: Plasma sFas may be an independent marker of PVD in type 2 diabetes mellitus patients.

Factors other than glucocorticoids are involved in the osteoblast activity decrease caused by tissue injury.

OBJECTIVE: Serum osteocalcin is a marker of bone formation. The concentration of osteocalcin is decreased with tissue injury. As glucocorticoids are known both to be increased in this situation and to diminish serum osteocalcin, we have hypothesized that they could be involved in this decrease. DESIGN AND PATIENTS: We compared osteocalcin levels in two groups of patients undergoing abdominal surgery, one receiving thiopental, and the other etomidate, a glucocorticoid synthesis blocker. For comparative reasons, another protein decreased by glucocorticoids (osteoprotegerin) was measured in patients anaesthetized with thiopental. MEASUREMENTS: Serum osteocalcin, cortisol and albumin were determined before and over the 24 h following surgery. Serum concentration of osteoprotegerin (OPG) and receptor activator of the nuclear factor kappaB ligand (RANKL) were also determined before and 24 h after surgery in a third group of nine patients who received thiopental for anaesthetic induction. RESULTS: Cortisol levels were increased in the thiopental group, whereas, as expected, were decreased in etomidate patients. However, serum osteocalcin concentration decreased in a similar way in both groups. Serum OPG and RANKL levels were within the normal range at baseline and did not significantly change after surgery. CONCLUSIONS: The decrease in serum osteocalcin induced by tissue injury is independent of the increase in cortisol secretion triggered by the latter. In addition, another pharmacologically proven effect of cortisol on bone metabolism, OPG inhibition, could not be demonstrated in the first 24 h following surgery, in spite of the physiological increase in endogenous cortisol secretion taking place in this period.

Levels of plasma total adrenomedullin are related with two acute phase inflammatory reactants (fibrinogen and sialic acid) but not with markers of endothelial dysfunction in Type 1 diabetes Adrenomedullin and vascular risk factors in Type 1 DM.

Adrenomedullin (AM), an ubiquitous regulatory peptide with different actions, is known to be elevated in different clinical situations, including diabetes mellitus (DM), but its potential role in the pathogenesis of diabetic vascular complications is not clear. In the present study, we examined plasma total AM levels, and their association with different markers of endothelial dysfunction and with other established risk factors for cardiovascular diseases, in patients with Type 1 DM. We studied a total of 155 patients, 117 patients without any kind of vascular complications, 24 patients with retinopathy only, and 14 patients with retinopathy and microalbuminuria but normal renal function. None of them had clinical evidence of atherosclerotic disease. Compared with the control group (64 healthy participants), patients had raised fibrinogen, soluble E-selectin ((s)E-selectin), vascular cellular adhesion molecule (VCAM), angiotensin converting enzyme (ACE), and von Willebrand factor (vWf) (P<.001 in all cases), but plasma total AM, endothelin (ET), sialic acid, and homocysteine were not raised. In the diabetic group, AM levels correlated significantly with sialic acid (r=.16; P<.05), but a more significant correlation was found with fibrinogen (r=.30; P<.001). No correlation was found with the other parameters studied. In summary, plasma total AM levels seem to correlate with inflammatory markers but not with endothelial dysfunction markers in Type 1 diabetic patients without atherosclerotic disease.

Fasting plasma ghrelin levels increase progressively after biliopancreatic diversion: one-year follow-up.

BACKGROUND: The role of ghrelin in weight control after surgery is not clear. We examined plasma ghrelin and leptin levels in patients with morbid obesity undergoing biliopancreatic diversion (BPD) of Scopinaro. METHODS: 30 adult patients (27 females, 3 males), undergoing elective BPD were recruited from the Hospital Surgery Service. Fasting blood samples for biochemical determinations were drawn before surgery and 1, 3 and 12 months after BPD. Human plasma ghrelin was measured by RIA. RESULTS: During the study period, weight, BMI and serum leptin levels decreased significantly at all sample points compared to preoperative values. Ghrelin plasma levels increased during the study, with statistical significance at 3 months and 1 year after surgery compared with preoperative levels. While leptin changes correlated with changes in BMI, no correlation was found between ghrelin and leptin or BMI changes. CONCLUSION: Plasma ghrelin levels could be decreased in obese patients as a compensatory mechanism to their nutritional state, but our results do not support the postulated beneficial role of ghrelin in the 1-year weight loss after BPD. They rather suggest that weight loss somehow stimulates ghrelin secretion, even in the absence of part of the stomach.

[Plasma leptin levels in patients with primary biliary cirrhosis and their relationship with degree of fibrosis]. / Concentraciones plasmáticas de leptina en los pacientes con cirrosis biliar primaria y su relación con el grado de fibrosis.

