Soluble RAGE and atherosclerosis in youth with type 1 diabetes: a 5-year follow-up study.

BACKGROUND: Advanced glycation end products (AGEs) play a role in the development of late complications and atherosclerosis in diabetes by engaging the receptor for advanced glycation end products, RAGE. Receptor binding leads to activation of the vascular endothelium and increased inflammation in the vessel wall. The soluble variants of the receptor, endogenous secretory RAGE (esRAGE) and the cleaved cell-surface part of RAGE, which together comprise soluble RAGE (sRAGE), are suggested to have a protective effect acting as decoys for RAGE. We aimed to test whether high levels of soluble variants of RAGE could be protective against atherosclerosis development. METHODS: Participants in the prospective atherosclerosis and childhood diabetes study were examined at baseline (aged 8-18) and at follow-up after 5 years. Both sRAGE and esRAGE were measured by immunoassay in 299 patients with type 1 diabetes and 112 healthy controls at baseline and 241 patients and 128 controls at follow-up. The AGEs methylglyoxal-derived hydroimidazolone-1 (MG-H1) and carboxymethyllysine (CML) were measured by immunoassay. The surrogate markers of atherosclerosis assessed were carotid intima-media thickness (cIMT), C-reactive protein (CRP) and Young's modulus, measures of arterial wall thickness, inflammation and arterial stiffness, respectively. RESULTS: Levels of sRAGE and esRAGE correlated strongly both at baseline and at follow-up in both diabetes patients and controls. With increasing age, mean values of both variants declined, independent of gender, diabetes or pubertal stage. In the diabetes group, multiple regression analysis showed a positive association between both variants of soluble RAGE and cIMT. There was no significant relationship with Young's modulus, but a negative association between sRAGE at baseline and CRP at follow-up. The ratios between the AGEs and the variants of soluble RAGE were increased in diabetes patients compared to controls. CONCLUSIONS: The results show a possible protective effect of high levels of sRAGE at baseline against inflammation 5 years later, but not on arterial stiffness or wall thickness, in this cohort of adolescents and young adults with T1D.

Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study.

PURPOSE: We investigated the association between serum levels of 25-hydroxyvitamin D (25-OHD) and risk of death in Norwegian cancer patients. METHODS: The study population was 658 patients with cancers of the breast (n = 251), colon (n = 52), lung (n = 210), and lymphoma (n = 145), obtained from JANUS, a population-based serum bank in Norway. Serum samples were collected within 90 days of cancer diagnosis and were analyzed for 25-OHD. Patients were diagnosed during 1984-2004 and were followed for death throughout 2008. We used Cox regression models to assess the relationship between serum 25-OHD and risk of death. RESULTS: Three hundred and ninety-nine patients died during follow-up, of whom 343 (86%) died from cancer. Adjusted for sex, age at diagnosis, and season of blood sampling, patients with 25-OHD levels below 46 nmol/L at diagnosis experienced shorter survival. Compared to patients in the lowest quartile of serum 25-OHD, the risk of cancer death among patients in the highest quartile was significantly reduced (HR 0.36 95% CI 0.27, 0.51). The estimated change in risk of cancer death was most pronounced between the first and the second quartile. The associations between 25-OHD levels and survival were observed for all four cancers. CONCLUSIONS: Higher circulating serum levels of 25-OHD were positively associated with the survival for cancers of the breast, colon, lung, and lymphoma.

Serum 25-hydroxyvitamin D levels predict cancer survival: a prospective cohort with measurements prior to and at the time of cancer diagnosis.

