Huntington's disease (HD) is caused by an expanded CAG repeat leading to the synthesis of an aberrant protein and to the formation of polyglutamine (polyQ)-containing inclusions and aggregates. Limited information is available concerning the association of neuropathological markers with the development of behavioral markers in HD. Using a previously generated transgenic rat model of HD (tgHD rat), we performed association studies on the time-course of behavioral symptoms (motor function, learning, anxiety) and the appearance of striatal atrophy, 1C2 immunopositive aggregates and polyQ recruitment sites, a precursor to these aggregates. At the age of 1 month, tgHD rats exhibited reduced anxiety and improved motor performance, while at 6 months motor impairments and at 9 months cognitive decline occurred. In contrast, polyQ recruitment sites appeared at around 6-9 months of age, indicating that HD-like behavioral markers preceded the appearance of currently detectable neuropathological markers. Interestingly, numerous punctate sites containing polyQ aggregates were also seen in areas receiving afferents from the densely recruiting regions suggesting either transport of recruitment-competent aggregates to terminal projections where initially 1C2 positive aggregates were formed or different internal properties of neurons in different regions. Furthermore, striatal atrophy was observed at the age of 12 months. Taken together, our findings support the hypothesis of a dynamic process leading to region- and age-specific polyQ recruitment and aggregation. The dissociation of onset between behavioral and neuropathological markers is suggestive of as yet undetected processes, which contribute to the early phenotype of these HD transgenic rats.

The majority of tinnitus patients are affected by chronic idiopathic tinnitus, and almost 60 different treatment modalities have been reported. The present study is a multidisciplinary systematic analysis of the evidence for the different forms of treatment for chronic tinnitus. The results are used to form the basis of an S3 guideline. A systematic search was carried out in PubMed and the Cochrane Library. The basis for presenting the level of evidence was the evidence classification of the Oxford Centre of Evidence-based Medicine. Whenever available, randomised controlled trials were given preference for discussing therapeutic issues. All systematic reviews and meta-analyses were assessed for their methodological quality, and effect size was taken into account. As the need for patient counselling is self-evident, specific tinnitus counselling should be performed. Due to the high level of evidence, validated tinnitus-specific, cognitive behavioural therapy is strongly recommended. In addition, auditory therapeutic measures can be recommended for the treatment of concomitant hearing loss and comorbidities; those should also be treated with drugs whenever appropriate. In particular, depression should be treated, with pharmacological support if necessary. If needed, psychiatric treatment should also be given on a case-by-case basis. With simultaneous deafness or hearing loss bordering on deafness, a CI can also be indicated. For auditory therapeutic measures, transcranial magnetic or direct current stimulation and specific forms of acoustic stimulation (noiser/masker, retraining therapy, music, and coordinated reset) for the treatment of chronic tinnitus the currently available evidence is not yet sufficient for supporting their recommendation.

Our findings suggest that the effect of stigmatization on skin-related QoL is driven by symptom severity and stigmatization combined, whereas its effect on mental health is driven mostly by stigmatization alone. Further, although women and men experience the social impact of psoriasis differently, the effect of stigmatization on QoL is similar for both genders.

Feelings of stigmatization are an important somatopsychic consequence of psoriasis, affecting the quality of life. It is thus relevant to supplement reliable statements about the detailed changes of stigmatization experience and psoriasis over time. In this study we compared the Psoriasis Area and Severity Index (PASI), the 'self-administered PASI' (SPASI) and the 'Questionnaire on Experience with Skin Complaints' of 166 psoriasis patients (64 women, 102 men) in a 1-year follow-up to assess the relation between these factors over time. The results suggest a more pronounced feeling of discrimination in women with no significant somatic differences between gender at the first measurement. In a prospective evaluation we found a clear proportion of 'discordant' courses of these parameters, mainly in women, indicating a contradictory relation of somatic improvement or deterioration vs subjective experience with skin complaints. All in all, these results show a moderate but significant relevance of skin state for feeling of stigmatization over time only in men, thus suggesting a considerable influence of other psychic variables, probably coping skills, especially in women.

Background: Clinical observations suggest that psychological stress can induce exacerbation of psoriasis. It is hypothesized that these stress effects on the course and outcome of psoriasis are caused by neuroendocrine modulation of immune functions. Therefore we investigated the cardiovascular, endocrine and immunological response to a laboratory stressor in psoriasis patients and healthy controls. Methods: Untreated (n = 7) and PUVA-treated (n = 4) psoriatics and healthy controls (n = 7) were exposed to a brief laboratory stressor (public speaking and mental arithmetic). Heart rate and blood pressure, catecholamine, cortisol, and DHEA plasma concentration, as well as distribution of T and NK lymphocytes were analyzed before, immediately after and 1 h after stress exposure. Results: Heart rate and blood pressure increased in all three groups during stress exposure with the most pronounced changes in PUVA-treated patients. Psoriasis patients displayed higher adrenaline values but diminished cortisol and DHEA plasma concentrations compared to controls. NK cell numbers (CD16⁺, CD56⁺), but not T lymphocyte subsets, increased immediately after stress exposure in untreated patients and controls. This effect was significantly diminished in PUVA-treated patients. Conclusions: The data of this pilot study indicate an enhanced stress-induced autonomic response and diminished pituitary-adrenal activity in psoriasis patients. PUVA treatment seems to interfere with the cardiovascular and NK cell response to acute psychological stress. Future studies will analyze the stress-induced neuroimmunological mechanisms in psoriatics in more detail.

Those patients who had changed to s.c. therapy were highly satisfied. However, others preferred to stay on i.v. treatment for different reasons. Perception of inconvenience, anxiety of side effects, but also personal traits may play a role.

Acute tinnitus can lead to substantial distress and eventually result in long-lasting impairment. The aim of this study was to compare the efficacy of a cognitive-behavioural intervention (delivered as Internet self-management, bibliotherapy or group training) to the information-only control condition. Applicants suffered from subjective tinnitus for up to six months, were between 18 and 75 years old and received no other tinnitus-related psychological treatment. A total of 304 participants were randomly assigned to one of the four study arms. Tinnitus distress, depressive symptoms, psychosomatic discomfort and treatment satisfaction were assessed. At the post-assessment tinnitus distress was significantly lower in the Internet and the group training conditions compared to the control condition. Inter-group effect sizes were moderate to large. At follow-up, all active training conditions showed significantly reduced tinnitus distress compared to the control condition (intention-to-treat analysis). An additional completer analysis showed a significant reduction in tinnitus distress only for the group condition. All effect sizes were moderate. There were no differences regarding psychosomatic discomfort, but depressive symptoms were reduced in the group condition at the post-assessment (intention-to-treat analysis). Treatment satisfaction was significantly higher in the training conditions. The dropout rate was 39%. The present study shows that distress can be reduced as early as the acute stadium and that minimal-contact interventions are a promising way to do this. In particular, the Internet and group conditions led to a large, immediate decrease in distress, and the participants were highly satisfied with the training.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.