Hair cortisol and changes in cortisol dynamics in chronic kidney disease.

Objective: We compared hair cortisol (HC) with classic tests of the hypothalamic-pituitary-adrenal (HPA) axis in chronic kidney disease (CKD) and assessed its association with kidney and cardiometabolic status. Design and methods: A cross-sectional study of 48 patients with CKD stages I-IV, matched by age, sex, and BMI with 24 healthy controls (CTR) was performed. Metabolic comorbidities, body composition, and HPA axis function were studied. Results: A total of 72 subjects (age 52.9 ± 12.2 years, 50% women, BMI 26.2 ± 4.1 kg/m2) were included. Metabolic syndrome features (hypertension, dyslipidaemia, glucose, HOMA-IR, triglycerides, waist circumference) and 24-h urinary proteins increased progressively with worsening kidney function (p < 0.05 for all). Reduced cortisol suppression after 1-mg dexamethasone suppression (DST) (p < 0.001), a higher noon (12:00 h pm) salivary cortisol (p = 0.042), and salivary cortisol AUC (p = 0.008) were seen in CKD. 24-h urinary-free cortisol (24-h UFC) decreased in CKD stages III-IV compared with I-II (p < 0.001); higher midnight salivary cortisol (p = 0.015) and lower suppressibility after 1-mg DST were observed with declining kidney function (p < 0.001). Cortisol-after-DST cortisol was >2 mcg/dL in 23% of CKD patients (12.5% in stage III and 56.3% in stage IV); 45% of them had cortisol >2 mcg/dL after low-dose 2-day DST, all in stage IV (p < 0.001 for all). Cortisol-after-DST was lineally inversely correlated with eGFR (p < 0.001). Cortisol-after-DST (OR 14.9, 95% CI 1.7-103, p = 0.015) and glucose (OR 1.3, 95% CI 1.1-1.5, p = 0.003) were independently associated with eGFR <30 mL/min/m2). HC was independently correlated with visceral adipose tissue (VAT) (p = 0.016). Cortisol-after-DST (p = 0.032) and VAT (p < 0.001) were independently correlated with BMI. Conclusion: Cortisol-after-DST and salivary cortisol rhythm present progressive alterations in CKD patients. Changes in cortisol excretion and HPA dynamics in CKD are not accompanied by significant changes in long-term exposure to cortisol evaluated by HC. The clinical significance and pathophysiological mechanisms explaining the associations between HPA parameters, body composition, and kidney damage warrant further study.

Thalidomide decreases gelatinase production by malignant B lymphoid cell lines through disruption of multiple integrin-mediated signaling pathways.

BACKGROUND: Thalidomide and its analogs are effective agents in the treatment of multiple myeloma. Since gelatinases (matrix metalloproteinases-2 and -9) play a crucial role in tumor progression, we explored the effect of thalidomide on gelatinase production by malignant B lymphoid cell lines. DESIGN AND METHODS: We investigated the effect of therapeutic doses of thalidomide on integrin-mediated production of gelatinases by malignant B lymphoid cell lines by gelatin zymography, western-blot, reverse transcriptase polymerase chain reaction and invasive capacity through Matrigel-coated Boyden chambers. We also explored the effect of thalidomide on the activation status of the main signaling pathways involved in this process. RESULTS: Thalidomide strongly inhibited gelatinase production by B-cell lines and primary myeloma cells in response to fibronectin, the most efficient gelatinase inducer identified in lymphoid cells. Thalidomide disrupted integrin-mediated signaling pathways involved in gelatinase induction and release, such as Src and MAP-kinase ERK activation, resulting in decreased cell motility and invasiveness. Unexpectedly, treatment with thalidomide elicited an increase in fibronectin-induced Akt phosphorylation through phosphoinositide 3-kinase-independent pathways since thalidomide decreased fibronectin-induced phosphoinositide 3-kinase phosphorylation and reversed the inhibition of Akt phosphorylation achieved by the phosphoinositide 3-kinase inhibitors wortmannin and LY294002. CONCLUSIONS: Disruption of integrin-mediated signaling may be an important mechanism through which thalidomide and its analogs impair tumor cell interactions with the microenvironment. The unexpected effects of thalidomide on Akt activation indicate the need for further studies to elucidate whether the interference with Akt downstream effects would synergize with the anti-tumor activity of thalidomide.

Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism.

BACKGROUND: Patients with giant-cell arteritis (GCA) who develop a strong acute-phase response are at low risk of disease-related ischemic events. METHODS AND RESULTS: To assess the potential protective role of proinflammatory cytokines in the development of ischemic events in GCA, we measured tissue expression (66 individuals) and/or circulating levels (80 individuals) of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6 in patients with biopsy-proven GCA. Tissue expression was determined by quantitative real-time polymerase chain reaction and immunohistochemistry. Circulating cytokines were determined by enzyme-linked immunoassay. We found that patients with disease-related ischemic events had lower IL-6 mRNA levels (5.9+/-2.1 versus 27.6+/-7.8 relative units, P=0.013), lower IL-6 immunohistochemical expression scores (1.5+/-0.9 versus 2.7+/-1, P=0.001), and lower circulating levels of IL-6 (13.6+/-2.1 versus 24+/-2.4 pg/mL, P=0.002) than patients without ischemic complications. No significant differences were found for either IL-1beta or TNF-alpha. We subsequently investigated direct effects of IL-6 on vessel wall components. We found that IL-6 stimulates endothelial cell proliferation and differentiation into capillary-like structures and induces full angiogenic activity in both ex vivo (aortic ring) and in vivo (chick chorioallantoic membrane) assays. CONCLUSIONS: GCA patients with ischemic complications have lower tissue expression and circulating levels of IL-6 than patients with no ischemic events. IL-6 has relevant direct effects on vascular wall components that might be protective: IL-6 activates a functional program related to angiogenesis that may compensate for ischemia in patients with GCA.

Circulating ghrelin in thyroid dysfunction is related to insulin resistance and not to hunger, food intake or anthropometric changes.

OBJECTIVE: Ghrelin is a gastric peptide that plays a role in appetite stimulation, energy balance and possibly in insulin resistance. Hyperthyroidism is a situation where negative energy balance and insulin resistance coexist, while in hypothyroidism a positive energy balance and normal insulin sensitivity predominate. We investigated ghrelin levels and their relationship with hunger, food intake and both anthropometric and insulin resistance parameters in patients with thyroid dysfunction. DESIGN AND METHODS: We studied 24 hyperthyroid and 17 hypothyroid patients before and after normalisation of thyroid hormone levels and their respective body mass index (BMI)-matched control group. We measured plasma ghrelin levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, a hunger score, mean three-day calorie intake and anthropometric parameters. RESULTS: In hyperthyroidism, HOMA-IR index was higher (3.21 +/- 0.60 vs 1.67 +/- 0.15 mMmU/l; P = 0.014, t test for independent data) and ghrelin levels were lower (463.6 +/- 36.4 vs 561.1 +/- 32.1 pg/ml; P = 0.041, Mann-Whitney U-test) than in its control group and both normalised after treatment (HOMA-IR: 2.28 +/- 0.38 mMmU/l; P = 0.106, t test for independent data, and ghrelin: 539.7 +/- 45.4 pg/ml; P = 0.549, Mann-Whitney U-test). Glucose, as a component of HOMA-IR index was the only predictor for ghrelin levels (beta = -0.415, P = 0.044, stepwise multiple regression analysis). In hypothyroidism, HOMA-IR index and ghrelin levels were similar to those in its control group both before and after treatment. In both thyroid dysfunction states, no correlations were observed between changes in ghrelin levels and in free T4, free T3, anthropometric parameters, total calorie intake and hunger score. CONCLUSIONS: In thyroid dysfunction states, ghrelin levels seemed to be in relation to insulin resistance and not to energy balance and food intake regulation, as seen in other physiological and pathological states.

[Low reporting of clinical characteristics of patients with diabetes mellitus included in the main clinical trials on hypertension]. / Escasa caracterización clínica de los pacientes con diabetes mellitus incluidos en los principales ensayos clínicos sobre hipertensión arterial.

