Auni Juutilainen

High Serum Levels of Advanced Glycation End Products Predict Increased Coronary Heart Disease Mortality in Nondiabetic Women but not in Nondiabetic Men A Population-Based 18-Year Follow-Up Study

Background—Advanced glycation end products (AGEs), modification products of glycation or glycoxidation of proteins and lipids, have been linked to premature atherosclerosis in patients with diabetes as well as in nondiabetic subjects. Methods and Results—Serum levels of AGEs were measured with an immunoassay in samples obtained at baseline examination of a random sample of 1141 nondiabetic individuals (535 men and 606 women), aged 45 to 64 years, living in Kuopio, East Finland, or Turku, West Finland in 1982 to 1984. After 18 years of follow-up, all-cause mortality, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality were registered on the basis of copies of death certificates. Multivariate Cox regression model showed a significant association of serum AGEs with all-cause (P=0.012), CVD (P=0.018), and CHD (P=0.008) mortality in women but not in men. Fasting serum AGEs in the highest quartile were an independent risk factor for all-cause (hazards ratio [HR], 1.90; 95% CI, 1.16 to 3.11; P=0.011) and CHD (HR, 6.51; 95% CI, 1.78 to 23.79; P=0.005) mortality in women, even after the adjustment for confounding factors, including highly sensitive C-reactive protein. Conclusions—The present study is the first to show that serum levels of AGEs can predict total, CVD, and CHD mortality in nondiabetic women.

Increased serum levels of methylglyoxal-derived hydroimidazolone-AGE are associated with increased cardiovascular disease mortality in nondiabetic women

OBJECTIVE To investigate the association of the levels of methylglyoxal-derived hydroimidazolone AGE modified proteins (MG-H1-AGE) with cardiovascular disease (CVD) mortality in an 18-year follow-up study in Finnish nondiabetic and diabetic subjects. METHODS The study design was a nested case-control study. Serum MG-H1-AGE levels in samples drawn at baseline were measured with a DELFIA type immunoassay in 220 diabetic subjects and 61 nondiabetic subjects who died from CVD during the follow-up, and age- and gender-matched 157 diabetic subjects and 159 nondiabetic subjects who did not die from CVD. RESULTS In type 2 diabetic subjects serum MG-H1-AGE levels were similar in subjects who died from CVD and in subjects who did not, 32.6 (24.6-42.1) (median (interquartile range)) vs. 31.3 (22.5-40.7)U/mL (p=0.281). In nondiabetic subjects serum MG-H1 levels were significantly higher in subjects who died from CVD than in subjects who were alive, 35.4 (28.1-44.7) vs. 31.3 (24.2-38.6)U/mL (p=0.025). Corresponding MG-H1 levels were 41.2 (35.6-58.7) vs. 31.1 (26.7-35.7)U/mL, p=0.003, in women, and 34.4 (26.3-41.2) vs. 32.0 (22.8-40.3)U/mL, p=0.270, in men. Multivariate logistic regression analysis showed a significant association of serum levels of MG-H1-AGE with CVD mortality in nondiabetic women (adjusted p=0.021), but not in nondiabetic men. CONCLUSIONS Our 18-year follow-up study shows that high baseline serum levels of MG-H1 type of AGE modified proteins were associated with CVD mortality in nondiabetic women, but not in nondiabetic men or in diabetic subjects.

Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia

Abstract Objective: To compare semi-quantitative procalcitonin with C-reactive protein in predicting bacteraemia in haematological patients with neutropenic fever. Methods: A total of 77 patients treated with intensive chemotherapy for haematological malignancy at Kuopio University Hospital were candidates for study entry. Eleven of these patients did not fulfil the criteria for neutropenic fever, and 66 patients were finally included. Nineteen patients had acute myeloid leukaemia and 47 had received high-dose chemotherapy supported by autologous stem cell transplant. Ninety neutropenic fever episodes in these 66 patients fulfilled the study entry criteria, with microbiological cultures, procalcitonin and C-reactive protein measurements available. Serum procalcitonin and C-reactive protein were analyzed at the onset of each neutropenic fever episode on day 0, and then daily from days 1 to 4. Results: Bacteraemia was observed in 21 episodes (23%) and the criteria for severe sepsis were fulfilled in 13 episodes (14%). Half of the bacteraemic episodes were caused by Gram-negative bacteria. The kinetics of procalcitonin and C-reactive protein were similar, with increasing levels for 2 to 4 days after the onset of fever. The procalcitonin level on days 1, 2, 3 and 4 was associated with bacteraemia and Gram-negative bacteraemia, but not with the development of severe sepsis. On day 1, a procalcitonin level above 0.5 ng/ml had a sensitivity of 57% and 70% and specificity of 81% and 77% to predict bacteraemia and Gram-negative bacteraemia, respectively. Conclusions: An elevated level of procalcitonin within 24 h after the onset of neutropenic fever predicts bacteraemia and Gram-negative bacteraemia in haematological patients.

