[Structures and Practice of Psychological Services in Oncological and Diabetological Rehabilitation: Results of a Nationwide Survey]. / Strukturen und Praxis der psychologischen Abteilungen in der onkologischen und diabetologischen Rehabilitation: Ergebnisse einer bundesweiten Befragung.

OBJECTIVE: To study the structural frame conditions and the contents of psychological activity in oncological rehabilitation as well as in rehabilitation of patients with type 2 diabetes. METHODS: We conducted a nationwide survey of psychological services in rehabilitation facilities treating oncological patients and patients with type 2 diabetes. RESULTS: 71 (of 145) oncological and 21 (of 63) diabetological rehabilitation facilities participated in the survey. In both indication areas an average of 1.1 psychologists is in charge of 100 patients. Between some rehabilitation facilities, however, there are considerable differences concerning the psychologist/patient ratio (in oncological rehabilitation facilities: standard deviation (SD)=0.52; in diabetological rehabilitation facilities: SD=0.35). Moreover, there is large heterogeneity among rehabilitation facilities as to the percentages of patients obtaining psychological interventions and the way in which psychological services allocate their working time. CONCLUSION: The general set-up of psychological services in oncological and diabetological rehabilitation facilities (especially the low psychologist/patient ratio in many facilities) can partly be considered insufficient. The heterogeneity with respect to the structural frame conditions and practice of psychological services reveals the low degree of standardization of psychological activity in both indication areas.

[Education, advanced and further training in the field "psychology in rehabilitation"]. / Aus-, Fort- und Weiterbildung "Psychologie in der Rehabilitation"

The commission for vocational training, training and further education of the German Society of Rehabilitation Science tends to discuss and to give recommendations for various professions in rehabilitation. The working group, which is led by J. Bengel/Freiburg and M. Morfeld/Magdeburg-Stendal created an inventory of Rehabilitation Psychology. The training programs for Rehabilitation Psychology at universities and universities of applied science in Germany are based on a job profile of psychologists in medical and vocational rehabilitation. The different universities have diverse priorities focusing on Rehabilitation Psychology. The offer changes because of the adaption of requirements and implementation of Bologna Reform. The training and further education offers are specific and available for large indication areas. Finally outstanding issues and problems are pointed out.

Aging impairs intestinal immunity.

The elderly are characterized by immunosenescence accompanied by high rates of morbidity and mortality associated with infectious diseases. Despite suggestions that the mucosal immune compartment is relatively unaffected by aging, there are marked deficits in the intestinal mucosal immune responses of old animals and elderly humans. Little is known about the mechanism(s) whereby aging disrupts intestinal immunity. However, several events in the genesis of the intestinal immune response may be perturbed during aging. The first step is the uptake of antigens by specialized epithelial cells (M cells) that overlie the domes of Peyer's patches. We are unaware of any studies on the efficacy of antigen uptake in the intestine as a function of age. The effects of aging on the next step, antigen presentation by dendritic cells and lymphocyte isotype switching, have not been resolved. The third event is the maturation of immunoglobulin A (IgA) immunoblasts and their migration from the Peyer's patches to the intestinal mucosa. Quantitative immunohistochemical analyses suggest that the migration of these putative plasma cells to the intestinal effector site is compromised in old animals. Local antibody production by mature IgA plasma cells in the intestinal mucosa constitutes the fourth step. We recently reported that in vitro IgA antibody secretion by intestinal lamina propria lymphocytes from young and senescent rats is equivalent. The last event is the transport of IgA antibodies across the epithelial cells via receptor-mediated vesicular translocation onto the mucosal surface of the intestine. Receptor-binding assays did not detect age-associated declines in receptor number or binding affinity in either rodent or primate enterocytes as a function of donor age. Efforts to identify the mechanism(s) responsible for the age-related decline in intestinal mucosal immune responsiveness may benefit by focusing on the homing of IgA immunoblasts to the effector site.

Kefir milk enhances intestinal immunity in young but not old rats.

