Eeva Moilanen’s research while affiliated with Tampere University Hospital (TAUH) and other places

Objective Associations between leptin ( LEP ) and leptin receptor ( LEPR ) gene polymorphisms and mood disorders have been found but not yet confirmed in multiple studies. The aim of our study was to study the associations between LEP and LEPR single nucleotide polymorphisms (SNPs) and treatment response of depression. Associations between leptin levels and depression severity were also investigated. Methods The data included 242 depressed patients in secondary psychiatric care. Symptoms of depression were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS). Previously found LEP and LEPR SNPs associated with depression and other mood disorders were studied. Furthermore, all available LEP and LEPR SNPs were clumped using proxy SNPs to represent gene areas in r ² > 0.2 linkage disequilibrium and their association with treatment response was analysed with logistic regression. Results Two proxy SNPs of LEPR gene, rs12564738 and rs12029311, were associated with MADRS response at 6 weeks ( p adjusted = 0.024, p adjusted = 0.024). SNPs from previous studies were not associated with MADRS response, but LEPR rs12145690 from a previous study was strongly associated with rs12564738 ( r ² = 0.94). The positive association between leptin levels and MADRS score at baseline after adjusting with age, sex, body mass index (BMI), Alcohol Use Disorders Identification Test score, and smoking was found ( p = 0.011). Conclusion Our findings suggest that LEPR polymorphisms are associated with depression treatment response. We also found associations between leptin levels and depression independently of BMI. Further studies and meta-analyses are needed to confirm the significance of found SNPs and the role of leptin in depression.

Objective: Hyperthyroidism increases cardiovascular morbidity and mortality, but the underlying mechanisms are not fully understood. In this study we compared non-invasive haemodynamics between 20 hyperthyroid patients and 60 euthyroid subjects. Methods: The measurements were performed median 6 days after the initiation of antithyroid medication when the patients were still hyperthyroid. Three controls matched for age, sex, body mass index, and smoking status were selected for each patient. Recordings were performed during rest and passive head-up tilt using whole-body impedance cardiography, radial pulse wave analysis, and finger blood pressure measurements. Results: Systolic and diastolic blood pressures in the aorta and radial artery were similar in hyperthyroid and euthyroid subjects, while finger blood pressure was 16/12 mmHg lower in hyperthyroidism (p<0.001). Pulse wave velocity and aortic pulse pressure were similar, but radial pulse pressure was ~5 mmHg higher in hyperthyroidism (p=0.040) due to augmented amplification (p=0.045). Systemic vascular resistance was reduced (-18%), whereas heart rate (+19 beats/min), cardiac index (+28%), and left cardiac work (+31%) were increased in hyperthyroidism (p<0.001). Subendocardial viability ratio, reflecting the balance between coronary perfusion and pressure load, was reduced by 19% in hyperthyroidism (p<0.001). Compared with euthyroid subjects, hyperthyroid patients presented with reductions in systolic and diastolic finger blood pressures (p<0.001), and higher increase in heart rate (p=0.014) during upright posture. Conclusions: Hyperthyroid patients exhibited hyperdynamic circulation, reduced vascular resistance, reduced peripheral but not central blood pressure, and higher pulse pressure amplification. Furthermore, left cardiac workload was increased in parallel with unfavourable changes in coronary perfusion conditions.

Inflammation is a complex biological process protecting the body from diverse external threats. Effectively performing this task requires an intricate, well‐regulated interplay of different cells and tissues. Furthermore, several cells participating in inflammation can assume diverse phenotypes. A classic and relatively well‐studied example of phenotypic diversity in inflammation is macrophage polarization. Based on the T H 1/T H 2 phenotypes of T helper cells, this scheme has proinflammatory “classical/M1” activation contrasted with the anti‐inflammatory and healing‐promoting “alternative/M2” phenotype. Some authors have extended the concept into an M17 phenotype induced by the classic T H 17 cytokine IL‐17. Phenotypic changes in chondrocytes have also been studied especially in the context of osteoarthritis (OA), and there are indications that these cells can also assume polarized phenotypes at least partly analogous to those of T H cells and macrophages. The therapeutic success of biological agents targeting T H 1/T H 2/T H 17 inductor and/or effector cytokines displays the utility of the concept of polarization. The aim of this focused review is to survey the internal and external factors affecting macrophage and chondrocyte phenotypes (such as inflammatory cytokines, widely used medications and natural products) and to explore the possibility of ameliorating pathological states by modulating these phenotypes.

