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P Jeppesen

Publications and source records attributed to P Jeppesen.

At least 19 recordsLinked to original sources
PubMed2006

Impaired retinal autoregulation in small retinal arterioles before and after focal laser treatment for diabetic maculopathy.

AIMS: To study the effect of an acute increase in the arterial blood pressure on the diameter response of retinal arterioles supplying areas with focal diabetic macular oedema before and after laser photocoagulation, and control arterioles supplying areas without oedema. METHODS: In 17 diabetic patients the diameter response of arterioles after an increase in the arterial blood pressure induced by isometric exercise was studied using the retinal vessel analyser (RVA). In each patient a study arteriole supplying a focal area of macular oedema as well as a control arteriole supplying a retinal area without retinopathy lesions was selected, and the diameter response of these vessels was performed immediately before, and 1 hour and 3 months after focal laser photocoagulation of the focal oedema area. RESULTS: The diameter response was impaired in both study arterioles and control arterioles before focal laser photocoagulation. The treatment induced regression of the focal retinal oedema, but did not affect the diameter response in the arteriole supplying this area (p = 0.85). CONCLUSION: Impairment of the diameter response in small arterioles from diabetic patients does not parallel the regional distribution of retinopathy lesions. Other factors than disturbed autoregulation are probably involved in generating flow disturbances and oedema in diabetic maculopathy.

Adult↗
PubMed2005

Integrated treatment ameliorates negative symptoms in first episode psychosis--results from the Danish OPUS trial.

PURPOSE: To investigate the effect of integrated treatment on negative, psychotic and disorganised symptoms in patients with first episode psychosis. METHOD: A RCT comparing integrated treatment (IT) with standard treatment (ST) was conducted, including 547 patients, aged 18-45, diagnosed with schizophrenia spectrum disorders. All patients were assessed with SCAN, SAPS and SANS at entry and after 1 and 2 years. The IT consisted of assertive community treatment, multifamily groups, psycho-education and social skills training, and the caseload was 1:10 compared with 1:25 in ST. Since attrition was considerable, a mixed model analysis with repeated measurements was used to examine the possible effects of IT statistically. RESULTS: IT reduced both negative and positive symptoms significantly better than ST. Most marked were the results from the negative dimension, where all five global scores from SANS had a significantly better reduction in IT. Sub-analyses did not single out any one element in the integrated treatment that could explain this result. CONCLUSION: Integrated treatment significantly reduced both negative and psychotic symptoms, assumably due to the different psychosocial treatment elements that were provided in the IT. The results indicate that the integrated approach is crucial, since, most likely, many aspects of the integrated treatment have contributed to the reduction of symptoms.

Adolescent↗
PubMed2002

Chromosomal aberrations: formation, identification and distribution.

Chromosomal aberrations (CA) are the microscopically visible part of a wide spectrum of DNA changes generated by different repair mechanisms of DNA double strand breaks (DSB). The method of fluorescence in situ hybridisation (FISH) has uncovered unexpected complexities of CA and this will lead to changes in our thinking about the origin of CA. The inter- and intrachromosomal distribution of breakpoints is generally not random. CA breakpoints occur preferentially in active chromatin. Deviations from expected interchromosomal distributions of breakpoints may result from the arrangement of chromosomes in the interphase nucleus and/or from different sensitivities of chromosomes with respect to the formation of CA. Telomeres and interstitial telomere repeat like sequences play an important role in the formation of CA. Subtelomeric regions are hot spots for the formation of symmetrical exchanges between homologous chromatids and cryptic aberrations in these regions are associated with human congenital abnormalities.

Animals↗
PubMed2002

OPUS study: suicidal behaviour, suicidal ideation and hopelessness among patients with first-episode psychosis. One-year follow-up of a randomised controlled trial.

