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A Malmberg

Publications and source records attributed to A Malmberg.

At least 19 recordsLinked to original sources
PubMed2005

Phenylketonuria screening registry as a resource for population genetic studies.

BACKGROUND: Neonatal screening for metabolic diseases, involving samples stored on filter paper (Guthrie spots), provides a potential resource for genetic epidemiological studies. OBJECTIVE: To develop a method to make these dried blood spots available for large scale genetic epidemiology. METHODS: DNA from untraceable Guthrie spots was extracted using a saponin and chelex-100 based method and preamplified by improved primer preamplification. Analyses were done on 38 samples each of fresh, 10, and 25 year old Guthrie spots and the success rate determined for PCR amplification for five amplicon lengths. RESULTS: The method was applicable even on 25 year old samples. The success rate was 100% for 100 bp amplicons and 80% for 396 bp amplicons. Ninety four Guthrie samples were genotyped, including carriers of two different PKU mutations; all carriers were found (six R158Q, four R252W), with no false positives. Finally, 2132 anonymous samples from the Swedish PKU registry were extracted and preamplified and the allele frequencies of APOepsilon4, PPARgamma Pro12Ala, and the CCR5 32 bp deletion determined. Local variations in allele frequencies suggested subpopulation structuring. There was a significant difference (p<0.01) in regional allele frequencies for the CCR5 32 bp deletion in the Swedish population. CONCLUSION: Whole genome amplification makes it feasible to conduct large genetic epidemiological studies using PKU screening registries.

Alleles↗
PubMed2000

Site-directed mutations in the third intracellular loop of the serotonin 5-HT(1A) receptor alter G protein coupling from G(i) to G(s) in a ligand-dependent manner.

The effect of mutations (V344E and T343A/V344E) in the third intracellular loop of the serotonin 5-HT(1A) receptor expressed transiently in human embryonic kidney 293 cells have been examined in terms of receptor/G protein interaction and signaling. Serotonin, (R)-8-hydroxy-2-dipropylaminotetralin [(R)-8-OH-DPAT], and buspirone inhibited cyclic AMP production in cells expressing native and mutant 5-HT(1A) receptors. Serotonin, however, produced inverse bell-shaped cyclic AMP concentration-response curves at native and mutant 5-HT(1A) receptors, indicating coupling not only to G(i)/G(o), but also to G(s). (R)-8-OH-DPAT, however, induced stimulation of cyclic AMP production only after inactivation of G(i)/G(o) proteins by pertussis toxin and only at the mutant receptors. The partial agonist buspirone was unable to induce coupling to G(s) at any of the receptors, even after pertussis toxin treatment. The basal activities of native and mutant 5-HT(1A) receptors in suppressing cyclic AMP levels were not found to be significantly different. The receptor binding characteristics of the native and mutant receptors were investigated using the novel 5-HT(1A) receptor antagonist [(3)H]NAD-299. For other receptors, analogous mutations have produced constitutive activation. This does not occur for the 5-HT(1A) receptor, and for this receptor the mutations seem to alter receptor/G protein coupling, allowing ligand-dependent coupling of receptor to G(s) in addition to G(i)/G(o) proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Doctors who kill themselves: a study of the methods used for suicide.

Medical practitioners have a relatively high rate of suicide. Death entry data for doctors who died by suicide or undetermined cause between 1979 and 1995 in England and Wales were used to compare methods used for suicide by doctors with those used by the general population. Methods used were analysed according to gender, occupational status and speciality, to assess the extent to which access to dangerous means influences the pattern of suicide. Self-poisoning with drugs was more common in the doctors than in general population suicides (57% vs. 26.6%; OR=3.65, 95% CI 2.85-4. 68), including in retired doctors. Barbiturates were the most frequent drugs used. Half of the anaesthetists who died used anaesthetic agents. Self-cutting was also more frequently used as a method of suicide. The finding that the greater proportion of suicide deaths in doctors were by self-poisoning may reflect the fact that doctors have ready access to drugs, and have knowledge of which drugs and doses are likely to cause death. The specific finding that a large proportion of suicides in anaesthetists involved anaesthetic agents supports this explanation. Availability of method may be a factor contributing to the relatively high suicide rate of doctors. This fact might influence clinical management of doctors who are known to be depressed or suicidal.

