[Admission and discharge decisions in psychiatric hospitals : The 7-day cycle: analysis based on the VIPP database]. / Aufnahme- und Entlassentscheidungen in der Psychiatrie : Der 7-Tage-Zyklus: Analyse auf Grundlage der VIPP-Datenbank.

BACKGROUND: The legislation requires all scientific societies in the field of inpatient psychiatric and psychosomatic healthcare to survey and assess the effects and financial incentives of the new flat rate day-based remuneration system in psychiatric and psychosomatic facilities (PEPP system). As day-based remuneration systems may be an incentive to extend treatment, it is necessary to measure and analyze the future development of the number of cases and the duration of treatment. OBJECTIVES: This article surveys admission and discharge decisions of psychiatric and psychosomatic facilities. The distribution of admissions and discharges throughout the days of the week were analyzed to search for evidence of a systematic extension of treatment over the weekend. MATERIAL AND METHODS: The analysis is based on data from the Versorgungsrelevante Indikatoren in der Psychiatrie und Psychosomatik (VIPP, treatment-relevant indicators in psychiatry and psychosomatics) project database, which contains routine data from psychiatric and psychosomatic facilities. On this basis the distributions of admissions and discharges throughout the days of the week were analyzed on aggregate and diagnosis-specific levels. RESULTS: Patients were mostly admitted to hospitals within the first 3 weekdays. The discharge mostly took place on Fridays and not as a financial incentive on Mondays. Regarding the patient length of stay a 7-day cycle can be observed, which may indicate the importance of medical and organizational factors in discharge decisions. CONCLUSION: The results do not show evidence for a systematic extension of treatment over the weekend. Over the next years it will be important to observe the development of the duration of treatment and the number of cases to assess the influence of the economic incentives of the PEPP system on the utilization of psychiatric and psychosomatic healthcare.

[The new payment system in psychiatry - do elderly people belong to the losers? An analysis on the basis of the VIPP1 data base]. / Das neue Entgeltsystem in der Psychiatrie - gehören ältere Patienten zu den Verlierern? Eine Analyse auf der Grundlage der VIPP-Datenbank.

The development of the lump-sum reimbursement System in psychiatry and psychosomatics (PEPP) (Klimke et al., 2014) is being negatively considered - also in gerontopsychiatry.Thus it is reasonable to make a timely analysis of the effects of PEPP on health-care structures. For this two analyses have been carried out. On the one hand the day mix index of elderly patients (> 64 years) was compared with that of younger ones (> 17 years, < 65 years). On the other hand younger and older were included in the analysis with regard to the available treatment minutes in exact daily classifications according to the PsychPV. It is seen that evaluation of the individual day was markedly higher for gerontopsychiatric patients not only in inpatient (difference > 0.1) but also in outpatient (difference > 0.07) setting. The exact daily classifications according to PsychPV, however, were markedly poorer for the elderly patients. Thus, on the basis of routine data of VIPP projects, a clear change can be seen in favour of the elderly patient under PEPP conditions as compared to financing according to PsychPV. However, concern remains that the ageing population and modernisation of therapy are not being sufficiently taken into account. The new reimbursement system merely regulates the distribution of available resources; if these resources are too low nothing will change by the PEPP-System.

Investigation of volatile metabolites during growth of Escherichia coli and Pseudomonas aeruginosa by needle trap-GC-MS.

A new method for the growth-dependent headspace analysis of bacterial cultures by needle trap (NT)-gas chromatography-mass spectrometry (GC-MS) was established. NTs were used for the first time as enrichment technique for volatile organic compounds (VOCs) in the headspace of laboratory cultures. Reference strains of Escherichia coli and Pseudomonas aeruginosa were grown in different liquid culture media for 48 h at 36 °C. In the course of growth, bacterial culture headspace was analysed by NT-GC-MS. In parallel, the abiotic release of volatile organic compounds (VOC) from nutrient media was investigated by the same method. By examination of microbial headspace samples in comparison with those of uninoculated media, it could be clearly differentiated between products and compounds which serve as substrates. Specific microbial metabolites were detected and quantified during the stationary growth phase. P. aeruginosa produced dimethyl sulfide (max. 125 µg L(-1) < limits of quantification (LOQ)), 1-undecene (max. 164 µg L(-1)) and 2-nonanone (max. 200 µg L(-1)), whereas E. coli produced carbon disulfide, butanal and indole (max. 149 mg L(-1)). Both organisms produced isoprene.

Dietary flavonoids do not affect vitamin E status in growing rats.