BACKGROUND: Patients with first-episode psychosis comprise a high-risk group in terms of suicide. AIMS: To identify predictive factors for suicidal behaviour and to examine the effect of integrated treatment on suicidal behaviour and hopelessness. METHOD: A total of 341 patients with a first-episode schizophrenia-spectrum disorder were randomised to integrated treatment or treatment as usual. RESULTS: During the 1-year follow-up period, 11% attempted suicide. This was associated with female gender, hopelessness, hallucinations and suicide attempt reported at baseline, with the two latter variables being the only significant ones in the final multivariate model. The integrated treatment reduced hopelessness. CONCLUSIONS: Hallucinations and suicide attempt before inclusion in the study were the most significant predictors of suicide attempt in the follow-up period.

Adolescent↗
PubMed2001

Low-copy-number human transgene is recognized as an X inactivation center in mouse ES cells, but fails to induce cis-inactivation in chimeric mice.

X chromosome inactivation is initiated from a segment of the mammalian X chromosome called the X inactivation center. Transgenes from this region of the murine X chromosome are providing the means to identify the DNA needed for cis inactivation in mice. We recently showed that chimeric mice carrying transgenes from the human X inactivation center (XIC) region also provide a functional assay for human XIC activity; approximately 6 copies of a 480-kb human transgene (ES-10) were sufficient to initiate random X inactivation in cells of male chimeric mice (Migeon et al., 1999, Genomics, 59, 113-121). Now, we report studies of another human transgene (ES-5), which contains less than 300 kb of the human XIC region on Xq13.2 including an intact XIST locus and which has inserted in one or two copies into mouse chromosome 6. The ES-5 transgene is recognized as an X inactivation center in mouse embryonic stem cells, but is not sufficient to induce random X inactivation in somatic cells of highly chimeric mice. Human transgenes in chimeric mice provide a means to uncouple the key steps in this complex pathway and facilitate the search for essential components of the human XIC region.

Animals↗
PubMed2001

Chromosome regions enriched in hyperacetylated histone H4 are preferred sites for endonuclease- and radiation-induced breakpoints.

Previously, we have shown that breakpoints induced by the endonucleases AluI, BamHI and DNase I in CHO chromosomes are localized mainly in G-light bands. Neutrons and gamma rays produced similar breakpoint clusters to endonucleases in most CHO chromosomes. Here we compare endonuclease- and radiation-induced breakpoint maps with hyperacetylation patterns of histone H4. The H4 acetylation pattern in chromosomes is similar to the pattern of G-light, or R-bands, and breakpoints are clustered in highly acetylated chromosome regions. These findings indicate that chromosomal aberrations occur more frequently in active than in inactive chromatin.

Acetylation↗
PubMed2000

Early detection and assertive community treatment of young psychotics: the Opus Study Rationale and design of the trial.

BACKGROUND: Recent research indicates that early detection of young persons suffering from psychosis and subsequent intensive intervention enhances treatment response and prognosis, but the data are only preliminary and suggestive. METHOD: We present the rationale and design of the largest study to date to evaluate two major issues in the field of secondary prevention: (1) Does education and intensified collaboration with general practice, social services etc. reduce the duration of untreated psychosis? and (2) Can modified assertive community treatment improve the course and outcome in young persons suffering from psychosis as compared to treatment in community mental health centres? The article aims additionally to put the study in context and assist in designing future studies. RESULTS: Preliminary experiences are described. The findings of the first 312 patients show that modified assertive community treatment results in patients adhering to treatment significantly better than standard treatment in community mental health centres. CONCLUSION: The surge of interest in preventively oriented detection and treatment models for untreated psychosis in young people calls for research programmes and evidence. The obstacles to this are manifold. The initial findings of the OPUS study suggest, however, that better adherence to treatment is possible.

Adolescent↗
PubMed2000

Active repression of methylated genes by the chromosomal protein MBD1.

