Unemployment and ill health: a connection through inflammation?

Background  

Unemployment is a source of acute and long-term psychosocial stress. Acute and chronic psychosocial stress can induce pronounced changes in human immune responses. In this study we tested our hypothesis that stress-induced low-grade tissue inflammation is more prevalent among the unemployed.     

Delayed tumor onset and reduced tumor growth progression after immunization with a Her-2/neu multi-peptide vaccine and IL-12 in c-<Emphasis Type="Italic">neu</Emphasis> transgenic mice

Passive immunotherapy with monoclonal antibodies is a routinely performed but cost intensive treatment against certain cancers. Induction of humoral anti-tumor responses by active peptide immunization has therefore become a favorable treatment concept. We have recently identified three peptides representing B-cell epitopes of the extracellular domain of Her-2/neu each of them inducing Her-2/neu specific immune responses with anti-tumor activity in vitro. The present study was performed to evaluate the in vivo protective capacity of a combined vaccination with these three peptides in FVB/N transgenic mice spontaneously developing c-neu overexpressing breast cancers. The three Her-2/neu peptides coupled to tetanus toxoid were administered with or without addition of recombinant IL-12. At the time all untreated mice had developed tumors about 40% of peptide-immunized mice and nearly 60% of mice immunized with the peptide vaccine co-applied with IL-12 remained tumor free. Moreover, co-administration of IL-12 had a significant impact on the retardation of tumor progression. The enhanced anti-tumor efficacy of the vaccine by IL-12 was associated with a Th1 biased immune response as demonstrated by an increased IFN-γ production in vitro and elevated Her-2-specific IgG levels. Our findings clearly demonstrate that this multi-peptide vaccine is effective in tumor prevention and support its use against minimal disease, drug-resistant tumors or even for prophylaxis against cancers overexpressing Her-2/neu. Stefan Wagner and Joanna Jasinska contributed equally to this work.     

Life dissatisfaction is associated with a poorer surgery outcome and depression among lumbar spinal stenosis patients: a 2-year prospective study

The aim of this study was to examine the life satisfaction of lumbar spinal stenosis (LSS) patients up to the 2-year postoperative phase. Patients (N = 102, mean age, 62 years) with symptomatic LSS underwent decompressive surgery. Data collection took place with the same set of questionnaires before surgery and 3 months, 6 months, 1 year and 2 years postoperatively. Life satisfaction was assessed with the four-item Life Satisfaction scale and depression symptoms with the 21-item Beck Depression Inventory (BDI). In addition, a depression burden variable was included, comprising the sum of preoperative, 3- and 6-month BDI scores. Physical functioning and pain were assessed with the Oswestry disability index, Stucki questionnaire, self-reported walking ability, visual analogy scale and pain drawing. Two years postoperatively, 18% of the LSS patients was dissatisfied with their lives. As a whole, the life satisfaction of the LSS patients improved during the postoperative follow-up, reaching the level of the healthy adult Finnish population. However, 2 years postoperatively, dissatisfied patients reported significantly more pain, a poorer functional ability and more depressive symptoms and depression than the patients who were satisfied with life. This difference was seen throughout the postoperative follow up. In regression analyses, the only significant associations were between the depression burden and postoperative life dissatisfaction. Thus, subjective well-being as well as depression among LSS patients should be assessed pre- and postoperatively in order to enable early intervention for those at risk of poorer life satisfaction.     

Acute changes in pulmonary artery pressures due to exercise and exposure to high altitude do not cause left ventricular diastolic dysfunction

BACKGROUND: Altitude-induced pulmonary hypertension has been suggested to cause left ventricular (LV) diastolic dysfunction due to ventricular interaction. In this study, we evaluate the effects of exercise- and altitude-induced increase in pulmonary artery pressures on LV diastolic function in an interventional setting investigating high-altitude pulmonary edema (HAPE) prophylaxis. METHODS: Among 39 subjects, 29 were HAPE susceptible (HAPE-S) and 10 served as control subjects. HAPE-S subjects were randomly assigned to prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo bid, starting 1 day before ascent. Doppler echocardiography at rest and during submaximal exercise was performed at low altitude (490 m) and high altitude (4,559 m). The ratio of early transmitral inflow peak velocity (E) to atrial transmitral inflow peak velocity (A), pulmonary venous flow parameters, and tissue velocity within the septal mitral annulus during early diastole (E') were used to assess LV diastolic properties. LV filling pressures were estimated by E/E'. Systolic right ventricular to atrial pressure gradients (RVPGs) were measured in order to estimate pulmonary artery pressures. RESULTS: At 490 m, E/A decreased similarly with exercise in HAPE-S and control subjects (HAPE-S, 1.5 +/- 0.3 to 1.3 +/- 0.3; control, 1.7 +/- 0.4 to 1.3 +/- 0.3; p = 0.12 between groups) [mean +/- SD], whereas RVPG increased significantly more in HAPE-S subjects (20 +/- 5 to 43 +/- 9 mm Hg vs 18 +/- 3 to 28 +/- 3 mm Hg, p < 0.001). Changes in RVPG levels during exercise did not correlate with changes in E/A (p > 0.1). From 490 to 4,559 m, no correlations between changes in RVPG and changes in E/A or atrial reversal (both p > 0.1) were observed. Neither of the groups showed an increase in E/E' from 490 to 4,559 m. CONCLUSION: Increased pulmonary artery pressure associated with exercise and acute exposure to 4,559 m appears not to cause LV diastolic dysfunction in healthy subjects. Therefore, ventricular interaction seems not to be of hemodynamic relevance in this setting.     