The adjuvant effect of kefir fermented milk on the mucosal and systemic immune systems was examined in young (6 mo old) and old (26 mo old) rats. Kefir-fed rats consisted of young or old rats consuming kefir-fermented milk ad libitum on a daily basis in addition to the standard diet, for 28 d. Control rats consumed only the standard diet. The rats were immunized intraduodenally with cholera toxin (CT) on d 7 and 21 and killed on d 28. The nonspecific serum immunoglobulin (Ig)A titers in kefir-fed and control rats did not differ in either age group. The serum anti-CT IgA antibody concentrations were significantly higher in the kefir-fed young rats compared with their age-matched controls (+86%, P: < or = 0.05). This difference was associated with enhanced in vitro antibody secretion by cultured lymphocytes isolated from the Peyer's patches and the intestinal lamina propria (+180%, P: < or = 0.05). These enhanced responses were found only in the young rats. However, the nonspecific serum IgG titer was higher (>120%, P: < or = 0.05) and the anti-CT IgG titer was lower (-80%, P: < or = 0.05), in both young and old kefir-fed rats compared with their respective controls. Nevertheless, these results demonstrate that a kefir-supplemented diet affects the intestinal mucosal and systemic immune responses to intraduodenal CT differently in young and old rats. Most importantly, our data suggest that orally administered kefir enhances the specific intestinal mucosal immune response against CT in young adult, but not in senescent rats.

Liver function and phase I drug metabolism in the elderly: a paradox.

Aging is accompanied by marked changes in the physiology of many organs, as well as in their constituent cells. These nonpathological alterations in structure and/or function may affect normal physiological processes in the elderly (individuals > 65 years), for example drug disposition. The liver plays a major role in drug clearance and aging has been reported to diminish this hepatic capacity, particularly the clearance of drugs that undergo mandatory oxidation by the microsomal cytochrome P450-dependent mono-oxygenase systems. Liver volume and blood flow decline with age in humans and, no doubt, this contributes to the diminished clearance of drugs that exhibit first-pass kinetic profiles. Changes in liver morphology with aging that have been described in rodents are limited to the hepatocytes, for example accumulation of dense bodies and loss of smooth surfaced endoplasmic reticulum. There is no evidence that the increase in intracellular lipofuscin adversely affects hepatocyte functions. A number of studies have documented significant age-related declines in the amounts, specific activities and rates of induction of liver microsomal mono-oxygenases in inbred male rats. On the basis of a variety of clinical tests, most liver functions in humans appear to be well preserved. The most remarkable characteristic of liver function in the elderly is the increase in interindividual variability, a feature that may obscure age-related differences. Most in vitro studies using nonhuman primate or human liver tissue did not detect age-related deficiencies in cytochrome P450-dependent microsomal mono-oxygenases. On the other hand, there have been recent reports of age-related, but not gender-related, declines in the in vitro activities of several human liver mono-oxygenases, for example the cytochrome P450 isoform CYP3A. Nevertheless, reduced liver volume and blood flow in the elderly permit the reconciliation of: the in vivo clinical pharmacokinetic data indicative of reduced hepatic drug clearance; and the absence of significant age-related declines in the amounts or in vitro activities of liver microsomal mono-oxygenases.

Intestinal lymphocyte number, migration and antibody secretion in young and old rats.

This study demonstrates that the mucosal immune response to cholera toxin (CT) is compromised in old rats in comparison with young animals. The total number of immunoglobulin A (IgA)-secreting cells is similar or higher in the intestinal inductor and effector sites in old animals. However, the number of specifically induced anti-CT IgA antibody-secreting cells is lower in these tissues in comparison with those in young animals. The kinetics of this immune response in the different gut-associated lymphoid tissues studied suggests that the age-associated decline in the number of anti-CT IgA-secreting cells in the intestinal mucosa reflects impaired IgA immunoblast migration. Our data from lymphocyte adoptive transfer studies indicate that factors intrinsic to both the donor cells and the host recipient influence the migration of immunoblasts from the Peyer's patches to the effector site. For example, donor cells from old donors transferred to either young or old recipient rats migrate slower than young donor lymphocytes transferred into old host animals. In vitro studies clearly indicate that ageing does not impair antibody secretion by intestinal mucosal plasma cells. Therefore, the age-related decline in the intestinal mucosal immune response, e.g. diminished specific antibody titres in intestinal lavage, reflects fewer antibody-secreting cells in the mucosa.

Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity.

A Drosophila homolog of human Down syndrome cell adhesion molecule (DSCAM), an immunoglobulin superfamily member, was isolated by its affinity to Dock, an SH3/SH2 adaptor protein required for axon guidance. Dscam binds directly to both Dock's SH2 and SH3 domains. Genetic studies revealed that Dscam, Dock and Pak, a serine/threonine kinase, act together to direct pathfinding of Bolwig's nerve, containing a subclass of sensory axons, to an intermediate target in the embryo. Dscam also is required for the formation of axon pathways in the embryonic central nervous system. cDNA and genomic analyses reveal the existence of multiple forms of Dscam with a conserved architecture containing variable Ig and transmembrane domains. Alternative splicing can potentially generate more than 38,000 Dscam isoforms. This molecular diversity may contribute to the specificity of neuronal connectivity.

The Drosophila gene abstrakt, required for visual system development, encodes a putative RNA helicase of the DEAD box protein family.

The molecular mechanisms underlying axonal pathfinding are not well understood. In a genetic screen for mutations affecting the projection of the larval optic nerve we isolated the abstrakt locus. abstrakt is required for pathfinding of the larval optic nerve, and it also affects development in both the adult visual system and the embryonic CNS. Here we report the molecular characterization of abstrakt. It encodes a putative ATP-dependent RNA helicase of the DEAD box protein family, with two rare substitutions in the PTRELA and the RG-D motifs, thought to be involved in oligonucleotide binding: serine for threonine, and lysine for arginine, respectively. Two mutant alleles of abstrakt show amino acid exchanges in highly conserved positions. A glycine to serine exchange in the HRIGR motif, which is involved in RNA binding and ATP hydrolysis, results in a complete loss of protein function; and a proline to leucine exchange located between the highly conserved ATPase A and PTRELA motifs results in temperature-sensitive protein function. Both the broad requirement for abstrakt gene function and its ubiquitous expression are consistent with a molecular function of the abstrakt protein in mRNA splicing or translational control.

Are the elderly underrepresented in clinical drug trials?

In many industrialized nations, the elderly comprise the fastest growing subpopulation and constitute an increasing proportion of the total population compared to other age groups. The elderly use a disproportionately larger amount of health care resources since they experience a higher incidence of disease-related morbidities, consume more drugs, are subject to more extensive multiple medication regimens, and account for more adverse drug events. In response to the great demand for geriatric pharmacotherapy, the pharmaceutical industry has targeted more drugs to the elderly. However, the elderly are too often excluded from clinical trials on drugs primarily destined for their consumption. Comprehensive analyses to assess participation of elderly subjects in clinical drug trials are needed to design and implement trials that will enhance the safety and efficacy of drugs intended for this pharmacologically sensitive subpopulation.

Efficacy of intraduodenal, oral and parenteral boosting in inducing intestinal mucosal immunity to cholera toxin in rats.

Considerable effort has been directed toward developing effective mucosal vaccines, especially those targeted to the intestine, and appropriate delivery systems. Numerous studies have demonstrated that direct immunization of the intestinal mucosa is the most efficient route for generating an intestinal IgA response. The present study examined the effect of three different routes of secondary immunization (boosting), i.e. intraduodenal, oral and parenteral (subcutaneous) on the intensity of the intestinal mucosal immune response in rats subjected to primary intraduodenal immunization with cholera holotoxin. Specific antibody titers and the relative numbers of antibody-secreting cells in the peripheral blood and antibody-containing cells in the intestinal lamina propria concur that vaccination of the intestinal mucosa directly or in combination with an oral boost yields a more vigorous mucosal immune response in comparison to a parenteral boost.

Aging and the liver: an update.