MBD1 belongs to a family of mammalian proteins that share a methyl-CpG binding domain. Previous work has shown that MBD1 binds to methylated sites in vivo and in vitro and can repress transcription from methylated templates in transcription extracts and in cultured cells. In the present study we established by several experimental criteria that, contrary to a previous report, MBD1 is not a component of the MeCP1 repressor complex. We identified a powerful transcriptional repression domain (TRD) at the C terminus of MBD1 that can actively repress transcription at a distance. Methylation-dependent repression in vivo depends on the presence of both the TRD and the methyl-CpG binding domain. The mechanism is likely to involve deacetylation, since the deacetylase inhibitor trichostatin A can overcome MBD1-mediated repression. Accordingly, we found that endogenous MBD1 is particularly concentrated at sites of centromeric heterochromatin, where acetylated histone H4 is deficient. Unlike MBD2 and MeCP2, MBD1 is not depleted by antibodies to the histone deacetylase HDAC1. Thus, the deacetylase-dependent pathway by which MBD1 actively silences methylated genes is likely to be different from that utilized by the methylation-dependent repressors MeCP1 and MeCP2.

Acetylation↗
PubMed1999

Human X inactivation center induces random X chromosome inactivation in male transgenic mice.

X chromosome inactivation is the means to downregulate the transcriptional output of X chromosomes in female mammals. Essential DNA from the murine X inactivation center (Xic) has been identified by introducing it into male embryonic stem (ES) cells. To identify the essential sequences on human X chromosomes, we transfected male mouse ES cells with a YAC transgene containing 480 kb of the putative human X inactivation center (XIC). Despite little DNA sequence conservation, the human transgene is recognized as a second Xic in these XY mouse cells and induces random inactivation in chimeric mice derived from these cells. Inactivation is extensive on the X chromosome, but more localized on chromosome 11 carrying the transgene, demonstrating that initial inactivation and spreading of inactivation signals along the chromosome are independent events. Our results show for the first time that the DNA included in the human XIC transgene is sufficient to initiate random X inactivation, even in cells of another species. Interspecies XIC trangenes should facilitate further investigation of this process in humans and other mammals.

Animals↗
PubMed1998

Amlodipine dynamic effects and myocardial pharmacokinetics in the isolated and perfused guinea-pig heart.

Myocardial dynamic effects and pharmacokinetics of amlodipine were studied in the isolated retrogradely perfused and spontaneously beating guinea-pig heart. Pharmacokinetic analysis of drug accumulation showed one-compartment characteristics with an half-life of 76 min. Whereas disposition exhibited two-compartment characteristics with phasic half-lives of 25 and 174 min., respectively. Myocardial drug accumulation was increased by 600 times at steady-state compared to the perfusion liquid. Dynamic effect parameters were studied during increasing amlodipine concentrations from 0.16 to 220 nM. Dynamic steady-states developed within 20 min. Coronary flow-rate increased with an Emax of 119% and an EC50 of 1.2 x 10(-8) M. Amlodipine produced inhibitory effects on contraction amplitude and velocities of contraction and relaxation. Observed Emax-values and curve-fitted EC50-values were: 97, 97 and 94% and 1.10(-8), 7.7 x 10(-9) and 2.1 x 10(-8) M, respectively. Heart frequency was not changed. Oxygen consumption increased markedly to a maximum of 44% at 3 x 10(-8) M amlodipine and then decreased to nearly initial values. The frequency-corrected QT-interval decreased to a maximal extent of 20% at the three highest concentrations. Myocardial efficiency expressed as the ratio of contraction velocity times frequency to oxygen consumption exhibited a progressive decline to about 2% of initial values. The PQ-interval was not changed and the QRS-interval showed only a small but significant decrease at the highest amlodipine concentration. No arrythmogenic effects were observed. The study demonstrated a very slow accumulation and disposition of amlodipine in the guinea-pig heart with a steady-state myocardial drug concentrating accumulation of 600 times. Marked increase in coronary flow-rate and oxygen consumption accompanied by a progressive negative inotropic effect were observed.

Amlodipine↗
PubMed1997

Histone acetylation: a possible mechanism for the inheritance of cell memory at mitosis.

