The validity of self-rated psychotic symptoms in depressed inpatients.

BACKGROUND: Self-ratings of psychotic experiences might be biased by depressive symptoms. METHOD: Data from a large naturalistic multicentre trial on depressed inpatients (n=488) who were assessed on a biweekly basis until discharge were analyzed. Self-rated psychotic symptoms as assessed with the 90-Item Symptom Checklist (SCL-90) were correlated with the SCL-90 total score, the SCL-90 depression score, the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale 21 item (HAMD-21) total score, the Montgomery Åsberg Depression Rating Scale (MADRS) total score and the clinician-rated paranoid-hallucinatory score of the Association for Methodology and Documentation in Psychiatry (AMDP) scale. RESULTS: At discharge the SCL-90 psychosis score correlated highest with the SCL-90 depression score (0.78, P<0.001) and with the BDI total score (0.64, P<0.001). Moderate correlations were found for the MADRS (0.34, P<0.001), HAMD (0.37, P<0.001) and AMDP depression score (0.33, P<0.001). Only a weak correlation was found between the SCL-90 psychosis score and the AMDP paranoid-hallucinatory syndrome score (0.15, P<0.001). Linear regression showed that change in self-rated psychotic symptoms over the treatment course was best explained by a change in the SCL-90 depression score (P<0.001). The change in clinician-rated AMDP paranoid-hallucinatory score had lesser influence (P=0.02). CONCLUSIONS: In depressed patients self-rated psychotic symptoms correlate poorly with clinician-rated psychotic symptoms. Caution is warranted when interpreting results from epidemiological surveys using self-rated psychotic symptom questionnaires as indicators of psychotic symptoms. Depressive symptoms which are highly prevalent in the general population might influence such self-ratings.

Relationship between baseline severity of depression and antidepressant treatment outcome.

INTRODUCTION: Assessment of depression severity is of key importance, since several clinical guidelines recommend choice of treatment dependent on the depression severity grade. Using different tools to assess baseline severity may result in different outcomes. METHODS: This paper describes the results of a multicentre, naturalistic study investigating the relationship between depression symptom severity (using 4 different measures of symptom severity) and clinical outcome among patients hospitalised for depression (N=1 014). Moreover, the impact of differences between methods of measuring depression severity has been investigated. Statistical analyses (univariate measurements, logistic regression models) were conducted to detect coherences and differences between the various methods of severity categorisation. RESULTS: Results revealed different associations between outcome and classification methods. Response or remission rates varied if baseline severity was assessed by different instruments. Moreover, the number of responders increased with higher baseline severity grades of depression, whereas the number of remitters decreased. Additional analyses dependent on outcome criteria using continuous instead of categorical data revealed similar results. DISCUSSION: Baseline severity may be only one of many other important clinical variables that mediate clinical outcome, but it is surely an important one deserving further research and consideration.

Towards systemic theories in biological psychiatry.

Although still rather controversial, empirical data on the neurobiology of schizophrenia have reached a degree of complexity that makes it hard to obtain a coherent picture of the malfunctions of the brain in schizophrenia. Theoretical neuropsychiatry should therefore use the tools of theoretical sciences like cybernetics, informatics, computational neuroscience or systems science. The methodology of systems science permits the modeling of complex dynamic nonlinear systems. Such procedures might help us to understand brain functions and the disorders and actions of psychiatric drugs better.

Studies on the chemopreventive potentials of vegetable oils and unsaturated fatty acids against breast cancer carcinogenesis at initiation.