Larger transient outward K+ current and shorter action potential duration in Gα11 mutant mice

The α₁-adrenoceptor as well as the AT₁- and the ET_A-receptor couple to G-proteins of the Gα_q/11 family and contribute to the regulation of the transient outward K⁺ current (I_to,f) under pathological conditions such as cardiac hypertrophy or failure. This suggests an important role of Gα_q/11-signalling in the physiological regulation of I_to,f. Here, we investigate mice deficient of the Gα₁₁ protein (gna11^?/?) to clarify the physiological role of Gα₁₁ signalling in cardiac ion channel regulation. Myocytes from endocardial and epicardial layers were isolated from the left ventricular free wall and investigated using the ruptured-patch whole-cell patch-clamp technique. At +40 mV, epicardial myocytes from gna11^?/? mice displayed a 23% larger I_to,f than controls (52.6?±?4.1 pApF^?1, n?=?20 vs 42.7?±?2.8 pApF^?1, n?=?26, p?<?0.05). Endocardial I_to,f was similar in gna11^?/? mice and controls. With the except of minor changes in endocardial myocytes, I_to,f kinetics were similar in both groups. In the epicardial layer, western blot analysis revealed a 19% higher expression of the K⁺-channel α-subunit Kv4.2 in gna11^?/? mice than in wild type (wt; p?<?0.05). The β-subunit KChIP2b was upregulated by 102% in epicardial myocytes of gna11^?/? mice (p?<?0.01, n?=?4). Consistent with the difference in I_to,f, action potential duration was shorter in epicardial cells of gna11^?/? mice than in wt (p?<?0.05), while no difference was found in endocardial myocytes. These results suggest that Gα₁₁-coupled signalling is a central pathway in the regulation of I_to,f. It physiologically exerts a tonic inhibitory influence on the expression of I_to,f and thereby contributes to the regulation of cardiac repolarisation.     

Comparative effects of high and low-dose simvastatin on prostate epithelial cells: the role of LDL

Epidemiological studies have linked statin use with a decreased risk of advanced prostate cancer and an improved recurrence-free survival after radical therapy. It is unclear, however, whether statins could have direct effects against prostate cancer in a clinical setting, as their growth-inhibiting effects on prostate cancer cells have been demonstrated at drug concentrations which exceed the level in plasma during standard clinical dosing. We compared responses to high-dose and therapeutic-dose simvastatin in normal and cancerous prostate epithelial cells. Simvastatin was more effective at inhibiting the growth of normal prostate epithelial cells than of cancer cells. At therapeutic 100 nM concentration simvastatin had a cytostatic effect on normal cells: apoptosis was only slightly induced, but a decrease in cell cycle activity and an increase in senescence were observed. At therapeutic concentrations, lipophilic simvastatin caused a stronger growth inhibition than did hydrophilic rosuvastatin. In contrast, 10 μM simvastatin had a cytotoxic effect both on normal and cancer cells. Addition of LDL-cholesterol effectively reversed the cytostatic effect in all cell lines, but overcoming the cytotoxicity of 10 μM simvastatin required a combination of LDL-cholesterol and mevalonate. As LDL-cholesterol completely prevented the growth-inhibiting effect of therapeutic-dose simvastatin already at low, subphysiological concentrations it is unlikely that statins have direct effects on growth of prostate epithelial cells in vivo. Statins' possible benefits against prostate cancer could be due to systemic cholesterol-lowering, as suggested by epidemiological studies. Future clinical studies evaluating the effects of statins on prostate cancer prevention should monitor serum LDL and should probably administer statins at higher concentrations than those currently used in the treatment of hypercholesterolemia.     

Serum IL-7 and G-CSF in major depressive disorder

Major depressive disorder (MDD) has been associated with dysregulated immune systems and impaired T cell function, but data on depression-related alterations in the levels of immunomodulatory growth factors are scarce. In order to further clarify the mechanisms underlying immune system dysregulation in depressed subjects, we examined the associations between MDD and serum levels of two immunomodulatory growth factors, interleukin (IL)-7 and granulocyte-colony stimulating factor (G-CSF), in 122 subjects (MDD with long-term symptomatology, n = 61; controls, n = 61). The MDD subjects had lowered levels of IL-7. In a model adjusted for age, gender and body mass index, subjects in the lowest tertile of IL-7 had a 3.4-fold increased likelihood for MDD (p = 0.010). Further adjustments for sleep disturbances, alcohol use, smoking, and metabolic syndrome did not alter these findings. Moreover, the exclusion of subjects with rheumatoid arthritis, coronary heart disease, or the use of non-steroidal anti-inflammatory medications or oral corticosteroids only slightly attenuated the findings. The G-CSF levels did not differ between the two groups. The lowering of the serum levels of IL-7, a regulator of T cell homeostasis, in MDD subjects may underlie the depression-related impaired T cell function.