Immunofluorescent labelling demonstrates that human metaphase chromosomes contain hyperacetylated histone H4. With the exception of the inactive X chromosome in female cells, where the bulk of histone H4 is underacetylated, H4 hyperacetylation is non-uniformly distributed along the chromosomes and clustered in cytologically resolvable chromatin domains that correspond, in general, with the R-bands of conventional staining. The strongest immunolabelling is often found in T-bands, the subset of intense R-bands having the highest GC content. The majority of mapped genes also occurs in R-band regions, with the highest gene density in T-bands. These observations are consistent with a model in which hyperacetylation of histone H4 marks the position of potentially active gene sequences on metaphase chromosomes. Since acetylation is maintained during mitosis, progeny cells receive an imprint of the histone H4 acetylation pattern that was present on the parental chromosomes before cell division. Histone acetylation could provide a mechanism for propagating cell memory, defined as the maintenance of committed states of gene expression through cell lineages.

Acetylation↗
PubMed1996

Epigenetic control of mammalian centromere protein binding: does DNA methylation have a role?

Chromosome 1 of the inbred mouse strain DBA/2 has a polymorphism associated with the minor satellite DNA at its centromere. The more terminal block of satellite DNA sequences on this chromosome acts as the centromere as shown by the binding of CREST ACA serum, anti-CENP-B and anti-CENP-E polyclonal sera. Demethylation of the minor satellite DNA sequences accomplished by growing cells in the presence of the drug 5-aza-2'-deoxycytidine results in a redistribution of the CENP-B protein. This protein now binds to an enlarged area on the more terminal block and in addition it now binds to the more internal block of minor satellite DNA sequences on chromosome 1. The binding of the CENP-E protein does not appear to be affected by demethylation of the minor satellite sequences. We present a model to explain these observations. This model may also indicate the mechanism by which the CENP-B protein recognises specific sites within the arrays of minor satellite DNA on mouse chromosomes.

Animals↗
PubMed1996

Chromatin organization in the homogeneously staining regions of a methotrexate-resistant mouse cell line: interspersion of inactive and active chromatin domains distinguished by acetylation of histone H4.

We have analyzed the organization of the homogeneously staining regions (HSRs) in chromosomes from a methotrexate-resistant mouse melanoma cell line. Fluorescence in situ hybridization techniques were used to localize satellite DNA sequences and the amplified copies of the dihydrofolate reductase (DHFR) gene that confer drug-resistance, in combination with immunofluorescence using antibody probes to differentiate chromatin structure. We show that the major DNA species contained in the HSRs is mouse major satellite, confirming previous reports, and that this is interspersed with DHFR DNA in an alternating tandem array that can be resolved at the cytological level. Mouse minor satellite DNA, which is normally located at centromeres, is also distributed along the HSRs, but does not appear to interfere with centromere function. The blocks of major satellite DNA are coincident with chromatin domains that are labelled by an autoantibody that recognizes a mammalian homologue of Drosophila heterochromatin-associated protein 1, shown previously to be confined to centric heterochromatin in mouse. An antiserum that specifically recognizes acetylated histone H4, a marker for active chromatin, fails to bind to the satellite DNA domains, but labels the intervening segments containing DHFR DNA. We can find no evidence for the spreading of the inactive chromatin domains into adjacent active chromatin, even after extended passaging of cells in the absence of methotrexate selection.

Acetylation↗
PubMed1996

Lack of X inactivation associated with maternal X isodisomy: evidence for a counting mechanism prior to X inactivation during human embryogenesis.