High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients

We evaluated pentraxin 3 as a marker for complications of neutropenic fever in 100 hematologic patients receiving intensive chemotherapy. Pentraxin 3 and C-reactive protein were measured at fever onset and then daily to day 3. Bacteremia was observed in 19 patients and septic shock in 5 patients (three deaths). In comparison to C-reactive protein, pentraxin 3 achieved its maximum more rapidly. Pentraxin 3 correlated not only with the same day C-reactive protein but also with the next day C-reactive protein. High pentraxin 3 on day 0 was associated with the development of septic shock (P=0.009) and bacteremia (P=0.046). The non-survivors had constantly high pentraxin 3 levels. To conclude, pentraxin 3 is an early predictor of complications in hematologic patients with neutropenic fever. High level of pentraxin 3 predicts septic shock and bacteremia already at the onset of febrile neutropenia. (ClinicalTrials.gov Identifier: NCT00781040.)

Risk factors for end-stage renal disease in a community-based population: 26-year follow-up of 25 821 men and women in eastern Finland

Abstract.  Kastarinen M, Juutilainen A, Kastarinen H, Salomaa V, Karhapää P, Tuomilehto J, Grönhagen‐Riska C, Jousilahti P, Finne P. (Kuopio University Hospital, Kuopio; National Institute for Health and Welfare, Helsinki; University of Helsinki, Helsinki; South Ostrobotnia Central Hospital, Seinäjoki; Finnish Registry for Kidney Diseases, Helsinki; Helsinki University Central Hospital, Helsinki; and University of Tampere, Tampere; Finland). Risk factors for end‐stage renal disease in a community‐based population: 26‐year follow‐up of 25 821 men and women in eastern Finland. J Intern Med 2010; 267:612–620.

Catheter-directed thrombolysis of proximal lower extremity deep vein thrombosis: A prospective trial with venographic and clinical follow-up

PURPOSE To prospectively evaluate the primary and long-term venographic and clinical results of catheter-directed thrombolysis in the treatment of proximal deep vein thrombosis (DVT) of lower extremity. MATERIALS AND METHODS Fifty-six patients with mean age of 48 (range 15-81) years with acute DVT (symptom duration of less than 2 weeks), extending to high femoral (16 patients) or iliac vein (40 patients) were treated with selective catheter-directed thrombolysis. The mean total dose of 3.8 (range 1.0-8.1) million units of urokinase was administered during a mean of 39 (range 6-72) hours. Endovascular stenting was performed in 9 of the iliac DVT patients. RESULTS Complete procedural venographic success was achieved in 79% of patients. Major complications were noted in 7% of patients and the total rate of complications was 13%. Mean venographic follow-up was 3.5 years (range 3 months to 9.6 years); well preserved femoral vein valves and fully recanalized deep crural veins were observed in 83% and 57% of patients. Normal clinical findings in the affected limb were noted during the latest follow-up visit in 67% of patients. Clinical post-thrombotic syndrome occurred in 9% of patients. CONCLUSION Catheter-directed thrombolysis achieves good primary success with acceptable complication rate and effectively reduces prevalence of post-thrombotic syndrome.

Kinetics of blood CD34+ cells after chemotherapy plus G-CSF in poor mobilizers: Implications for pre-emptive plerixafor use

Mobilization and collection of stem cells is difficult in a proportion of patients intended for autologous stem cell transplantation (ASCT). We have evaluated mobilization kinetics of blood CD34+ cells (B-CD34+) to form basis for algorithm to facilitate rational pre-emptive plerixafor use. Altogether 390 chemomobilized patients were included. Forty-three patients (11%) did not reach B-CD34+ count ≥10 × 106/l. Mobilization kinetics differed according to the mobilization capacity observed. Among those who were very poor or inadequate mobilizers (peak B-CD34+ count ≤5 × 106/l and 6–10 × 106/l, respectively), B-CD34+ counts rarely rose after white blood cells (WBC) >5–10 × 109/l, whereas in many standard mobilizers a later rise in CD34+ counts could be observed. Four algorithms based on WBC and CD34+ counts were constructed. According to this patient series, algorithm II (WBC >5 × 109/l and B-CD34+ ≤10 × 106/l) and algorithm IV (WBC >10 × 109/l and B-CD34+ ≤10 × 109/l) were the most applicable. For algorithm II the sensitivity was 0.97 and specificity 1.00, respectively, to identify patients for plerixafor use provided that all patients with B-CD34+ maximum ≤10 × 106/l would have needed plerixafor. This simple model needs a prospective validation.