The percentage of obese people is increasing worldwide, causing versatile health problems. Obesity is connected to diseases such as diabetes and cardiovascular diseases, which are preceded by a state called metabolic syndrome. Diets rich in fruits and vegetables have been reported to decrease the risk of metabolic syndrome and type 2 diabetes. Berries with a high polyphenol content, including lingonberry (Vaccinium vitis-idaea L.), have also been of interest to possibly prevent obesity-induced metabolic disturbances. In the present study, we prepared an extract from the by-product of a lingonberry juice production process (press cake/pomace) and investigated its metabolic effects in the high-fat diet-induced model of obesity in mice. The lingonberry skin extract partly prevented weight and epididymal fat gain as well as a rise in fasting glucose level in high-fat diet-fed mice. The extract also attenuated high-fat diet-induced glucose intolerance as measured by an intraperitoneal glucose tolerance test (IPGTT). The extract had no effect on the levels of cholesterol, triglyceride or the adipokines adiponectin, leptin, or resistin. The results extend previous data on the beneficial metabolic effects of lingonberry. Further research is needed to explore the mechanisms behind these effects and to develop further health-promoting lingonberry applications.

Background Angiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF). Materials and methods An analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member. Results The patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11–5.82, p = 0.02) and 3.11 (95% CI 1.30–7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97–19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02–8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19–0.98, p = 0.04)]. Conclusion Especially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival. Trial registration ClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.

Glucocorticoids are widely used in the treatment of allergic and inflammatory diseases. Glucocorticoids have a widespread action on gene expression resulting in their pharmacological actions and also an array of adverse effects which limit their clinical use. It remains, however, to be studied which target gene effects are essential for the anti‐allergic activity of glucocorticoids. Mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) inhibits proinflammatory signalling by suppressing the activity of mitogen activated protein kinase (MAP kinase) pathways. MKP‐1 is one of the anti‐inflammatory genes whose expression is enhanced by glucocorticoids. In the present study, we aimed to investigate the role of MKP‐1 in the therapeutic effects of the glucocorticoid dexamethasone in acute allergic reaction. The effects of dexamethasone were studied in wild‐type and MKP‐1 deficient mice. The mice were first sensitized to ovalbumin, and the allergic reaction was then induced by a subcutaneous ovalbumin injection in the hind paw. Inflammatory edema was quantified with plethysmometer and expression of inflammatory factors was measured by quantitative reverse transcription polymerase chain reaction (RT‐PCR). Dexamethasone reduced the ovalbumin‐induced paw edema at 1.5, 3 and 6 h time points in wild‐type mice by 70%, 95% and 89%, respectively. The effect was largely abolished in MKP‐1 deficient mice. Furthermore, dexamethasone significantly attenuated the expression of ovalbumin‐induced inflammatory factors cyclooxygenase‐2 (COX‐2); inducible nitric oxide synthase (iNOS); interleukins (IL) 1β, 6 and 13; C‐C motif chemokine 11 (CCL‐11); tumour necrosis factor (TNF) and thymic stromal lymphopoietin (TSLP) in wild‐type mice by more than 40%. In contrast, in MKP‐1 deficient mice dexamethasone had no effect or even enhanced the expression of these inflammatory factors. The results suggest that dexamethasone alleviates allergic inflammation through an MKP‐1‐dependent mechanism. The results also demonstrate MKP‐1 as an important conveyor of the favourable glucocorticoid effects in ovalbumin‐induced type I allergic reaction. Together with previous findings, the present study supports the concept of MKP‐1 enhancing compounds as potential novel anti‐inflammatory and anti‐allergic drugs.

Objectives We examined haemodynamics, focusing on volume balance and forward and backward wave amplitudes, before and after 2.8 years of targeted treatment of primary aldosteronism. Patients with essential hypertension and normotensive individuals were examined for comparison ( n = 40 in each group). Methods Recordings were performed using radial artery pulse wave analysis and whole-body impedance cardiography. Unilateral aldosteronism was treated with adrenalectomy ( n = 20), bilateral aldosteronism with spironolactone-based medication ( n = 20), and essential hypertension with standard antihypertensive agents. Results Aortic SBP and DBP, forward and backward wave amplitudes, and systemic vascular resistance were equally elevated in primary aldosteronism and essential hypertension. All these haemodynamic variables were similarly reduced by the treatments. Primary aldosteronism presented with 1 litre (∼10%) extracellular water excess ( P < 0.001) versus the other groups, and this excess was normalized by treatment. Initial pulse wave velocity (PWV) was similarly increased in primary aldosteronism and essential hypertension, but final values remained higher in primary aldosteronism ( P < 0.001). In regression analyses, significant explanatory factors for treatment-induced forward wave amplitude reduction were decreased systemic vascular resistance ( β = 0.380) and reduced extracellular water volume ( β = 0.183). Explanatory factors for backward wave amplitude reduction were changes in forward wave amplitude ( β = 0.599), heart rate ( β = −0.427), and PWV ( β = 0.252). Conclusion Compared with essential hypertension, the principal haemodynamic difference in primary aldosteronism was higher volume load. Volume excess elevated forward wave amplitude, which was subsequently reduced by targeted treatment of primary aldosteronism, along with normalization of volume load. We propose that incorporating extracellular water evaluation alongside routine diagnostics could enhance the identification and diagnosis of primary aldosteronism.