We have previously reported functional disomy for X-linked genes in females with tiny ring X chromosomes and a phenotype significantly more abnormal than Turner syndrome. In such cases the disomy results from failure of these X chromosomes to inactivate because they lack DNA sequences essential for cis X inactivation. Here we describe a novel molecular mechanism for functional X disomy that is associated with maternal isodisomy. In this case, the severe mental retardation and multiple congenital abnormalities in a female with a mosaic 45,X/ 46,X,del(X)(q21.3-qter)/ 46X,r(X) karyotype are associated with overexpression of the genes within Xpter to Xq21.31 in many of her cells. Her normal X, ring X, and deleted linear X chromosomes originate from the same maternal X chromosome, and all are transcriptionally active. None expresses X inactive specific transcript (XIST), although the locus and region of the putative X inactivation center (XIC) are present on both normal and linear deleted X chromosomes. To our knowledge, this is the first report of a functional maternal X isodisomy, and the largest X chromosome to escape inactivation. In addition, these results (1) show that cis inactivation does not invariably occur in human females with two X chromosomes, even when the XIC region is present on both of them; (2) provide evidence for a critical time prior to the visible onset of X inactivation in the embryo when decisions about X inactivation are made; and (3) support the hypothesis that the X chromosome counting mechanism involves chromosomal imprinting, occurs prior to the onset of random inactivation, and is required for subsequent inactivation of the chromosome.

Cell Division↗
PubMed1996

Analysis of loss of inactive X chromosomes in interphase cells.

We have developed a method that allows, for the first time, a specific analysis of the inactive X chromosome (Xi) in interphase cells. By combining immunolabeling of acetylated histone H4 with specific antisera and FISH with an X-chromosome centromere-specific DNA probe, micronucleated whole Xis in human female cells may be identified by their lack of histone H4 acetylation. As one example of the potential applications of this methodology in genetic studies in humans, an artifact-free X-chromosome aneuploidy detection in lymphocytes of women of different ages has been performed. Our results indicate that not only the Xi but also the active X chromosome is preferentially lost during aging, indicating that the high frequency of sex-chromosome aneuploidy in human females cannot be explained solely by a lack of negative selection of Xi aneuploid cells. Further applications of the proposed methodology in genetic studies are discussed.

Adult↗
PubMed1994

Human autoimmune sera recognize a conserved 26 kD protein associated with mammalian heterochromatin that is homologous to heterochromatin protein 1 of Drosophila.

Immunofluorescence indicated that autoimmune sera from certain scleroderma/CREST patients, in addition to binding to the primary constrictions or centromeres, also labelled pericentromeric heterochromatin in mouse and human metaphase chromosomes. Immunoblotting has revealed that two conserved nuclear antigens are recognized by this CREST subgroup, one of mol. wt 26 kD (p26), and the other of mol. wt 23 kD (p23). In situ immunolabelling with affinity purified antibodies demonstrated that p26, but not p23, is concentrated in pericentromeric heterochromatin. Further studies have shown that both p26 and p23 are immunologically related to the Drosophila heterochromatin-associated protein HP1, and to other chromodomain proteins.

Animals↗
PubMed1994

Analysis of centromere structure in the fly Megaselia scalaris (Phoridae, Diptera) using CREST sera, anti-histone antibodies, and a repetitive DNA probe.

We have used CREST anti-centromere sera, rabbit anti-histone antibodies, and repetitive DNA analysis to study centromere structure in the fly Megaselia scalaris (Phoridae). In a panel of eight CREST sera, four were positive in immunofluorescence experiments for prekinetochores, ie centromeres in interphase nuclei. The access of the antibodies to CREST antigens may be compromised in the condensed state, since centromeres of prometaphase and metaphase chromosomes remained unstained. When Western blots of embryonic nuclei were probed with these four CREST sera, three of them showed a 17 kDa band. Human CENP-A, likewise recognized by the CREST sera, is a 17 kDa protein. The remaining sera were negative for centromeres although some detected centrosomes and non-histone chromosomal proteins not confined to the centromeres. The use of antibodies generated against histone H4 acetylated at four different sites of the N-terminal domain revealed that heterochromatic regions of M scalaris mitotic chromosomes, ie pericentric and NOR-associated segments, are hyperacetylated. This is at variance with a variety of other systems, where transcriptionally active chromatin is hyperacetylated. Finally, a repetitive 165 base pair fragment was isolated from genomic DNA of the fly and sequenced. An oligonucleotide from this sequence mapped to the centromere region of interphase nuclei and the pericentric regions of condensed chromosomes.

Animals↗