OBJECTIVES: a) To analyze plasma leptin levels in patients with primary biliary cirrhosis (PBC) and b) to investigate the relationship between leptin levels and liver fibrosis stage in a cohort of patients with PBC. PATIENTS AND METHODS: Serum leptin levels were evaluated through radioimmunoassay in 30 patients with PBC (mean age: 37.2 +/- 11.0 years; range:19-75) and in 29 controls matched for age and weight. Venous blood obtained after a 12-hour fast was centrifuged in EDTA tubes. Weight, height and body mass index (BMI) were measured using standard methods. Hepatitis C virus RNA was determined using qualitative and quantitative polymerase chain reaction. In all patients liver biopsies were performed and the degree of fibrosis and extent of inflammatory infiltrate were evaluated. RESULTS: Plasma leptin levels in patients with PBC were lower than those obtained in control subjects (p<0.0001). No significant differences were found between the two groups in age, weight, height, BMI or body fat index. There was a clear increase in serum leptin levels according to histological stage of PBC (stage I: 2.1 ng/ml; stage II: 4.3 ng/ml; stage III: 5.3 ng/ml; stage IV: 12.1 ng/ml; p<0.01) CONCLUSIONS: The present study demonstrates the correlation between leptin and stage of liver fibrosis in a cohort of patients with PBC, providing further evidence of the involvement of leptin in the process of liver fibrosis.

Autoantibodies against oxidized LDL and serum total antioxidant status in active cyclists and ex-cyclists.

There is an apparent paradox between the benefits of aerobic exercise and the potentially deleterious effects of increased free radicals and decreased circulating antioxidants generated during exercise. To assess the oxidative/antioxidative status in competitive cyclists and ex-cyclists, we measured two markers not well studied in these situations, serum total antioxidant status (TAS) and antibodies against oxidized LDL (AuAb-ox-LDL) in 18 competitive male cyclists, 10 ex-competitive cyclists and 14 healthy males. AuAb-ox-LDL was evaluated by enzyme immunoassay, and serum TAS concentration was analyzed by spectrophotometry. Ex-cyclists had serum TAS levels statistically higher than the control group and cyclists group (p = 0.001 and p < 0.001, respectively). Active sportsmen showed significantly less AuAb-ox-LDL than healthy sedentary males, while there was a non-significant trend in the ex-cyclists to have lower AuAb-ox-LDL than the corresponding control group. AuAb-ox-LDL levels were not statistically different between the groups of active and previously active sporting men. There was a positive correlation between TAS and LDL-cholesterol in active cyclists under heavy training. In the ex-cyclist group, there was a negative correlation between serum TAS and the time elapsed since they had ended the competition. Competitive cycling decreases AuAb-ox-LDL levels, suggesting that it may decrease ox-LDL levels. After ending physical training, antioxidative status remains increased for at least one year, but the effect on AuAb-ox-LDL levels is lost.

Fármacos antirresortivos óseos e hiperparatiroidismo primario / Antiresorptive drugs and primary hyperparathyroidism

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Parathyroidectomy in dialysis patients.

Subtotal parathyroidectomy or total parathyroidectomy (PTx) with autotransplantation are surgical procedures considered while the patient is included on the waiting list for renal transplantation. Total PTx alone is based in the possibility that a fragment of tissue (nodular hyperplasia in particular) left in the same pathophysiological environment of long term dialysis would show the same behavior and reproduce in time the same clinicopathological picture. The persistence of uremia induces a continued growth stimulus developing residual hyperplasia and consequently a very high risk of recurrence. We performed total PTx alone in 15 uremic patients excluded for renal transplantation 10 patients with undetectable iPTH serum concentration and were followed up for 37 to 144 months. There was no evidence of clinical bone disease (bone pain or fractures). Bone mineral lumbar spine and hip density was measured at the end of follow-up. The z score data showed that all patients had a bone mass similar than that expected for their age. Bone biopsies performed in four patients showed a uniform picture of low turnover without aluminium staining. Calcification of small arteries (digital and arcade vessels in hands and feet) were evaluated pre and post total PTx alone in nine out of the 10 patients with undetectable PTH levels. The small vessel calcification was present in five patients at the moment of PTx. At the end of the long term follow-up only one patient showed progression. In conclusion, total PTx without autotransplantation is a very effective and adequate treatment for refractory severe hyperparathyroidism in patients excluded for renal transplantation. Aluminium related osteopathy post PTx is a risk to be controlled with aluminium "free" dialysis water and avoiding aluminium containing phosphate binders.

Assessment of cerebral perfusion and cerebrovascular reserve in insulin-dependent diabetic patients without central neurological symptoms by means of 99mTc-HMPAO SPET with acetazolamide.