Circulating CXCR5+PD-1+ICOS+ Follicular T Helper Cells Are Increased Close to the Diagnosis of Type 1 Diabetes in Children With Multiple Autoantibodies

Although type 1 diabetes (T1D) is primarily perceived as a T cell–driven autoimmune disease, islet autoantibodies are the best currently available biomarker for autoimmunity and disease risk. These antibodies are produced by autoreactive B cells, the activation of which is largely dependent on the function of CD4+CXCR5+ follicular T helper cells (Tfh). In this study, we have comprehensively characterized the Tfh- as well as B-cell compartments in a large cohort of children with newly diagnosed T1D or at different stages of preclinical T1D. We demonstrate that the frequency of CXCR5+PD-1+ICOS+–activated circulating Tfh cells is increased both in children with newly diagnosed T1D and in autoantibody-positive at-risk children with impaired glucose tolerance. Interestingly, this increase was only evident in children positive for two or more biochemical autoantibodies. No alterations in the circulating B-cell compartment were observed in children with either prediabetes or diabetes. Our results demonstrate that Tfh activation is detectable in the peripheral blood close to the presentation of clinical T1D but only in a subgroup of children identifiable by positivity for multiple autoantibodies. These findings suggest a role for Tfh cells in the pathogenesis of human T1D and carry important implications for targeting Tfh cells and/or B cells therapeutically.

IL-10 combined with procalcitonin improves early prediction of complications of febrile neutropenia in hematological patients.

Early diagnosis of complicated course in febrile neutropenia is cumbersome due to the non-specificity of clinical and laboratory signs of severe infection. This prospective study included 100 adult hematological patients with febrile neutropenia after intensive chemotherapy at the onset of fever (d0) and for 3 days (d1-d3) thereafter. The study aim was to find early predictors for complicated course of febrile neutropenia, defined as bacteremia or septic shock. Interleukin 6 (IL-6), interleukin 10 (IL-10), procalcitonin (PCT) and C-reactive protein (CRP) all predicted complicated course of febrile neutropenia on d0, but only PCT was predictive throughout the study period. For IL-10 on d0-1 with cut-off 37 ng/L, sensitivity was 0.71, specificity 0.82, positive predictive value 0.52 and negative predictive value 0.92. For PCT on d0-1 with cut-off 0.13 μg/L, the respective measures were 0.95, 0.53, 0.36, and 0.98. For the combination of IL-10 and PCT on d0-1 with the same cut-offs, specificity improved to 0.85 and positive predictive value to 0.56. In conclusion, the present study confirms the high negative predictive value of PCT and provides new evidence for IL-10 as an early predictor for complicated course of febrile neutropenia in hematological patients. Combining IL-10 with PCT improves the early prediction for complicated course of febrile neutropenia.

Combination of LC-MS/MS aldosterone and automated direct renin in screening for primary aldosteronism.

BACKGROUND Aldosterone to renin ratio (ARR) is used in screening for primary aldosteronism (PA). However, there are only few studies on the influence of assay methods on ARR and its cut-off limits. METHODS Plasma direct renin immunoreactivity by chemiluminescence immunoassay (DR) was compared to renin activity assay (PRA), and a specific liquid chromatography-mass spectrometric method (LC-MS/MS) to radioimmunoassay (RIA) for plasma aldosterone. There were 75 samples for renin assays, and 42 samples of 39 patients for both renin and aldosterone assays. PA screening was considered positive if ARR by the aldosterone RIA:PRA was ≥800pmol/L:μg/L/h or by LC-MS/MS:DR≥44pmol/L:ng/L. RESULTS The correlation between the DR and PRA methods (n=75, r(2)=0.845) and between LC-MS/MS and RIA (n=42, r(2)=0.973) was high in general, but low between the renin methods (n=49, r(2)=0.435) at low PRA values. When ARR was used in screening for PA, there were three divergent cases (positive only by alternative methods), but when applied in combination with criteria for elevated aldosterone, the methods showed good agreement, resulting in eight positive and 31 negative screening results. CONCLUSIONS The automated DR assay combined with LC-MS/MS method for aldosterone provides a rapid, reliable, and specific method for screening of PA.