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Biomedical subjects

H S Andersen

Publications and source records attributed to H S Andersen.

At least 19 recordsLinked to original sources
PubMed2002

Analysis of scenarios for sewerage, wastewater treatment and prioritised load on environment from the Greater City of Copenhagen.

The sewer system for the Greater Copenhagen area covers an area of 4460 ha contributing to the runoff. The total area serves in total 8 municipalities, however it is dominated by the areas in the City of Copenhagen proper. The catchments merge into interceptors, which feed two large treatment plants. The effluent from the two treatment plants discharges during dry weather to Oresund, the sound between Denmark and Sweden. This large system has been analysed for selected scenarios with respect to handling runoff in an optimal way in order to minimise the loads on the most sensitive receiving waters and optimising treatment plant performance.

Cities↗
PubMed2001

Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases.

Utilizing structure-based design, we have previously demonstrated that it is possible to obtain selective inhibitors of protein-tyrosine phosphatase 1B (PTP1B). A basic nitrogen was introduced into a general PTP inhibitor to form a salt bridge to Asp48 in PTP1B and simultaneously cause repulsion in PTPs containing an asparagine in the equivalent position [Iversen, L. F., et al. (2000) J. Biol. Chem. 275, 10300-10307]. Further, we have recently demonstrated that Gly259 in PTP1B forms the bottom of a gateway that allows easy access to the active site for a broad range of substrates, while bulky residues in the same position in other PTPs cause steric hindrance and reduced substrate recognition capacity [Peters, G. H., et al. (2000) J. Biol. Chem. 275, 18201-18209]. The current study was undertaken to investigate the feasibility of structure-based design, utilizing these differences in accessibility to the active site among various PTPs. We show that a general, low-molecular weight PTP inhibitor can be developed into a highly selective inhibitor for PTP1B and TC-PTP by introducing a substituent, which is designed to address the region around residues 258 and 259. Detailed enzyme kinetic analysis with a set of wild-type and mutant PTPs, X-ray protein crystallography, and molecular modeling studies confirmed that selectivity for PTP1B and TC-PTP was achieved due to steric hindrance imposed by bulky position 259 residues in other PTPs.

Animals↗
PubMed2001

Post-traumatic stress disorder: a review of psychobiology and pharmacotherapy.

OBJECTIVE: To review the literature on the psychobiology and pharmacotherapy of PTSD. METHODS: Relevant studies were identified by literature searches (Pub-med, Web of Science) and through reference lists. The search was ended by May 2001. RESULTS: There is evidence of involvement of opioid, glutamatergic, GABAergic, noradrenergic, serotonergic and neuroendocrine pathways in the pathophysiology of PTSD. Medications shown to be effective in double-blind placebo-controlled trials includes selective serotonin reuptake inhibitors, reversible and irreversible MAO-inhibitors, tricyclic antidepressants and the anticonvulsant lamotrigine. Still more agents appear promising in open-label trials. CONCLUSION: The complexity of the psychobiology is reflected by the difficulties in treating the disorder. According to the present knowledge, suggestions for drug treatment of PTSD are made.

Glutamic Acid↗
PubMed2001

Ganser syndrome after solitary confinement in prison: a short review and a case report.

A short review of the Ganser syndrome is given. The condition is a rare, probably dissociative, disorder with transient Vorbeireden as the central symptom. The case of a middle-aged man developing a transient Ganser syndrome after long-term solitary confinement in a remand prison is presented. Systematic investigation of 268 remand prisoners confirms the rarity of the syndrome, as only the case subject had this disorder.

Attention↗
PubMed2001

Psychosis and pregnancy: five cases of severely ill women.

An increasing number of patients with chronic mental disease are now integrated in society. As a consequence, women with severe psychiatric illness may become pregnant and wish to complete the pregnancy and to give birth to a child. The lack of sensation of reality in these patients and their social situation may result in particular problems in their treatment, and it may be necessary to admit them to a psychiatric ward before delivery. In this paper five cases of pregnant women with severe and chronic psychosis are described. These patients had many problems in common. Thus, they were all schizophrenics with very severe psychopathology, had poor understanding of their own situation, and lacked social networks. All the fathers were non-Danish. Coercion was used in all cases. To help women with severe mental illness to go through pregnancy and childbirth requires close collaboration between psychiatric and obstetric staff and social workers, and this should be organized in an institution with experience in the treatment of this type of patient.

Adult↗
PubMed2000

Residue 259 is a key determinant of substrate specificity of protein-tyrosine phosphatases 1B and alpha.

