[Opportunities and challenges of active patient involvement in clinical research in Germany - from the perspectives of a patient representative, a clinical researcher and two staff members of research funding management]. / Chancen und Herausforderungen der aktiven Beteiligung von Patient*innen an klinischer Forschung in Deutschland ­ Eine Betrachtung aus den Perspektiven eines Patient*innenvertreters, einer klinischen Forscherin und zweier Mitarbeiterinnen des Forschungsfördermanagements.

BACKGROUND: Active involvement of patients in clinical research is increasingly demanded in Germany. It has great potential to increase the quality and relevance of research and to contribute to patient empowerment. However, patients, researchers and research funders have experienced that the implementation of patient involvement is accompanied by cultural, practical and personal challenges. The aim of this article is to discuss the opportunities and challenges of patient involvement in Germany from the perspective of the stakeholders involved. METHOD: A patient representative, a clinical researcher and two staff members from research funding management were invited to discuss the opportunities and challenges of patient involvement. Their perspectives were recorded in two written open survey rounds. The answers were analyzed using qualitative content analysis. RESULT: In the opinion of the stakeholders involved, the increasing involvement of patients in clinical research is an opportunity to promote the practical relevance of research and the implementation of studies, to increase their acceptance by the target group and to improve the uptake of research results in practice. However, the implementation of patient involvement was also perceived as challenging. They described problems with regard to the acquisition and selection of patients, the training of the patients and the specifications and support structures for the implementation of patient involvement. DISCUSSION: While patient involvement in clinical research offers great potential, the development of appropriate structures and framework conditions for its implementation is still virtually unestablished in Germany. This needs to include, among other things, creating a broader awareness of the potential of patient involvement, developing training programs for patients and researchers, providing sufficient, mainly project-independent resources and ensuring regular evaluations.

Children with high-functioning autism show a normal cortisol awakening response (CAR).

Individuals with high-functioning autism spectrum disorders (HFA) show difficulties in the ability to react to change. A recent study suggested that variations in the functioning of the hypothalamus-pituitary-adrenal axis, especially in one of its markers--the cortisol awakening response (CAR)--may be related to those difficulties in adolescents with Asperger's syndrome. The current study investigated the CAR in a younger sample with diagnoses from the whole autism spectrum: A group of children with HFA (N=15) was compared to a group of typically developing children (N=25). Findings suggest that the frequency of a CAR as well as the increase in cortisol levels from awakening to 30 min later were similar between groups, indicating that variations in the CAR in HFA may not be present early in life but only develop later in adolescence or may only occur in some diagnoses from the autism spectrum.

Visuospatial short-term memory explains deficits in tower task planning in high-functioning children with autism spectrum disorder.

Previous findings on planning abilities in individuals with high-functioning autism spectrum disorder (HFA) are inconsistent. Exploring possible reasons for these mixed findings, the current study investigated the involvement of memory in planning performance in 15 children with HFA and 17 typically developing controls. In addition to planning abilities (measured with the Tower of London), short-term memory and delayed recall for verbal as well as visuospatial material were assessed. Findings suggest that particularly reduced efficiency in visuospatial short-term memory is associated with Tower task planning deficits in children with HFA.

The role of the serotonin transporter polymorphism for the endocrine stress response in newborns.

A functional polymorphism in the 5'flanking region of the serotonin transporter gene (17q11.2, 5-HTTLPR) alters the transcription of the 5-HT transporter gene and seems to be associated with depression and anxiety-related personality traits in humans. This effect appears to be the most pronounced in individuals who are homozygous for the low-expressing "S" allele who have experienced significant critical life events in the past. Animal studies now link this polymorphism to an increased stress reactivity of the hypothalamus-pituitary-adrenal (HPA) axis. In humans, it remains unknown whether this polymorphism by itself affects HPA axis or only in interaction with environmental factors. The aim of the present study was to investigate the role of the 5-HTTLPR polymorphism for the HPA axis in humans early in the development at a time when individuals were exposed to very few or no early adverse experiences so far. We genotyped DNA for the 5-HTTLPR polymorphism including the A/G single-nucleotide polymorphism (SNP) in 126 three-day old newborns. The newborn's stress response was stimulated by a heel prick which is a part of a routine medical procedure. The heel prick induced a significant biological (i.e., cortisol) stress response in all newborns. Newborns with the "S/S" genotype showed a significantly higher endocrine response in comparison to newborns with "L/L" or "S/L" genotype. In this sample of newborn babies, the 5-HTTLPR genotype affected the HPA stress response to painful stimulation irrespective of additional influence of pre- or perinatal environmental factors we measured.