This study aimed at investigating potential effects of the flavonoids genistein, quercetin and catechin and the role of co-ingested dietary fat on vitamin E concentrations in rats. In experiment 1, genistein, quercetin and catechin were fed to rats, incorporated into semisynthetic diets at concentrations of 2 g/kg, either as individual compounds or in combination to investigate their individual and possible synergistic actions towards alpha-tocopherol in plasma and selected tissues. For experiments 2 and 3, quercetin was selected as a representative model flavonoid to study the effects of the quantity (5% vs. 10%) and type of dietary fat (coconut fat plus corn oil vs. rapeseed oil; experiment 2) and the role of cholesterol (experiment 3) on potential flavonoid-vitamin E interactions. The concentrations of alpha-tocopherol and gamma-tocopherol in the plasma, liver, lung and cortex of flavonoid-fed rats were not significantly different from the concentrations measured in control rats in all three experiments. However, increasing the amount of coconut fat plus corn oil from 5 to 10% resulted in lower alpha-tocopherol concentrations in plasma and tissue. The alpha-tocopherol concentrations in the rats fed rapeseed oil were significantly higher than in rats fed coconut fat plus corn oil. The addition of 0.2% cholesterol to the diet did not influence the tocopherol concentrations in plasma and tissue in both quercetin-supplemented and control rats. Additionally, the mRNA levels of alpha-TTP, CYP3A4, CYP4F and Mdr2, which are integral proteins involved in vitamin E homeostasis were measured. Only genistein reduced the Mdr2 mRNA level, but none of the other transcripts. All other flavonoids were without effect. In conclusion, co-ingested dietary fat appears to influence vitamin E concentrations in rats, but does not seem to be an important determinant of flavonoid-vitamin E interactions.

FTY720 pharmacokinetics in mild to moderate hepatic impairment.

The influence of mild and moderate hepatic impairment on FTY720 pharmacokinetics was assessed. The authors enrolled 32 subjects consisting of 8 with mild and 8 with moderate hepatic impairment based on Child-Pugh criteria and 16 demographically matched control subjects. A single 1-mg oral dose of FTY720 was administered under fasting conditions. Blood, plasma, and urine samples were obtained over a 14-day period for measurement of FTY720 and metabolite concentrations and protein binding. Total blood lymphocyte counts and heart rate were serially monitored to assess pharmacologic responses to FTY720. Peak FTY720 blood concentrations were similar across groups. Oral clearance (CL/F) was reduced 10% in mild hepatic impairment (P = .493) and 31% in moderate hepatic impairment (P = .034). There were no significant differences in blood exposure to the hexanoic or butanoic acid metabolites among groups. The effect of FTY720 on blood lymphocytes was similar across groups, with a mean decrease of 44% from the predose value. Like-wise, the effect of FTY720 on supine heart rate was similar across groups, with a mean 13% decrease from the predose rate occurring 2 to 4 hours postdose and recovering within 1 to 2 days. Although hepatic impairment elicited changes in the disposition of FTY720, the magnitude of these changes suggests that the FTY720 dose does not need to be adjusted in mild or moderate hepatic-impaired patients.

Using viral species specificity to define a critical protein/RNA interaction surface.

The Tap protein mediates the sequence-specific nuclear export of mRNAs bearing the retroviral constitutive transport element (CTE) and also plays a critical role in the sequence nonspecific export of cellular mRNAs. Previously, we have demonstrated that CTE function displays species specificity, that is, the CTE functions in human but not quail cells. Here, we demonstrate that quail Tap fails to support CTE function because it cannot bind the CTE. However, changing a single residue in quail Tap, glutamine 246, to arginine, the residue found in human Tap, rescues both CTE function and CTE binding. This residue, which is located on the exterior of a recently reported molecular structure of Tap, defines a surface on Tap that is critical for CTE binding. These data emphasize the potential importance of cross-species genetic complementation in the identification and characterization of cellular factors that are critical for different aspects of viral replication.

Scientific analysis of the proposed uses of the T25 dose descriptor in chemical carcinogen regulation.