Adult↗
PubMed2000

Non-psychotic psychiatric disorder and subsequent risk of schizophrenia. Cohort study.

BACKGROUND: Those with schizophrenia often give a history of premorbid non-psychotic psychiatric disorder. AIMS: To investigate the association between non-psychotic psychiatric disorders and the later development of schizophrenia. METHOD: Men aged 18 or 19 years, conscripted to the Swedish army in 1970 (n=50 054) were linked to the Swedish National Psychiatric Case Register. RESULTS: There was an increased risk of schizophrenia in those with ICD-8 diagnoses of neurosis (OR=4.6,95% Cl 3.2-6.9), personality disorder (OR=8.2, 95% Cl 5.4-12.3), alcohol abuse (OR=5.5, 95% Cl 1.7-17.5) or substance abuse (OR=14.0, 95% Cl 7.8-25.0) at age 18. Of those who developed schizophrenia, 38% (95% Cl 32-45) received a diagnosis of non-psychotic psychiatric disorder at age 18. Only those with personality disorder had a significantly increased risk of schizophrenia (OR=2.4, 95% Cl 1.1-5.2) with onset after age 23. CONCLUSIONS: Personality factors could represent an underlying vulnerability to schizophrenia. Other diagnoses occurring before schizophrenia may reflect a prodromal phase of the illness.

Adolescent↗
PubMed1999

Derivatives of (R)-2-amino-5-methoxytetralin: antagonists and inverse agonists at the dopamine D2A receptor.

A series of N-arylmethyl substituted (R)-5-methoxy-2-(propylamino)tetralins has been prepared and evaluated for affinity and efficacy at dopamine (DA) D2A receptors. The novel compounds appeared to be antagonists or inverse agonists. (R)-2-[(Benzyl)propylamino]-5-methoxytetralin (7) was characterized as a potent inverse agonists at DA D2A receptors in a [35S]GTPgammaS binding assay.

Dopamine Antagonists↗
PubMed1999

The geographical distribution of suicides in farmers in England and Wales.

Farmers in England and Wales have an elevated risk of suicide. The aim of this study was to investigate the geographical distribution of suicides in farmers. Rates of suicide (including suicide and open verdicts) of farmers in England and Wales between 1981 and 1993 were calculated on a county basis. Trends in rates and differences in rates between counties, regions and England and Wales were then analysed. There were 719 suicides (634 suicide verdicts and 85 open verdicts). There was evidence of a decline in annual rates of suicide in farmers during the study period in England but not Wales. There was no evidence of geographical heterogeneity of farming suicides according to counties, but a relatively high rate for Devon (N = 62 suicides). County farming suicide rates did not appear to be related to local general population suicide rates, density of farmers or type of farm holding. While identification of counties with relatively large numbers of farming suicides should assist targeting of local preventive programmes, it is clear that any significant prevention strategies should be implemented on a national basis.

Adolescent↗
PubMed1999

An introductory hospice experience for third-year medical students.

BACKGROUND: An organized and distinct curriculum in hospice and palliative care education is lacking in most United States medical school programs. Because of this knowledge deficit, physicians are often not able to meet the needs of their terminally ill patients and their families. METHODS: A five-day combined didactic and clinical rotation in hospice and palliative care for third-year medical students was developed and is presented. The program is run through a home-based hospice in conjunction with the state's medical school. RESULTS: The pilot program has been well accepted by the participating students as a valuable learning experience. Although brief, it has also been successful in changing some of their attitudes about death and the care of the dying. CONCLUSIONS: This one-week program is an effective means to provide an intense course in hospice education. It should be easily transportable to other health care curricula.