The effect of dietary fat on breast cancer is a longstanding and an unresolved issue. We found that 17beta-estradiol (E2) could be activated by the epoxide-forming oxidant dimethyldioxirane (DMDO) to bind DNA-forming DNA adducts both in vitro and in vivo, and to inhibit nuclear RNA synthesis. We proposed that E2 epoxidation is the underlying mechanism for the initiation of breast cancer carcinogenesis (Carcinogenesis 17, 1957-61, 1996). This report is on the transcriptional and DNA-binding properties of vegetable oils and fatty acids, and on the potentials of these compounds to prevent the formation of E2 epoxide. The results show that vegetable oils, having no effect on nuclear RNA synthesis either before or after DMDO treatment, were all able to prevent the formation of E2 epoxide independent of their mono- or polyunsaturated fatty acid content. Similarly, unsaturated fatty acids, regardless of chain length and number of double bonds, were all able to prevent the formation of E2 epoxide as reflected by the loss of the ability of [3H]E2 to bind DNA. In contrast to vegetable oils, the results indicated that the unsaturated fatty acids palmitoleic, oleic, linoleic, linolenic and arachidonic acid could be activated by DMDO to inhibit nuclear RNA synthesis, and that the mono-unsaturated fatty acids (i.e. palmitoleic and oleic acid) were stronger inhibitors than fatty acids with more than one double bond (e.g. linoleic, linolenic and arachidonic acid). [32P]Post-labeling analysis revealed that under identical DMDO activation, the DNA adducts formed for oleic acid were 17098 adducts/10(8) nucleotides, which was 20-fold more than palmitoleic acid (815), and 120-fold more than alpha-linolenic acid (142). This result strongly suggests that oleic acid could be a potential initiating carcinogen after epoxidation.

Medical students' experiences of diseases in internal medicine in university and community hospitals.

Because medical students in The Netherlands should achieve common national objectives, it is important to know whether clinical experiences in different hospitals are comparable. The research questions were: (1) Do students achieve learning experiences of the required diseases during the internship in Internal Medicine and to what extent do they achieve these experiences? (2) Are there differences between the diseases experienced at a university hospital and at community hospitals? Completed logbooks of students were analysed; the percentage of students that achieved the required diseases and the mean number of experiences of diseases were calculated. A t-test was done to test for differences. Medical students in the university and in community hospitals get broad experience (76-131%) of the required diseases. In both hospitals there are many students who are not achieving the requirements, but the mean number of experiences of students at the community hospitals is higher than those at the university hospital. To eliminate the differences between students from the university hospital and the community hospitals, the educational programmes within both hospitals should be adjusted.

Novel non-nucleoside inhibitors of cytomegaloviruses (BAY 38-4766): in vitro and in vivo antiviral activity and mechanism of action.

For two decades it has been impossible to develop drugs with novel mechanisms of action against herpesviruses, and treatment has been confined largely to the use of inhibitors of viral DNA polymerase. As a representative of a novel inhibitory approach, the non-nucleosidic BAY 38-4766 was identified as a highly selective inhibitor of human cytomegalovirus (HCMV). The compound selectively inhibits not only HCMV strains, including ganciclovir-resistant, ganciclovir/foscarnet and ganciclovir/cidofovir double-resistant clinical isolates, but also a number of monkey and rodent cytomegaloviruses. In a murine cytomegalovirus (MCMV) pathogenicity model in mice, antiviral efficacy and excellent tolerability were demonstrated. BAY 38-4766-resistant HCMV and MCMV strains are not cross-resistant to the nucleoside analogues ganciclovir and cidofovir or the pyrophosphate analogue foscarnet, indicating a different mode of action. Mechanistic studies demonstrated that the high selectivity of this drug class is most likely due to the inhibition of a late stage of the viral replication cycle. Sequence analyses of resistant HCMV and MCMV strains revealed mutations in UL89 and UL104, proteins known to be involved in viral DNA cleavage and packaging. Consequently, the drug is highly specific for the viral as opposed to cellular functions, since UL89 is related to a bacteriophage terminase and no human equivalent exists. In addition, because some of the genes of the viral DNA cleavage and packaging complex are highly conserved among herpesviruses, development of broad-spectrum agents covering additional human herpesviruses might be possible using this approach.

msh specifies dorsal cell fate in the Drosophila wing.

Drosophila limbs develop from imaginal discs that are subdivided into compartments. Dorsal-ventral subdivision of the wing imaginal disc depends on apterous activity in dorsal cells. Apterous protein is expressed in dorsal cells and is responsible for (1) induction of a signaling center along the dorsal-ventral compartment boundary (2) establishment of a lineage restriction boundary between compartments and (3) specification of dorsal cell fate. Here, we report that the homeobox gene msh (muscle segment homeobox) acts downstream of apterous to confer dorsal identity in wing development.

Susceptibilities of human cytomegalovirus clinical isolates to BAY38-4766, BAY43-9695, and ganciclovir.