The detection of subclinical abnormalities in cerebral blood flow could be of great value in identifying diabetic patients at risk of stroke. The aim of this study was to assess the contribution of semiquantified post-acetazolamide technetium-99m hexamethylpropylene amine oxime single-photon emission tomography (99mTc-HMPAO SPET) in 15 diabetic patients with no clinical history of central neurological disease. After baseline 99mTc-HMPAO SPET, a second SPET scan was acquired after activation of the cerebrovascular reserve (CVR) with an injection of 1 g of acetazolamide (post-ACZ SPET). Semiquantitative analysis was made in 16 regions of interest (ROIs) drawn for each of the three supratentorial slices selected, and in two ROIs in the infratentorial slice. The CVR was calculated in each ROI by subtracting the decay-corrected baseline images from those obtained in the post-ACZ SPET and expressed as the percent increase in the average counts between the two scans. Baseline perfusion and CVR values in the study group were compared with the corresponding values in a control group. Of 750 cortical ROIs studied, 332 showed a decreased CVR (44.3%). The baseline perfusion SPET study showed hypoperfusion in 65 ROIs (8.6%) and hyperperfusion in 56 (7.4%). Of the 65 hypoperfused regions, 66.2% had a normal CVR and 33.8% had a decreased CVR, whereas of the 56 hyperperfused regions, 51.8% had a CVR within normal limits and 48.2% showed a decreased CVR. In conclusion, in comparison with baseline 99mTc-HMPAO SPET, the ACZ activation test provided additional information in the study of cerebrovascular impairment, and allowed characterisation of the subclinical abnormalities in the population studied. The technique may therefore prove useful in evaluating future preventive strategies for stroke in diabetic patients.

Dendroaspis natriuretic peptide in hepatic cirrhosis.

OBJECTIVES: Dendroaspis natriuretic peptide (DNP) is a novel peptide that is structurally similar to atrial, brain, and C-type natriuretic peptides. Many natriuretic peptides are increased in hepatic cirrhosis, but the role of DNP in cirrhosis is unknown at present. The aim of the study was to investigate plasma levels of dendroaspis natriuretic-like immunoreactivity in cirrhosis. METHODS: We measured plasma concentrations of DNP by radioimmunoassay methods in 12 cirrhotic patients without ascites and 44 cirrhotic patients with ascites, and compared these values with 20 age-matched healthy subjects. Renal function, plasma cGMP concentration, plasma renin activity, and plasma endothelin concentration were measured in each patient. RESULTS: Patients without ascites had circulating levels of DNP similar to those of healthy subjects. By contrast, patients with ascites had increased circulating DNP levels compared to both patients without ascites and healthy subjects. In addition, circulating levels of DNP increased in relation to the severity of cirrhosis. Significant positive correlations were also found between DNP levels, endothelin concentrations, and plasma renin activity. CONCLUSIONS: The results of this study indicate that plasma DNP is increased in cirrhotic patients with ascites.

Effects of long-term treatment with antipsychotics on serum leptin levels.

BACKGROUND: Abnormal regulation of the adipocyte-derived hormone leptin could play a role in body weight gain induced by antipsychotics. AIMS: To study the effects of long-term antipsychotic treatment on leptin levels in patients with schizophrenia. METHOD: Serum leptin levels were determined in 59 out-patients with chronic schizophrenia and in the same number of healthy subjects controlled by gender, age and body mass index. RESULTS: Leptin levels did not differ between patients and controls. Leptin levels in patients with schizophrenia correlated with weight gain, even after controlling for current weight, but did not show any association with clinical variables. Antipsychotic class tended to exert different effects over leptin levels (among atypicals, olanzapine induced a greater increase). CONCLUSIONS: Elevation of leptin levels induced by chronic antipsychotic treatment can be attributed to weight gain, but other mechanisms could be involved.

Venous endothelial function in postmenopausal women after six months of tibolone therapy.

STUDY OBJECTIVE: To test venous endothelial function in long-term climateric therapy with tibolone. DESIGN: Measurement of dorsal hand-vein diameter by venous occlusion plethysmography during infusion of norepinephrine (NE), bradykinin (BK), NG-monomethyl L-arginine (L-NMMA) and sodium nitroprusside (SNP). SETTING: Plethysmography and Menopause Units. University Hospital Valdecilla. Santander. Spain. PATIENTS: Eleven postmenopausal women having continuous treatment with oral tibolone (2.5 mg/day) for 6 months. INTERVENTIONS: Three plethysmography studies were made: at baseline, and at three and six months of treatment. MAIN OUTCOME MEASURES: Dorsal hand-vein diameter measured by venous occlusion plethysmography during infusion of NE, BK, L-NMMA and SNP. RESULTS: (a) Baseline study: maximum dilation with BK was 54.2+/-10.2%. (b) Three-month study: BK dilation of 71.5+/-11.9%, with a significant increase of 17.3% (P=0.019) compared with baseline. (c) Six-month study: BK dilation of 77.5+/-11.9%, with a significant increase 23.3% (P=0.002) compared with baseline. Maximal vasodilation was reached with SNP in the three studies and L-NMMA infusion has a similar vasoconstrictor response in the three studies. CONCLUSIONS: Long-term climateric therapy with tibolone improves vein endothelium-dependent vasodilation suggesting a positive impact of this drug on endothelial function.