The aim of this study was to define the structural elements that determine the differences in substrate recognition capacity of two protein-tyrosine phosphatases (PTPs), PTP1B and PTPalpha, both suggested to be negative regulators of insulin signaling. Since the Ac-DADE(pY)L-NH(2) peptide is well recognized by PTP1B, but less efficiently by PTPalpha, it was chosen as a tool for these analyses. Calpha regiovariation analyses and primary sequence alignments indicate that residues 47, 48, 258, and 259 (PTP1B numbering) define a selectivity-determining region. By analyzing a set of DADE(pY)L analogs with a series of PTP mutants in which these four residues were exchanged between PTP1B and PTPalpha, either in combination or alone, we here demonstrate that the key selectivity-determining residue is 259. In PTPalpha, this residue is a glutamine causing steric hindrance and in PTP1B a glycine allowing broad substrate recognition. Significantly, replacing Gln(259) with a glycine almost turns PTPalpha into a PTP1B-like enzyme. By using a novel set of PTP inhibitors and x-ray crystallography, we further provide evidence that Gln(259) in PTPalpha plays a dual role leading to restricted substrate recognition (directly via steric hindrance) and reduced catalytic activity (indirectly via Gln(262)). Both effects may indicate that PTPalpha regulates highly selective signal transduction processes.

Animals↗
PubMed2000

Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.

Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.

Animals↗
PubMed2000

2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases.

Protein-tyrosine phosphatases (PTPs) are critically involved in regulation of signal transduction processes. Members of this class of enzymes are considered attractive therapeutic targets in several disease states, e.g. diabetes, cancer, and inflammation. However, most reported PTP inhibitors have been phosphorus-containing compounds, tight binding inhibitors, and/or inhibitors that covalently modify the enzymes. We therefore embarked on identifying a general, reversible, competitive PTP inhibitor that could be used as a common scaffold for lead optimization for specific PTPs. We here report the identification of 2-(oxalylamino)-benzoic acid (OBA) as a classical competitive inhibitor of several PTPs. X-ray crystallography of PTP1B complexed with OBA and related non-phosphate low molecular weight derivatives reveals that the binding mode of these molecules to a large extent mimics that of the natural substrate including hydrogen bonding to the PTP signature motif. In addition, binding of OBA to the active site of PTP1B creates a unique arrangement involving Asp(181), Lys(120), and Tyr(46). PTP inhibitors are essential tools in elucidating the biological function of specific PTPs and they may eventually be developed into selective drug candidates. The unique enzyme kinetic features and the low molecular weight of OBA makes it an ideal starting point for further optimization.

Binding Sites↗
PubMed2000

A longitudinal study of prisoners on remand: psychiatric prevalence, incidence and psychopathology in solitary vs. non-solitary confinement.

OBJECTIVE: To compare two levels of stress (solitary confinement (SC) and non-SC) among remand prisoners as to incidence of psychiatric disorders in relation to prevalent disorders. METHOD: Longitudinal repeated assessments were carried out from the start and during the remand phase of imprisonment. Both interview-based and self-reported measures were applied to 133 remand prisoners in SC and 95 remand prisoners in non-SC randomly selected in a parallel study design. RESULTS: Incidence of psychiatric disorders developed in the prison was significantly higher in SC prisoners (28%) than in non-SC prisoners (15%). Most disorders were adjustment disorders, with depressive disorders coming next. Incident psychotic disorders were rare. The difference regarding incidence was primarily explained by level of stress (i.e. prison form) rather than confounding factors. Quantitative measures of psychopathology (Hamilton Scales and General Health Questionnaire) were significantly higher in subjects with prevalent and incident disorders compared to non-disordered subjects. CONCLUSION: Different levels of stress give rise to different incidence of psychiatric morbidity among remand prisoners. The surplus of incident disorders among SC prisoners is related to SC, which may act as a mental health hazard.

Adult↗
PubMed1999

Peroxyvanadium compounds inhibit glucose-6-phosphatase activity and glucagon-stimulated hepatic glucose output in the rat in vivo.

The present investigation was undertaken to characterize the direct inhibitory action of the peroxyvanadium compounds oxodiperoxo(1, 10-phenanthroline) vanadate(V) (bpV(phen)) and oxodiperoxo(pyridine-2-carboxylate) vanadate(V) (bpV(pic)) on pig microsomal glucose-6-phosphatase (G-6-Pase) activity and on glucagon stimulated hyperglycemia in vivo. Both bpV(phen) and bpV(pic) were found to be potent competitive inhibitors of G-6-Pase with Ki values of 0.96 and 0.42 microM (intact microsomes) and 0.50 and 0.21 microM (detergent-disrupted microsomes). The corresponding values for ortho-vanadate were 20.3 and 20.0 microM. Administration of bpV(phen) to postprandial rats did not affect the basal glucose level although a modest and dose-dependent increase in plasma lactate levels was seen. Injection of glucagon raised the plasma glucose level from 5.5 mM to about 7.5 mM in control animals and this increase could be prevented dose-dependently by bpV(phen). The inhibition of the glucagon-mediated blood glucose increase was accompanied by a dose-dependent increase in plasma lactate levels from 2 mM to about 11 mM. In conclusion, the finding that vanadate and bpV compounds are potent inhibitors of G-6-Pase suggests that the blood-glucose-lowering effect of these compounds which is seen in diabetic animals may be partly explained by a direct effect on this enzyme rather than, as presently thought, being the result of inhibition of phosphoprotein tyrosine phosphatases and thereby insulin receptor dephosphorylation.