BAY38-4766 and BAY43-9695 are nonnucleosidic compounds with activities against human cytomegalovirus (HCMV). Two phenotypic assays were used to determine the drug susceptibilities of 36 HCMV clinical isolates to the BAY compounds and ganciclovir. Using either assay, both BAY compounds at a concentration of approximately 1 microM inhibited the replication of all 36 HCMV clinical isolates, including 11 ganciclovir-resistant clinical isolates, by 50%.

A novel nonnucleoside inhibitor specifically targets cytomegalovirus DNA maturation via the UL89 and UL56 gene products.

3-Hydroxy-2,2-dimethyl-N-[4([[5-(dimethylamino)-1-naphthyl]sulfonyl]amino)-phenyl]propanamide (BAY 38-4766) is a novel selective nonnucleoside inhibitor of cytomegalovirus (CMV) replication with an excellent safety profile. This compound and structural analogues inhibit neither viral DNA synthesis nor viral transcription and translation. Accumulation of dense bodies and noninfectious enveloped particles coincides with inhibition of both concatemer processing and functional cleavage at intergenomic transitions, pointing to interference with viral DNA maturation and packaging of monomeric genome lengths. Resistant virus populations, including a murine CMV (MCMV) isolate with 566-fold-decreased drug sensitivity, were selected in vitro. Sequencing of the six open reading frames (ORFs) known to be essentially involved in viral DNA cleavage and packaging identified mutations in ORFs UL56, UL89, and UL104. Construction of MCMV recombinants expressing different combinations of murine homologues of mutant UL56, UL89, and UL104 and analysis of drug susceptibilities clearly demonstrated that mutant ORFs UL89 exon II (M360I) and M56 (P202A I208N) individually confer resistance to BAY 38-4766. A combination of both mutant proteins exhibited a strong synergistic effect on resistance, reconstituting the high-resistance phenotype of the in vitro mutant. These findings are consistent with genetic mapping of resistance to TCRB (2,5,6-trichloro-1-beta-D-ribofuranosyl benzimidazole) (P. M. Krosky et al., J. Virol. 72:4721-4728, 1998) and provide further indirect evidence that proteins encoded by UL89 and UL56 function as two subunits of the CMV terminase. While these studies also suggest that the molecular mechanism of BAY 38-4766 is distinct from that of benzimidazole ribonucleosides, they also offer an explanation for the excellent specificity and tolerability of BAY 38-4766, since mammalian DNA does not undergo comparable maturation steps.

Polycomb group repression reduces DNA accessibility.

The Polycomb group proteins are responsible for long-term repression of a number of genes in Drosophila melanogaster, including the homeotic genes of the bithorax complex. The Polycomb protein is thought to alter the chromatin structure of its target genes, but there has been little direct evidence for this model. In this study, the chromatin structure of the bithorax complex was probed with three separate assays for DNA accessibility: (i) activation of polymerase II (Pol II) transcription by Gal4, (ii) transcription by the bacteriophage T7 RNA polymerase (T7RNAP), and (iii) FLP-mediated site-specific recombination. All three processes are restricted or blocked in Polycomb-repressed segments. In contrast, control test sites outside of the bithorax complex permitted Gal4, T7RNAP, and FLP activities throughout the embryo. Several P insertions in the bithorax complex were tested, providing evidence that the Polycomb-induced effect is widespread over target genes. This accessibility effect is similar to that seen for SIR silencing in Saccharomyces cerevisiae. In contrast to SIR silencing, however, episomes excised from Polycomb-repressed chromosomal sites do not show an altered superhelix density.

The reliability of logbook data of medical students: an estimation of interobserver agreement, sensitivity and specificity.

OBJECTIVE: Logbooks are widely used in medical schools as an evaluation tool to assess students' progress towards objectives. To estimate whether students fill in their logbooks reliably, we measured interobserver agreement by comparing doctors' data and students' data. METHOD: Completed logbooks were collected at two subdivisions of the department of Internal Medicine at the University Hospital of Groningen. The logbook contains 231 preprinted diseases. Doctors and students recorded the diseases they had encountered. Interobserver agreement, expressed by the Jaccard coefficient (J), was calculated for the complete set of diseases and for a subset of core diseases. To assess the kinds of errors which students made, sensitivity and specificity were determined. RESULTS: Logbook data of doctors and students are not fully consistent (mean J for the complete set of diseases was.23 and for the core diseases.36). The quality of the logbook data is high in the sense that students do not record many false identifications (mean specificity for the complete set of diseases and for the core diseases were.96 and.93, respectively); the quality is poor in the sense that students do not record all the diseases which could be seen at the department (mean sensitivity for the complete set of diseases is.36 and for the core diseases it is.51). CONCLUSION: This study shows inconsistencies in recording diseases in a logbook by students compared with doctors. In particular the diseases which are present at a department are under-reported by students. Supervision and feedback are important mechanisms to optimize the students' use of (1) all diseases which could be encountered and (2) the logbook.