BACKGROUND AND OBJECTIVE: Subjects with diabetes mellitus (DM) are at high risk of cardiovascular events. However, their cardiovascular risk varies according to several clinical characteristics like age, sex, ethnicity, type and duration of the DM, quality of glycemic control, type of hypoglycemic treatment, or the presence of nephropathy or previous cardiovascular events. It is not known if these characteristics have been sufficiently reported in clinical trials on hypertension including subjects with DM. MATERIAL AND METHOD: We analyzed randomized controlled clinical trials about treatment of hypertension published before May 2003 with the following characteristics: a) inclusion of subjects with DM and b) a primary end-point including at least one of the following events: myocardial infarction, cerebrovascular disease or total mortality. In these trials we evaluated the above-mentioned clinical characteristics concerning cardiovascular risk. RESULTS: Sixteen trials were eventually analyzed. These trials were classified into: a) trials designed only for subjects with DM (RENAAL, UKPDS 38, UKPDS 39, IDNT); b) trials with a subgroup analysis for subjects with DM (SHEP, Syst-Eur, MICRO-HOPE, HOT, STOP-2, LIFE), and c) trials without a subgroup analysis for subjects with DM (CAPP, NORDIL, INSIGHT, ALLHAT, SANBPSG, CONVINCE). All these trials included a total of 33984 subjects with DM, most of them > or = 55 years old. The percentage of women evaluated ranged from 33.5 to 71.9% although in 2 trials no data were found regarding this percentage (12.5%). There was no information on ethnicity in 10 trials (62.5%), on the type of DM in 7 (43.8%), on the duration of the disease in 13 (81.3%), on the degree of glycemic control in 10 (62.5%), on the type of hypoglycemic treatment in 11 (68.8%), on the presence or absence of nephropathy in 11 (68.8%) and on the presence or absence of previous cardiovascular events in 3 (18.8%). Trials without subgroup analysis for subjects with DM had a lower reporting of the clinical characteristics of the subjects evaluated than the rest of the trials. CONCLUSIONS: The reporting of relevant clinical characteristics of cardiovascular risk in subjects with DM in the main clinical trials on hypertension is low, diminishing their external validity. To optimize the therapeutic recommendations in the treatment of hypertension in DM these deficiencies should be overcome.

Advanced glycation end products are associated with arterial stiffness in type 1 diabetes.

The aim of this study was to investigate the relationship between advanced glycation end products (AGEs) and arterial stiffness (AS) in subjects with type 1 diabetes without clinical cardiovascular events. A set of 68 patients with type 1 diabetes and 68 age- and sex-matched healthy subjects were evaluated. AGEs were assessed using serum concentrations of N-carboxy-methyl-lysine (CML) and using skin autofluorescence. AS was assessed by aortic pulse wave velocity (aPWV), using applanation tonometry. Patients with type 1 diabetes had higher serum concentrations of CML (1.18 vs 0.96 µg/ml; P=0.008) and higher levels of skin autofluorescence (2.10 vs 1.70; P<0.001) compared with controls. These differences remained significant after adjustment for classical cardiovascular risk factors. Skin autofluorescence was positively associated with aPWV in type 1 diabetes (r=0.370; P=0.003). No association was found between CML and aPWV. Skin autofluorescence was independently and significantly associated with aPWV in subjects with type 1 diabetes (ß=0.380; P<0.001) after adjustment for classical cardiovascular risk factors. Additional adjustments for HbA1c, disease duration, and low-grade inflammation did not change these results. In conclusion, skin accumulation of autofluorescent AGEs is associated with AS in subjects with type 1 diabetes and no previous cardiovascular events. These findings indicate that determination of tissue AGE accumulation may be a useful marker for AS in type 1 diabetes.

Arterial stiffness is increased in patients with type 1 diabetes without cardiovascular disease: a potential role of low-grade inflammation.