The uncertainties that surround the methods used for risk assessment of exposure to carcinogens have been highlighted by a recent document advocating an approach based on the T25 dose (the dose giving a 25% incidence of cancer in an appropriately designed animal experiment). This method relies on derivation of the T25 dose then assesses risk at the exposure dose using proportionality provided by a linear extrapolation (T25/linear). To promote discussion of the scientific issues underlying methods for the risk assessment of chemical carcinogens, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) hosted a one-day workshop in Brussels on 10 November 2000. Several invited presentations were made to participants, including scientists from regulatory authorities, industry and academia. In general, it was felt that there was sufficient basis for using the T25 dose as an index of carcinogenic potency and hence as part of the hazard assessment process. However, the use of the T25 in risk assessment has not been validated. The T25/linear and other extrapolation methods based on metrics such as LED 10 assume linearity which may be invalid. Any risk calculated using the T25/linear method would provide a precise risk figure similar to the output obtained from the Linearised Multistage (LMS) method formerly used by the Environmental Protection Agency (EPA) in the United States of America. Similarity of output does not provide validation but rather reflects their reliance on similar mathematical approaches. In addition to the T25 issue, evidence was provided that using two separate methods (linearised non-threshold model for genotoxic carcinogens; no-observable-effect level with a safety factor (NOEL/SF) method for all other toxicity including non-genotoxic carcinogens) is not justified. Since the ultimate purpose of risk assessment is to provide reliable information to risk managers and the public, there was strong support at the workshop for harmonisation of approaches to risk assessment for all genotoxic and nongenotoxic carcinogens. In summary, the T25 method has utility for ranking potency to focus efforts in risk reduction. However, uncertainties such as the false assumption of precision and non-linearity in the dose-response curve for tumour induction raise serious concerns that caution against the use of T25/linear method for predicting human cancer risk.

Mutational definition of functional domains within the Rev homolog encoded by human endogenous retrovirus K.

Nuclear export of the incompletely spliced mRNAs encoded by several complex retroviruses, including human immunodeficiency virus type 1 (HIV-1), is dependent on a virally encoded adapter protein, termed Rev in HIV-1, that directly binds both to a cis-acting viral RNA target site and to the cellular Crm1 export factor. Human endogenous retrovirus K, a family of ancient endogenous retroviruses that is not related to the exogenous retrovirus HIV-1, was recently shown to also encode a Crm1-dependent nuclear RNA export factor, termed K-Rev. Although HIV-1 Rev and K-Rev display little sequence identity, they share the ability not only to bind to Crm1 and to RNA but also to form homomultimers and shuttle between nucleus and cytoplasm. We have used mutational analysis to identify sequences in the 105-amino-acid K-Rev protein required for each of these distinct biological activities. While mutations in K-Rev that inactivate any one of these properties also blocked K-Rev-dependent nuclear RNA export, several K-Rev mutants were comparable to wild type when assayed for any of these individual activities yet nevertheless defective for RNA export. Although several nonfunctional K-Rev mutants acted as dominant negative inhibitors of K-Rev-, but not HIV-1 Rev-, dependent RNA export, these were not defined by their inability to bind to Crm1, as is seen with HIV-1 Rev. In total, this analysis suggests a functional architecture for K-Rev that is similar to, but distinct from, that described for HIV-1 Rev and raises the possibility that viral RNA export mediated by the approximately 25 million-year-old K-Rev protein may require an additional cellular cofactor that is not required for HIV-1 Rev function.

Functional differences between human and bovine immunodeficiency virus Tat transcription factors.

Transcriptional transactivation of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) promoter element by the essential viral Tat protein requires recruitment of positive transcription elongation factor b (P-TEFb) to the viral TAR RNA target. The recruitment of P-TEFb, which has been proposed to be necessary and sufficient for activation of viral gene expression, is mediated by the highly cooperative interaction of Tat and cyclin T1, an essential component of P-TEFb, with the HIV-1 TAR element. Species, such as rodents, that encode cyclin T1 variants that are unable to support TAR binding by the Tat-cyclin T1 heterodimer are also unable to support HIV-1 Tat function. In contrast, we here demonstrate that the bovine immunodeficiency virus (BIV) Tat protein is fully able to bind to BIV TAR both in vivo and in vitro in the absence of any cellular cofactor. Nevertheless, BIV Tat can specifically recruit cyclin T1 to the BIV TAR element, and this recruitment is as essential for BIV Tat function as it is for HIV-1 Tat activity. However, because the cyclin T1 protein does not contribute to TAR binding, BIV Tat is able to function effectively in cells from several species that do not support HIV-1 Tat function. Thus, BIV Tat, while apparently dependent on the same cellular cofactor as the Tat proteins encoded by other lentiviruses, is nevertheless unique in terms of the mechanism used to recruit the BIV Tat-cyclin T1 complex to the viral LTR promoter.

An ancient family of human endogenous retroviruses encodes a functional homolog of the HIV-1 Rev protein.