Inhibition of murine cytomegalovirus and human cytomegalovirus by a novel non-nucleosidic compound in vivo.

Novel non-nucleosidic compounds have recently been identified as potent inhibitors of the human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) in vitro. We have now investigated the antiviral activity of these compounds in MCMV-infected NOD/LtSz-scid/j mice that lack functional T, B and, in contrast to C.B-17/Icr scid/scid mice, natural killer cells, and represent a novel model for cytomegalovirus infection in immunocompromised hosts. BAY 38-4766 (3-hydroxy-2,2-dimethyl-N-[4(([5-(dimethylamino)-1-naphthyl]sulfonyl)amino)- phenyl]propanamide) was identified as the most potent representative of this class of antiviral compounds. Per os administration of BAY 38-4766 at dosages > or = 10 mg/kg body weight led to antiviral effects that were comparable to ganciclovir 9-(1,3-dihydroxy-2-propoxymethyl)-guanine (Cymevene) as measured by survival and levels of viral DNA in organs of infected mice. In order to assess the anti-HCMV activity of BAY 38-4766 in vivo, we used a model, in which HCMV-infected human cells were entrapped in hollow fibers and subsequently transplanted into immunodeficient mice. Using this model, we demonstrated antiviral activity of BAY 38-4766 similar to that of ganciclovir. We conclude that BAY 38-4766 shows potential as an anti-HCMV drug.

Mutations in Drosophila heat shock cognate 4 are enhancers of Polycomb.

The homeotic genes controlling segment identity in Drosophila are repressed by the Polycomb group of genes (PcG) and are activated by genes of the trithorax group (trxG). An F(1) screen for dominant enhancers of Polycomb yielded a point mutation in the heat shock cognate gene, hsc4, along with mutations corresponding to several known PcG loci. The new mutation is a more potent enhancer of Polycomb phenotypes than an apparent null allele of hsc4 is, although even the null allele occasionally displays homeotic phenotypes associated with the PcG. Previous biochemical results had suggested that HSC4 might interact with BRAHMA, a trxG member. Further analyses now show that there is no physical or genetic interaction between HSC4 and the Brahma complex. HSC4 might be needed for the proper folding of a component of the Polycomb repression complex, or it may be a functional member of that complex.

P element homing to the Drosophila bithorax complex.

P elements containing a 7 kb DNA fragment from the middle of the Drosophila bithorax complex insert preferentially into the bithorax complex or into the adjacent chromosome regions. This 'homing' property is similar to that reported for the engrailed promoter (Hama, C., Ali, Z. and Kornberg, T. B. (1990) Genes Dev. 4, 1079-1093). The 7 kb fragment does not contain any known promoter, but it acts as a boundary element separating adjacent segmental domains. An enhancer-trap P element was constructed with the homing fragment and the selectable marker flanked by FRT sites. P insertions can be trimmed down by Flp-mediated recombination to just the lacZ reporter, so that the (beta)-galactosidase pattern is not influenced by sequences inside the P element. Twenty insertions into the bithorax complex express (beta)-galactosidase in segmentally limited patterns, reflecting the segmental domains of the bithorax complex where the elements reside. The mapping of segmental domains has now been revised, with enlargement of the abx/bx, bxd/pbx, and the iab-3 domains. The FRT sites in the P elements permit recombination between pairs of elements on opposite chromosomes, to generate duplications or deletions of the DNA between the two insertion sites. Using this technique, the length of the Ultrabithorax transcription unit was varied from 37 to 138 kb, but there was surprisingly little effect on Ultrabithorax function.

Ligands for the common allosteric site of acetylcholine M2-receptors: development and application.