OBJECTIVE: To investigate the relationship between arterial stiffness and low-grade inflammation in subjects with type 1 diabetes without clinical cardiovascular disease. RESEARCH DESIGN AND METHODS: Sixty-eight patients with type 1 diabetes and 68 age- and sex-matched healthy subjects were evaluated. Arterial stiffness was assessed by aortic pulse wave velocity (aPWV). Serum concentrations of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and soluble fractions of tumor necrosis factor-α receptors 1 and 2 (sTNFαR1 and sTNFαR2, respectively) were measured. All statistical analyses were stratified by sex. RESULTS: Subjects with diabetes had a higher aPWV compared with healthy control subjects (men: 6.9 vs. 6.3 m/s, P < 0.001; women: 6.4 vs. 6.0 m/s, P = 0.023). These differences remained significant after adjusting for cardiovascular risk factors. Men with diabetes had higher concentrations of hsCRP (1.2 vs. 0.6 mg/L; P = 0.036), IL-6 (0.6 vs. 0.3 pg/mL; P = 0.002), sTNFαR1 (2,739 vs. 1,410 pg/mL; P < 0.001), and sTNFαR2 (2,774 vs. 2,060 pg/mL; P < 0.001). Women with diabetes only had higher concentrations of IL-6 (0.6 vs. 0.4 pg/mL; P = 0.039). In men with diabetes, aPWV correlated positively with hsCRP (r = 0.389; P = 0.031) and IL-6 (r = 0.447; P = 0.008), whereas in women with diabetes no significant correlation was found. In men, multiple linear regression analysis showed that the following variables were associated independently with aPWV: age, BMI, type 1 diabetes, and low-grade inflammation (R(2) = 0.543). In women, these variables were age, BMI, mean arterial pressure, and type 1 diabetes (R(2) = 0.550). CONCLUSIONS: Arterial stiffness assessed as aPWV is increased in patients with type 1 diabetes without clinical cardiovascular disease, independently of classical cardiovascular risk factors. In men with type 1 diabetes, low-grade inflammation is independently associated with arterial stiffness.

Men with hyperferritinemia and diabetes in the Mediterranean area do not have a higher iron overload than those without diabetes.

AIM: To assess the role of iron overload in type 2 diabetic men with hyperferritinemia. METHODS: 150 men were recruited from a genetic screening programme for hereditary hemocromatosis (HH) and were tested for type 2 diabetes, other components of the metabolic syndrome, beta cell function (BCF), insulin sensitivity, high-sensitivity C-reactive protein and iron overload. RESULTS: Fifty-one men had type 2 diabetes. They were older (p=0.017) and 99 had lower BCF (p<0.001) than non-diabetic men. None of the iron overload indexes was associated with diabetes. CONCLUSIONS: Our findings dispute a role of iron overload in the pathogenesis of type 2 diabetes.

[Is diabetes mellitus a coronary heart disease equivalent? Results of a meta-analysis of prospective studies]. / La diabetes mellitus es un equivalente de riesgo coronario? Resultados de un metaanálisis de estudios prospectivos.

INTRODUCTION AND OBJECTIVES: Several guidelines on the treatment of cardiovascular risk factors base their recommendations on the assertion that diabetes mellitus (DM) is a coronary heart disease (CHD) or cardiovascular disease (CVD) risk equivalent. To date, no systematic review of studies substantiating this assertion has been carried out. METHODS: A systematic search of the PubMed database up to February 2006 was performed to identify prospective studies meeting the following criteria: a) follow-up was >5 years; b) groups of subjects with DM and without CHD (i.e., DM+CHD-), without DM and with CHD (DM-CHD+), and without either DM or CHD (DM-CHD-) were all included; and c) data on CHD or CVD mortality was reported. The characteristics of the studies were assessed, and data were combined separately for men and women using a random effects model and taking the DM-CHD- group as a reference. RESULTS: In total, 13 studies met the inclusion criteria. Overall, CHD mortality was non-significantly lower in DM+CHD- men than in DM-CHD+ men, hazard ratio [HR] (95% confidence interval [CI]), 3.06 (2.45-3.83) vs 4.28 (3.24-5.66), respectively (P=.066); as was CVD mortality, HR (95% CI), 2.55 (2.00-3.26) vs 3.61 (2.81-4.62), respectively (P=.051). In women, there was no significant difference between the DM+CHD- and DM-CHD+ groups with regard to either CHD mortality, HR (95% CI), 4.68 (3.40-6.45) vs 3.51 (1.75-7.04), respectively (P=.42), or CVD mortality, HR (95% CI), 4.70 (4.23-5.22) vs 3.39 (1.51-9.02), respectively (P=.59). CONCLUSIONS: The findings of this meta-analysis support the view that women in the DM+CHD- group have similar CHD and CVD mortality to those in the DM-CHD+ group, whereas men in the DM+CHD- group demonstrated a non-significant trend towards lower CHD and CVD mortality than those in the DM-CHD+ group.