The issue of whether or not liver function is compromised in the elderly population remains unresolved. Numerous age-related changes in hepatic structure and function have been described, but many of these observations are qualitative, were made under suboptimal experimental conditions, or are simply contradictory. Changes in hepato-cellular structural parameters, e.g., increased hepatocyte size, increase in the number of binucleated cells, altered mitochondria, and endoplasmic reticulum, have been reported. However, quantitative morphological analyses have refuted many of these observations. There are few functional data that correlate with structural changes. Serum and biliary cholesterol appear to rise, predisposing elderly people to increased incidences of coronary disease and gallstones, respectively. The rate of liver regeneration declines in old animals, but the regenerative capacity remains unchanged, perhaps reflecting an age-associated reduction in the response to hepatotrophic factors. This senescent change has important clinical implications with regard to surgical intervention for liver disease, e.g., resection or transplantation. Nevertheless, most outcomes studies suggest that age alone should not be a determining factor in such clinical decisions. Geriatric patients exhibit a decline in the hepatic clearance of certain drugs and a marked increase in the frequency of adverse drug reactions, reflecting an increase in polypharmacy regimens and declines in liver volume and blood flow rather than reduced Phase I metabolism. Although the livers of elderly subjects are characterized by a decline in adaptive responsiveness and reduced reserve capacity, clinical tests suggest that liver function is well-maintained in this age group.

Effect of dehydroepiandrosterone (DHEA) on intestinal mucosal immunity in young adult and aging rats.

The present study assesses the effectiveness of oral DHEA on the intestinal mucosal immune response in aging rats. Young adult (6 months) and aging (21 months) female rats received powdered rat chow with or without 0.2% DHEA for 23 days. The animals were immunized intraduodenally with either cholera toxin (CTx) or vehicle alone and boosted two weeks later. Seven days after boosting, serum, bile, small intestinal tissue, and liver were collected for analysis. Anti-CTx IgA antibody titers were measured in serum and bile and the concentration of anti-CTx antibody containing cells (ACCs) in the small intestinal lamina propria and liver were determined by quantitative immunohistochemistry. Intergroup comparisons indicated that there was only one significant difference in serum and none in bile anti-CTx IgA titers between CTx-immunized animals fed DHEA or the diet alone. Immunohistochemical analysis determined that the density and distribution patterns of ACCs within the lamina propria were unaffected by DHEA. Both DHEA-treated and control young immunized animals exhibited similar numbers of ACCs. Only 40% of the aging rats responded to intraduodenal immunization with CTx, as determined by the presence of ACCs in the intestine, regardless of the presence or absence of DHEA in the diet. These data suggest that DHEA in the diet does not enhance the intestinal mucosal immune response to intraduodenal CTx in either young adult or aging rats.

Direct regulation of rhodopsin 1 by Pax-6/eyeless in Drosophila: evidence for a conserved function in photoreceptors.

Pax-6 is a transcription factor containing both a homeodomain (HD) and a Paired domain (PD). It functions as an essential regulator of eye development in both Drosophila and vertebrates, suggesting an evolutionarily conserved origin for different types of metazoan eyes. Classical morphological and phylogenetic studies, however, have concluded that metazoan eyes have evolved many times independently. These apparently contradictory findings may be reconciled if the evolutionarily ancient role of Pax-6 was to regulate structural genes (e.g., rhodopsin) in primitive photoreceptors, and only later did it expand its function to regulate the morphogenesis of divergent and complex eye structures. In support of this, we present evidence that eyeless (ey), which encodes the Drosophila homolog of Pax-6, directly regulates rhodopsin 1 (rh1) expression in the photoreceptor cells. We detect ey expression in both larval and adult terminally differentiated photoreceptor cells. We show that the HD of Ey binds to a palindromic HD binding site P3/RCS1 in the rh1 promoter, which is essential for rh1 expression. We further demonstrate that, in vivo, P3/RCS1 can be replaced by binding sites specific for the PD of Ey. P3/RCS1 is conserved in the promoters of all Drosophila rhodopsin genes as well as in many opsin genes in vertebrates. Mutimerized P3 sites in front of a basal promoter are able to drive the expression of a reporter gene in all photoreceptors. These results suggest that Pax-6/Ey directly regulates rhodopsin 1 gene expression by binding to the conserved P3/RCS1 element in the promoter.

Genetic analysis of the larval optic nerve projection in Drosophila.