Ligands for the allosteric site of acetylcholine M2 receptors are able to retard the dissociation of simultaneously bound ligands for the orthosteric site. This effect promotes receptor occupation by the orthosteric ligand. The allosteric effect opens various therapeutic perspectives, e.g., in organophosphorus poisoning. The aim of our studies was to optimize the affinity of the modulators for the common allosteric binding site of muscarinic M2 receptors, the orthosteric site of which was liganded with the N-methylscolopamine. The phthalimido substituted hexane-bisammonium compound W84 served as a starting point. Previous molecular modelling studies revealed two positive charges and two aromatic imides in a sandwich-like arrangement to be essential for a high allosteric potency. A three-dimensional quantitative structure activity relationship (3D QSAR) analysis predicted compounds with substituents of increasing size on the lateral imide moieties to enhance the affinity for the allosteric binding site. Thus, we synthesized and pharmacologically evaluated compounds bearing "saturated" phthalimide moieties as well as phthalimidines with substituents of systematically increasing size in position 3 or on the aromatic ring at one or both ends of the molecule. Within each series, QSAR could be derived: 1. "Saturation" of the aromatic ring of the phthalimide moiety results in less potent compounds. 2. Increasing the size of the substituents in position 3 of the phthalimide enhances the potency. 3. Putting substituents on the aromatic part of the phthalimide increases the potency more effectively: the introduction of a methyl group in position 5 gave a compound with a potency in the nanomolar concentration range which was subsequently developed as the first radioligand for the allosteric binding site.

Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors.

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are known to have a rather high affinity for the allosteric site of muscarinic M2 receptors. In order to get more insight into the contribution of the lateral substituents for alloster binding affinity, a series of compounds with unilaterally varying imide substituents were synthesized and tested for their ability to retard allosterically the dissociation of [3H]N-methylscopolamine from the receptor protein (control t1/2 = 2 min; 3 mM MgHCO4, 50 mM Tris, pH 7.3, 37 degrees C). Among the test compounds, the naphthalimide containing agent (half maximum effect at ECs5,diss = 60 nM) revealed the highest potency. Apparently, its affinity for the allosteric site in NMS-occupied receptors is 20fold higher compared with the phthalimide containing parent compound W 84. Analysis of quantitative structure-activity relationships yielded a parabolic correlation between the volume of the lateral substituents and the allosteric potency. The maximal volume was determined to be approximately 600 A3 suggesting that the allosteric binding site contains a binding pocket of a defined size for the imide moiety.

A Drosophila model of Parkinson's disease.

Parkinson's disease is a common neurodegenerative syndrome characterized by loss of dopaminergic neurons in the substantia nigra, formation of filamentous intraneuronal inclusions (Lewy bodies) and an extrapyramidal movement disorder. Mutations in the alpha-synuclein gene are linked to familial Parkinson's disease and alpha-synuclein accumulates in Lewy bodies and Lewy neurites. Here we express normal and mutant forms of alpha-synuclein in Drosophila and produce adult-onset loss of dopaminergic neurons, filamentous intraneuronal inclusions containing alpha-synuclein and locomotor dysfunction. Our Drosophila model thus recapitulates the essential features of the human disorder, and makes possible a powerful genetic approach to Parkinson's disease.

Objectives for an internship internal medicine: from the Dutch Blueprint (Raamplan 1994) to implementation into a practical logbook.

BACKGROUND: The Dutch Blueprint 1994 (Raamplan 1994) describes the objectives of undergraduate medical education. The Blueprint, developed in order to improve medical education in the Netherlands, is accepted by all Dutch medical schools and has been legislated. AIM: Translation of global objectives of the Blueprint into specific requirements of a Logbook (guideline and evaluation tool) for the internship Internal Medicine. DESCRIPTION: The Blueprint as such is impracticable as a guideline during the Internal Medicine internship. The content covers the objectives for the entire field of medicine, and the volume dedicated to Internal Medicine is too large to fit in with a twelve week internship. The practicability of the Blueprint leaves much to be desired because it is complex, and not easily accessible. So, the Blueprint was adapted on three points: (1) selecting those objectives out of the whole content, which are specifically relevant to Internal Medicine; (2) decreasing the volume Internal Medicine by clustering and defining the requirements; (3) making the Logbook usable as a guideline and evaluation instrument. CONCLUSION: The Logbook is a good starting-point to evaluate whether students meet the objectives of the Blueprint related to the discipline Internal Medicine.