Animals↗
PubMed1999

Psychopathy and psychopathological profiles in prisoners on remand.

A total of 178 Danish male remand prisoners were examined using comprehensive interviews and questionnaires on psychopathological, personality and social measures, and file data. These data were compared with scores on the Hare Psychopathy Checklist - Revised (PCL-R). Subjects were divided into four groups according to quartile PCL-R scores. In general there were high rates of psychiatric morbidity in all PCL-R quartile groups. The medium-high scorers represent a more vulnerable group with a high prevalence of dependence disorders, relatively high neuroticism score and relatively high prevalence of neurotic and stress-related disorders. The high scorers were more psychosocially maladjusted, had more often made previous suicidal attempts, and had a higher psychoticism score. Chronic psychotic disorders did occur, mostly in the high-scoring group. The population had lower scores on the PCL-R than in most previous studies, suggesting a lower prevalence of psychopathic features among Danish criminals and possibly a lower cut-off point when using the PCL-R as a categorical measure. Both findings are consistent with the results of other European studies. Further studies on cross-cultural differences with regard to PCL-R psychopathic features and on psychic vulnerability related to PCL-R scores and factor 1/factor 2 of the PCL-R are suggested.

Adolescent↗
PubMed1999

Progressive atrophy of the frontal lobes in first-episode schizophrenia: interaction with clinical course and neuroleptic treatment.

OBJECTIVE: This prospective study examined the interaction of clinical course of disease and brain structure with time in schizophrenic patients. METHOD: A total of 21 first-episode schizophrenic patients, 10 patients with other psychiatric disorders and a control group of 9 healthy volunteers had CT at first admission and at reinvestigation 5 years later. RESULTS: At first admission all of the patients had enlarged cortical fissures and sulci compared to controls, and the duration of untreated psychosis was significantly correlated with sulcal enlargement. At reinvestigation, frontal and central brain atrophy had progressed in schizophrenic patients. CONCLUSION: The study indicated that ongoing psychosis and lifetime dose of classical antipsychotics were the main candidates accounting for the finding of progressively disturbed brain structure during the first 5 years of schizophrenia.

Adolescent↗
PubMed1998

[The epidemiology of post-traumatic stress disorders].

Post-traumatic stress disorder (PTSD) has been subjected to several epidemiological studies during the last 10 years. Large differences in prevalence between different studies can only partly be explained by differences in methodology, impact of the trauma and populations. Changes in diagnostic criteria, the stressor criteria, general mentality over time and cultural differences may account for some of the differences. In general populations a lifetime prevalence of PTSD of between 1% and 9% has been found. In unselected traumatized populations 20-45% will develop PTSD after exposure to significant traumas. Among soldiers who have participated in battles of war a PTSD prevalence of 15-20% has been found. After exposure to lesser traumas and among well-trained corps 5-10% develop PTSD. Over long periods the point prevalence of PTSD in a given traumatized population diminishes. Predictive factors related to PTSD are complex.

Combat Disorders↗
PubMed1996

[Heroin abuse among Danish prisoners on remand. I. Prevalence related to form of administration].

Two groups of Danish prisoners on remand (in solitary confinement and not in solitary confinement) were examined by interview on reception (n = 133 & n = 95) in order to evaluate the prevalence and form of administration of opioid abuse/dependence. About 50% had abused opioids during their lifetime; one third were dependent at the time of reception. Twenty percent of opioid dependent prisoners administered opioids by smoking. More intravenous users were treated with methadone before and during imprisonment than those who were dependent on smoking opioids. Few were objectively suffering from withdrawal symptoms. The psycho-social impact of dependence on smoking heroin and intravenous heroin one month prior to imprisonment was at the same level and substantial as measured by the Global Assessment Scale.

Administration, Inhalation↗
PubMed1996

[Heroin abuse among Danish prisoners on remand. II. Consequences related to form of administration].

Heroin-abusing Danish prisoners remanded in custody were based on interviews grouped as either smoking dependent (n = 18) or intravenous dependent (n = 55). Intravenous users had a longer duration and earlier debut of abuse than users who smoked opiates. Only intravenous users had serious somatic complications. Both groups of opioid dependent prisoners were marked by severe psychosocial dysfunction and considerable psychiatric co-morbidity. The intravenous users were generally more affected than the smokers concerning social and psychiatric parameters and earlier criminality, perhaps due to their longer duration of abuse.

Administration, Inhalation↗