The human endogenous retrovirus K (HERV-K) family of endogenous retroviruses consists of approximately 50 proviral copies per haploid human genome. Herein, the HERV-Ks are shown to encode a sequence-specific nuclear RNA export factor, termed K-Rev, that is functionally analogous to the HIV-1 Rev protein. Like HIV-1 Rev, K-Rev binds to both the Crm1 nuclear export factor and to a cis-acting viral RNA target to activate nuclear export of unspliced RNAs. Surprisingly, this HERV-K RNA sequence, which is encoded within the HERV-K long terminal repeat, is also recognized by HIV-1 Rev. These data provide surprising evidence for an evolutionary link between HIV-1 and a group of endogenous retroviruses that first entered the human genome approximately 30 million years ago.

Determination of the functional domain organization of the importin alpha nuclear import factor.

Although importin alpha (Imp alpha) has been shown to act as the receptor for basic nuclear localization signals (NLSs) and to mediate their recruitment to the importin beta nuclear import factor, little is known about the functional domains present in Imp alpha, with the exception that importin beta binding is known to map close to the Imp alpha NH2 terminus. Here, we demonstrate that sequences essential for binding to the CAS nuclear export factor are located near the Imp alpha COOH terminus and include a critical acidic motif. Although point mutations introduced into this acidic motif inactivated both CAS binding and Imp alpha nuclear export, a putative leucine-rich nuclear export signal proved to be neither necessary nor sufficient for Imp alpha nuclear export. Analysis of sequences within Imp alpha that bind to the SV-40 T antigen NLS or to the similar LEF-1 NLS revealed that both NLSs interact with a subset of the eight degenerate armadillo (Arm) repeats that form the central part of Imp alpha. However, these two NLS-binding sites showed only minimal overlap, thus suggesting that the degeneracy of the Arm repeat region of Imp alpha may serve to facilitate binding to similar but nonidentical basic NLSs. Importantly, the SV-40 T NLS proved able to specifically inhibit the interaction of Imp alpha with CAS in vitro, thus explaining why the SV-40 T NLS is unable to also function as a nuclear export signal.

Inhibition of long-term potentiation in developing rat visual cortex but not hippocampus by in utero exposure to polychlorinated biphenyls.

The neurotoxic potential of polychlorinated biphenyls (PCBs) depends on the structure of the congener as well as on the age of the exposure. We exposed rats prenatally to a coplanar congener (PCB-77) or to a non-coplanar congener (PCB-47) and measured the amount of long-term potentiation (LTP) at postnatal days 11-19 in the visual cortex and hippocampus. While PCB-77 exposure affected LTP statistically significantly in cortical but not hippocampal slices, the exposure to PCB-47 was much less effective.

Synaptic plasticity in the CA1 and CA3 hippocampal region of pre- and postnatally lead-exposed rats.

The effects of low level lead exposure on synaptic plasticity in hippocampal regions CA1 and CA3 were determined in adult rats in vitro. In the CA3 region the NMDA (N-methyl-D-aspartate)-independent mossy fiber-CA3 synapse potentiation was not influenced by chronic pre- and postnatal lead exposure, while in the same rats, in the CA1 region the NMDA-dependent long-term potentiation was slightly reduced as compared to controls. Paired-pulse facilitation was neither impaired in CA1 nor in CA3 region in the lead-exposed rats. These findings suggest that NMDA-dependent forms of synaptic plasticity are more susceptible to chronic low level lead exposure than NMDA-independent forms of potentiation or paired-pulse facilitation.

Blockade of voltage-operated calcium channels, increase in spontaneous catecholamine release and elevation of intracellular calcium levels in bovine chromaffin cells by the plant alkaloid tetrandrine.

Experiments were performed in bovine chromaffin cells in short term primary culture. Tetrandrine is a plant alkaloid from the chinese medical herb Stefania tetrandra. The aim of the present study was to investigate the mechanisms by which tetrandrine interacts with calcium signalling and to provide a quantitative description of effects. Tetrandrine blocked voltage-operated calcium channel currents concentration-dependently as shown in whole cell patch-clamp recordings. The blockade of calcium channels reduced the potassium-stimulated catecholamine release. Besides, the drug increased the spontaneous (not stimulated) release of catecholamines in the presence of extracellular calcium. Measurements of intracellular calcium levels [Ca]i showed a calcium release from intracellular stores by tetrandrine. This tetrandrine-induced [Ca]i elevation was higher in calcium containing as compared to calcium free solution. Tetrandrine effects partially overlap with those of thapsigargin, but tetrandrine has additional targets, since it increased [Ca]i in cells pretreated with thapsigargin. We conclude that tetrandrine blocks voltage-operated calcium channels and increases [Ca]i by blocking endoplasmic and other calcium pumps.