The Drosophila larval optic nerve, called Bolwig's nerve (BN), projects into the central brain along a simple invariant path. The growth of the BN proceeds in three phases, during which the nerve changes direction at two intermediate targets, P1 and P2. Here we show that the projection of the BN is amenable to genetic dissection. In a mutagenesis screen, we have isolated mutations in 13 genes that disrupt the BN projection in distinct phases of its development. The mutant phenotypes in combination with the expression patterns of corresponding candidate genes define cellular components necessary for directing the growth of the BN toward P2 and for redirecting its growth at P2, and reveal developmental strategies employed in the establishment of the BN projection.

Impact of aging on gastrointestinal mucosal immunity.

There is considerable evidence that the mucosal or secretory immune response in the gastrointestinal tract is compromised by aging. The generation of a mucosal immune response is an extremely complex process that involves antigenic stimulation of a specific subpopulation of immunologically competent cells in the Peyer's patches, differentiation and migration of these cells to the small intestinal lamina propria, initiation and regulation of local antibody production in the intestinal wall, and mucosal epithelial cell receptor-mediated transport of antibodies to the intestinal lumen. Available data suggest that gastrointestinal mucosal immunosenescence reflects deficits in: (1) the differentiation and/or migration (homing) of immunoglobulin A immunoblasts to the intestinal lamina propria, and (2) the initiation and/or regulation of local antibody production. The significant age-related increases in the incidence and severity of gastrointestinal infectious diseases, coupled with the potential for immunopharmacologic manipulation of the mucosal immune compartment, substantiate the merit of studies designed to resolve the etiology of mucosal immunodeficiency in the elderly.

Characterization of the independent and combined effects of two inhibitors on oxidative drug metabolism in rat liver microsomes.

To evaluate how two inhibitors influence oxidative drug metabolism, this study investigated the inhibitory effects of mexiletine with cimetidine and mexiletine with lidocaine, both individually and in combination, on the oxidative metabolism of two probe substrates, aminopyrine and aniline in rat liver microsomes. Mexiletine was a competitive inhibitor of aminopyrine N-demethylation, whereas cimetidine was a mixed type of inhibitor (Ki = 2.00 +/- 0.04 and 0.20 +/- 0.02 mM, respectively). For aniline hydroxylation, mexiletine exhibited a mixed type of inhibition, whereas lidocaine was a noncompetitive inhibitor (Ki = 0.60 +/- 0.07 and 8.50 +/- 0.12 mM, respectively). The combined inhibition of either mexiletine with cimetidine or mexiletine with lidocaine on aminopyrine and aniline metabolism was close to the fully additive effects of the individual compounds when their individual concentrations were below a 2-fold Ki concentration, regardless of the apparent kinetic inhibition type. The combined inhibition was less than fully additive when the individual concentrations were twice the Ki or above. These results demonstrate that, when two inhibitors of oxidative drug metabolism are combined, both the Ki values and the concentrations of inhibitors play important roles in determining the extent of additive inhibition of enzyme activity.

Aging effects on hepatic NADPH cytochrome P450 reductase, CYP2B1&2, and polymeric immunoglobulin receptor mRNAs in male Fischer 344 rats.

Aging perturbs the expression of many liver proteins, but the mechanisms remain unresolved. Expression of hepatic NADPH cytochrome P450 reductase, phenobarbital-induced CYP2B1&2, and the polymeric immunoglobulin receptor (pIgR) decline as a function of aging. We examined the effect of aging on the expression of the mRNA transcripts of these proteins, as well as those of alpha 2u-globulin and beta-actin in male F344 rats. Despite age-related losses in the expression of P450 reductase and plasma membrane-bound pIgR in the rat liver (approximately 30-50%), aging is is accompanied by 1) no change and 2) a modest decline (< 20%) in their respective mRNA steady state levels. On the other hand, the expression of phenobarbital-induced microsomal CYP2B1&2 and the steady state level of its mRNA exhibit parallel age-dependent shifts. The mRNA transcript for alpha 2u-globulin declines between maturity and old age, whereas the beta-actin mRNA level remains unchanged. These preliminary data are consistent with previous studies which suggest that aging may perturb hepatic CYP2B1&2 and alpha 2u-globulin at the transcriptional level, whereas changes in the expression of P450 reductase and pIgR may reflect posttranscriptional modifications.