Decreased vagal activity and increased sympathetic arousal have been proposed as major contributors to the increased risk of cardiovascular mortality in patients with depression. It was aim of the present study to assess the feasibility of using heart rate variability (HRV) biofeedback to treat moderate to severe depression. This was an open-label study in which 14 patients with different degrees of depression (13 f, 1 m) aged 30 years (18-47; median; range) and 12 healthy volunteers attended 6 sessions of HRV biofeedback over two weeks. Another 12 healthy subjects were observed under an active control condition. At follow up BDI was found significantly decreased (BDI 6; 2-20; median 25%-75% quartile) as compared to baseline conditions (BDI 22;15-29) in patients with depression. In addition, depressed patients had reduced anxiety, decreased heart rate and increased HRV after conduction of biofeedback (p < 0.05). By contrast, no changes were noted in healthy subjects receiving biofeedback nor in normal controls. In conclusion, HRV biofeedback appears to be a useful adjunct for the treatment of depression, associated with increases in HRV.

Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer disease. Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid ␤-peptide (A␤) from the ␤-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular A␤ by microglia. The statin-dependent clearance of extracellular A␤ is mainly exerted by insulindegrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and A␤ degradation were also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and up-regulation of exosome secretion by fusion of multivesicular bodies with the plasma membrane. These data demonstrate a novel pathway for the nonconventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of A␤. Alzheimer disease (AD)3 is associated with extracellular deposits of the amyloid ␤-peptide (A␤) and intraneuronal aggregates of hyperphosphorylated Tau protein in the brain (1). Evidence suggests that the pathogenesis of AD involves deleterious neurotoxic effects of aggregated A␤ peptides (2), which are derived by sequential proteolytic processing of the ␤-amyloid precursor protein (APP) by ␤-and ␥-secretases (3). APP can also be cleaved in a nonamyloidogenic pathway that involves initial cleavage by ␣-secretase within the A␤ domain that precludes the later generation of A␤ peptides (4). Brain A␤ levels are not only determined by the rate of production but also by different clearance mechanisms, including receptor-mediated endocytosis/phagocytosis and subsequent degradation in the endosomal/lysosomal compartment, transcytosis via the blood-brain barrier, as well as proteolytic degradation of extracellular A␤ by cell surface-localized and secreted proteases (5-10).Several studies indicated a dysregulation of lipid metabolism as an important aspect of AD-associated neurodegeneration. In particular, increased cholesterol levels seem to correlate with increased AD risk. Retrospective studies revealed the beneficial effects of statins (11). However, molecular mechanisms by which statins could offer protection against AD remain to be characterized in detail (12, 13). Most studies with cultured cells and animal models indicate that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) could decrease the generation of A␤ by promoting nonamyloidogenic processing of APP. Other studies also showed that extraction of cholesterol from cellular membranes by cyclodextrins differentially affects A␤ generation. Although strong reduction of cholesterol decreased A␤ generation, a moderate extraction rather promoted the secretion of A␤. These effects were attributed to alterations in the distribution of APP and secretases within membrane microdomains (14 -18). In ...

Background: Depression is one of the most frequent and costly mental disorders. While there is increasing evidence for the efficacy of online self-help to improve depression or prevent relapse, there is little evidence in blended care settings, especially combined with inpatient face-to-face psychotherapy. Therefore, we evaluated whether an evidence-based online self-help program improves the efficacy of inpatient psychotherapy. Methods: A total of 229 depressed patients were randomly allocated either to an online self-help program (intervention group [IG]; Deprexis) or an active control group (CG; weekly online information on depression) in addition to inpatient psychodynamic psychotherapy. Both groups had access to their respective experimental intervention for 12 weeks, regardless of inpatient treatment duration. Reduction of depressive symptoms, as measured with the Beck Depression Inventory-II, was the primary outcome at the end of the intervention (T2). Results: Depressive symptoms were statistically significantly lower in the IG compared to the active CG at T2 with a moderate between-group effect size of d = 0.44. The same applied to anxiety (d = 0.33), quality of life (d = 0.34), and self-esteem (d = 0.38) at discharge from inpatient treatment (T1). No statistically significant differences were found regarding dysfunctional attitudes (d = 0.14) and work ability (d = 0.08) at T1. Conclusions: This is the first evidence for blended treatment combining online self-help with inpatient psychotherapy. The study opens new and promising avenues for increasing the efficacy of inpatient psychotherapy. Future studies should determine how integration of online self-help into the therapeutic process can be developed further.

The mechanism of client protein activation by Hsp90 is enigmatic, and it is uncertain whether Hsp90 employs a common route for all proteins. Using a mutational analysis approach, we investigated the activation of two types of client proteins, glucocorticoid receptor (GR) and the kinase v-Src by the middle domain of Hsp90 (Hsp90M) in vivo. Remarkably, the overall cellular activity of v-Src was highly elevated in a W300A mutant yeast strain due to a 10-fold increase in cellular protein levels of the kinase. In contrast, the cellular activity of GR remained almost unaffected by the W300A mutation but was dramatically sensitive to S485Y and T525I exchanges. In addition, we show that mutations S485Y and T525I in Hsp90M reduce the ATP hydrolysis rate, suggesting that Hsp90 ATPase is more tightly regulated than assumed previously. Therefore, the activation of GR and v-Src has various demands on Hsp90 biochemistry and is dependent on separate functional regions of Hsp90M. Thus, Hsp90M seems to discriminate between different substrate types and to adjust the molecular chaperone for proper substrate activation.Heat shock protein 90 (Hsp90) is a highly conserved, abundant and constitutively expressed homodimeric molecular chaperone of the eukaryotic cytosol. It is specifically involved in the folding and conformational regulation of a limited subset of client proteins. Many natural substrates of Hsp90 are medically relevant signal transduction molecules, e.g., the nuclear receptors for steroid hormones and several kinases, some of them with oncogenic potential (19,23,24). To fulfill its biological function, Hsp90 cooperates with different cochaperones, such as Hop, p50, p23, Aha1, the immunophilins, and others, and acts as part of a multichaperone machine together with Hsp70.Hsp90 is composed of a N-terminal nucleotide binding domain (Hsp90N), a middle domain (Hsp90M), and a C-terminal domain (Hsp90C) that mediates the dimerization of the protein. A hallmark of the Hsp90 reaction cycle is binding and hydrolysis of ATP (20,21,26,34). Although the catalytic center for this reaction has been identified within the N-terminal domain of the protein, the interplay between this part and the other domains of Hsp90 during substrate activation is poorly understood. Emerging evidence suggests that the middle domain of Hsp90 plays an important role in this process. For example, it has been shown that Hsp90M interacts with Aha1, a cochaperone that stimulates Hsp90's rate of ATP hydrolysis and increases the efficiency of client protein activity (8,11,22). Moreover, communication between the middle and N-terminal domains of Hsp90 is essential in vivo (13), probably due to the role of a Hsp90M segment in the proper orientation of the ␥-phosphate group of ATP for hydrolysis by the N-terminal catalytic domain (15). Furthermore, a peptide spanning 14 amino acid residues within Hsp90M has been suggested as the binding site for a natural client protein (30). Several point mutations within Hsp90M that exhibit temperature-sensitive growth defects...

Cognitive and psychomotor performance are not altered in healthy humans receiving multiple dosing with sertraline. The observed decreases in heart rate and SCL may be due to a sympatho-inhibitory effect of sertraline.