PURPOSE: Circulating 25-hydroxyvitamin D (25-OHD) levels have been inversely associated with cancer death, but the nature of this relationship is unclear. We investigated this association using repeated measurements of serum 25-OHD. PATIENTS AND METHODS: Pre-diagnostic serum samples were collected in population health surveys in Norway (1973-2004). Participants who subsequently developed cancer (1984-2004) provided a second serum sample at the time of cancer diagnosis. Samples were stored in the Janus Serum Bank. Repeated samples existed from 202 breast cancers, 193 lung cancers, 124 lymphomas, and 37 colon cancers. Serum 25-OHD was measured via competitive radioimmunoassay. Cox regression models assessed associations between 25-OHD and cancer-specific death (case fatality) through 2012, given as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: The median time between pre-diagnostic and diagnostic samples was 14.4 years. The median 25-OHD levels were 63.3 and 62.5 nmol/L, respectively. During follow-up, 313 cancer deaths occurred. Compared to low pre-diagnostic 25-OHD levels (<46 nmol/L), higher levels (≥46 nmol/L) had significantly lower HRs (39-54%) of case fatality. This result was also seen for the diagnostic samples. Donors who had both samples at high (≥62 nmol/L) levels had 59% lower HR of case fatality, compared to those for whom both samples were at low levels (<46 nmol/L). Furthermore, versus a decline in serum 25-OHD (median -22.4 nmol/L) from pre-diagnostic to diagnostic samples, a rise (median 22.3 nmol/L) was associated with lower case fatality (HR 0.57, 95% CI 0.43-0.75). CONCLUSION: Our findings suggest a causal relationship between vitamin D and cancer case fatality.

Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial.

OBJECTIVES: Gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins, which appear to be proinflammatory, undergo profound secretory changes during events associated with rheumatoid arthritis (RA) onset, flares, or improvement e.g. menopausal transition, postpartum, or pregnancy. Potential anti-inflammatory effects of GnRH-antagonists may be most pronounced in patients with high GnRH and gonadotropin levels. Therefore, we investigated the efficacy and safety of a GnRH-antagonist, cetrorelix, in RA patients with high gonadotropin levels. METHODS: We report intention-to-treat post hoc analyses among patients with high gonadotropin levels (N = 53), i.e. gonadotropin levels>median, from our proof-of-concept, double-blind AGRA-study (N = 99). Patients with active longstanding RA, randomized to subcutaneous cetrorelix (5mg days1-2; 3mg days 3-5) or placebo, were followed through day 15. Only predefined primary and secondary endpoints were analyzed. RESULTS: The primary endpoint, Disease Activity Score of 28-joint counts with C-reactive protein (DAS28-CRP), improved with cetrorelix compared with placebo by day 5 (-1.0 vs. -0.4, P = 0∙010). By day 5, more patients on cetrorelix achieved at least a 20% improvement in the American College of Rheumatology scale (44% vs. 19%, P = 0.049), DAS28-CRP≤3.2 (24% vs. 0%, P = 0.012), and European League against Rheumatism 'Good-responses' (19% vs. 0%, P = 0.026). Tumor necrosis factor-α, interleukin-1ß, interleukin-10, and CRP decreased with cetrorelix (P = 0.045, P = 0.034, P = 0.020 and P = 0.042 respectively) compared with placebo by day 15. Adverse event rates were similar between groups. CONCLUSIONS: GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00667758.

The advanced glycation end product methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in childhood diabetes.

BACKGROUND: Advanced protein glycation is an important mechanism for the development of late diabetic complications including atherosclerosis. Methylglyoxal-derived hydroimidazolone-1 is the most abundant advanced glycation end product in human plasma. AIM: To investigate the relationship between methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in children and adolescents with type 1 diabetes and healthy controls. METHODS: A total of 314 diabetes patients aged 8-18 years were compared with 120 healthy controls. Serum methylglyoxal-derived hydroimidazolone-1 was measured by immunoassay. Atherosclerosis was evaluated by assessing carotid intima-media thickness by ultrasound, arterial stiffness by Young's modulus and inflammation by C-reactive protein. RESULTS: Methylglyoxal-derived hydroimidazolone-1 was significantly increased in the diabetes group compared with controls, 155.3 (standard deviation (SD) = 41.0) versus 143.0 (SD = 35.1) U/mL, p = 0.003, as was C-reactive protein, median 0.51 (0.27, 1.83) versus 0.31 (0.19, 0.67) mg/L, p < 0.001. There was no significant difference between the groups regarding carotid intima-media thickness or Young's modulus. Multiple regression analysis showed a significant positive association between methylglyoxal-derived hydroimidazolone-1 and C-reactive protein in the diabetes group. CONCLUSION: Serum levels of methylglyoxal-derived hydroimidazolone-1 in diabetes patients are increased and associated with low-grade inflammation, but not yet arterial stiffness or wall thickness. This indicates that methylglyoxal-derived hydroimidazolone-1 may be important in the early phase of the accelerated atherosclerotic process in diabetes.