The cortisol awakening response (CAR): facts and future directions.

In humans, the secretion of cortisol from the adrenal glands follows a diurnal cycle with a profound increase after awakening. This increase after awakening, a phenomenon termed the cortisol awakening response (CAR), appears to be a distinct feature of the hypothalamus-pituitary-adrenal (HPA) axis, superimposing the circadian rhythmicity of cortisol secretion. Several studies point towards an important role of the hippocampus and, additionally, other brain structures (e. g. amygdala, prefrontal cortex, suprachiasmatic nucleus) in the regulation of the CAR. There is increasing knowledge that the CAR is influenced by a variety of factors such as gender, health status, and health behavior or stress perception. However, the exact function of the profound cortisol increase after awakening is still not clarified. We hypothesize that the anticipation of the upcoming day is of major relevance for the magnitude of the CAR. The present paper reviews the current knowledge on the neural regulation of the CAR and factors influencing this phenomenon and considerations are addressed concerning the exact function of the CAR.

Attenuation of the hypothalamic-pituitary-adrenal axis responsivity to the Trier Social Stress Test by the benzodiazepine alprazolam.

Little is known about effects of commonly used anxiolytic drugs on psychologically evoked responses of two major stress systems, the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) axis. The purpose of the present study was to assess effects of the anxiolytic alprazolam on responses of the HPA and the SAM axes to a standardized psychosocial stress protocol, the Trier Social Stress Test (TSST). Forty-six healthy, non-smoking, non-medicated males, aged between 18 and 45 years, were invited once to the laboratory and received a single oral dose of 1mg alprazolam or placebo, respectively, 1h prior to the TSST. The secretion of ACTH, cortisol, epinephrine, norepinephrine as well as changes in heart rate, blood pressure, and psychological states (anxiety, wakefulness, good mood, calmness) in response to the TSST were measured. Subjects pre-treated with alprazolam showed a strongly blunted response of ACTH as well as total and free cortisol to the TSST. Whereas alprazolam-treated subjects displayed significantly lower systolic blood pressure immediately before the TSST, neither the secretion of epinephrine, norepinephrine nor changes of heart rate in response to the stress test differed from placebo-treated subjects. Regarding psychological parameters, alprazolam clearly decreased subjective ratings on the questionnaire scale "wakefulness" and increased ratings on the scale "good mood", whereas ratings on scales assessing "state anxiety" or "agitation" were not affected. In healthy subjects, we observed a dissociation of the effects of alprazolam on the endocrine and the autonomic response to psychosocial stress. The psychological responses seemed to be masked by sedative properties of alprazolam.

A new view on hypocortisolism.

Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post-traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue. This overview will present data on the development, mechanisms and consequences of hypocortisolism on different bodily systems. We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic-pituitary-adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.

Preliminary evidence of altered sensitivity to benzodiazepines as a function of maternal care in the rat.

Variations in maternal care over the first week of life alter the expression of genes encoding for various subunits of the GABA(A)/benzodiazepine (BZ) receptor in the amygdala, a brain region associated with fear behavior. Increased maternal licking/grooming and arched-back nursing are associated with decreased fearfulness and enhanced expression of the subunits that confer BZ sensitivity. In these studies we found that the offspring of high licking/grooming-arched-back nursing mothers also showed increased behavioral sensitivity to acute BZ treatment, suggesting a functional relation between the effect on gene expression and fear behavior.