Visual functions in 6-year-old children in relation to lead and mercury levels.

Within a larger comparative environmental health screening program in East and West Germany we investigated functions of the developing visual system in field experiments in a total of 384 children living in three different areas. Visual functions were assessed neurophysiologically by visual-evoked potentials (VEPs) and psychophysically by measuring the contrast sensitivity (CS). Blood lead concentrations and urinary mercury levels were used as markers of environmental and/or amalgam-derived exposure, respectively. The relationships among lead and mercury concentrations and the neurophysiological and psychophysical outcomes were investigated by means of linear regression analysis. After adjusting for confounding effects, statistically significant lead-related changes were found only for some of the VEP interpeak latencies, while some of the CS values were significantly reduced with increasing mercury concentrations. All other outcome variables were not significantly related to lead or mercury levels. It is concluded that even at blood lead levels in the range of 14 to 174 micrograms/l and at very low urinary mercury levels subtle changes in visual system functions can be measured.

A 50 kilodalton protein associated with raf and pp60(v-src) protein kinases is a mammalian homolog of the cell cycle control protein cdc37.

Several oncogenic protein kinases including c-raf-1 and pp60(v-src) are known to directly interact with the 90 kDa heat shock protein (hsp90)/p50 complexes. Using a monoclonal antibody to detect p50 during a purification scheme, p50 was purified to homogeneity. Internal amino acid sequence information was obtained and used to clone a partial cDNA. Comparison of the p50 sequence to other cloned proteins revealed 89% homology with a glycosaminoglycan-binding protein and 54% homology with Drosophila cell cycle control protein (cdc) 37. Monoclonal and polyclonal antibodies were produced against a cleaved fusion protein that recognizes p50 with a high level of specificity. These antibodies recognize the 50 kDa protein present in c-raf-1 and pp60(v-src) complexes. No other proteins were recognized with these antibodies suggesting that p50 is a unique protein. Immunocytochemical visualization of p50 in NIH 3T3 cells indicates a primarily cytoplasmic localization around the nuclear membrane. A survey of p50 expression in murine tissues on a protein blot revealed the following relative levels of expression; thymus > spleen > brain > heart > kidney > liver > lung > skeletal muscle. These results link studies demonstrating complexation of certain kinases with hsp90/p50 in mammalian cells and a number of reports in yeast and Drosophila, demonstrating the importance of cdc37 in cell cycle and kinase function.

Congener specific effects by polychlorinated biphenyls on catecholamine content and release in chromaffin cells.

The effects of the non-planar polychlorinated biphenyl (PCB) congener 2,2',4,4'-tetrachlorobiphenyl (2,4-TCB) and of the coplanar PCB congener 3,3',4,4'-tetrachlorobiphenyl (3,4-TCB) were investigated on the catecholamine content and release from bovine adrenal chromaffin cells in culture. Each congener was tested at three concentrations (20, 50 and 100 microM) and two exposure periods (24 h and 5 days). Catecholamine release induced by K(+)-stimulation as well as catecholamine content of Triton X-100 treated cell cultures were examined using high-performance liquid chromatography (HPLC). 2,4-TCB showed dose- and time-dependent effects. 2,4-TCB at 100 microM reduced the K(+)-stimulated catecholamine release after 24 h of exposure. After 5 days of exposure, 2,4 TCB at 50 and 100 microM drastically reduced the K(+)-stimulated catecholamine release. 3,4-TCB even at a concentration of 100 microM over exposure of either 24 h or 5 days had no effects on the K(+)-stimulated secretion. When chromaffin cells, exposed to 2,4-TCB, were lysed with 0.5% Triton X-100, a dose- and time-dependent reduction of the catecholamine content appeared. The 3,4-TCB did not reduce the catecholamine content. Conversely there seemed to be a trend towards an increase in catecholamine content. Spontaneous release of catecholamines was strongly increased by the non-planar 2,4 TCB, while the coplanar 3,4 TCB showed no effects on this parameter. Furthermore, the effects of 2,4 TCB appeared to be reversible after replacing the highest concentration (100 microM) of the TCB-solution with culture-medium at the end of the 24-h exposure. Thus, K(+)-stimulated catecholamine release and the catecholamine content of bovine adrenal chromaffin cells was effectively reduced by the non-planar PCB congener whereas spontaneous catecholamine release was strongly increased. The coplanar PCB congener was ineffective at the same conditions.