Attitude to Death↗
PubMed1998

Interactions of ligands with active and inactive conformations of the dopamine D2 receptor.

The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.

Cells, Cultured↗
PubMed1998

The psychological autopsy approach to studying suicide: a review of methodological issues.

The psychological autopsy approach to studying suicide is becoming an increasingly used research method. It presents considerable methodological problems. In order to assist future researchers in this field and to help readers assess reports of psychological autopsy studies the authors have reviewed these issues on the basis of their own experience and those of other workers. The areas covered include research design, identification of subjects, sources of information and the particular issues concerned with approaching relatives and other informants, choice and recruitment of controls, the difficulties of conducting psychological autopsy interviews with relatives, problems for interviewers, the selection of appropriate measures to obtain information, and achieving valid and reasonably reliable conclusions from diverse information sources.

Autopsy↗
PubMed1998

Stress in farmers: a survey of farmers in England and Wales.

OBJECTIVES: To investigate potential sources of stress for farmers in England and Wales METHOD: A postal questionnaire was sent to a randomly selected group of 800 members of the National Farmers' Union and 200 members of the Farmers' Union of Wales. RESULTS: 500 questionnaires (51%) were returned completed between October 1995 and March 1996. Farmers had problems with record keeping and paperwork (62%), difficulty understanding forms (56%), and problems arising from the effects of new legislation and regulations (49%). Nearly a quarter (23%) reported financial problems and most worried about money (79%). Very few were socially isolated, with over 90% having at least one confidant. 70% worked > 10 hours a day, and 31% had health problems which interfered with their work, including more than a quarter of those < 50. 16% of the sheep farmers reported symptoms which they attributed to organophosphate poisoning. The farmers most vulnerable to financial and other problems were those with small farms and mixed farming operations. Farmers in Wales also seemed more vulnerable than those in England, but a lower response rate from members of the Farmers' Union of Wales means this difference should be interpreted cautiously. CONCLUSION: The survey confirms findings from several regional studies that many farmers are experiencing considerable stress from various causes. Local and national initiatives to assist farmers, including outreach programmes, should be encouraged. Policy makers should be aware of the potential impact of legislation, particularly on the more vulnerable groups.

Adult↗
PubMed1998

Premorbid adjustment and personality in people with schizophrenia.

BACKGROUND: Schizoid personality and poor social adjustment have been thought of as common antecedents of schizophrenia but the existing literature is inconclusive. We have carried out a large cohort study with improved methodology. METHOD: The premorbid personality and adjustment of 50,054 Swedish men were assessed on entry into the army at the age of 18. Individuals who developed schizophrenia or another psychosis after 15-year follow-up were identified. Odds ratios for variables independently associated with the later development of schizophrenia were calculated, adjusting for potential confounders. RESULTS: Four variables reflecting early problems with interpersonal relationships were strongly associated with later schizophrenia and, to a lesser extent, non-schizophrenic psychoses, but also occurred commonly in the cohort as a whole. These associations with schizophrenia persisted after early-onset cases were excluded, though their predictive value was low (3.0%, 95% CI 1.5-4.5). CONCLUSIONS: Some aspects of premorbid personality and adjustment may act as risk factors for schizophrenia. The results appear to be most consistent with a multi-factorial aetiology for schizophrenia and offer tentative support for a psychological disturbance mediating genetic and environmental effects on the causal pathway to the illness.

Adolescent↗
PubMed1998

Methods used for suicide by farmers in England and Wales. The contribution of availability and its relevance to prevention.

BACKGROUND: Farmers in the UK have an elevated risk of suicide. It has been suggested that this may be related to their ease of access to dangerous means for suicidal behaviour. The extent to which farmers use these means and changes in their use may be relevant to suicide prevention. METHOD: Data on 719 deaths in farmers of both genders in England and Wales between 1981 and 1993 in which a verdict of suicide or undetermined cause (open verdict) was recorded were analysed. RESULTS: Of 702 deaths in male farmers, firearms were involved in 40.0%, hanging in 29.6%, carbon monoxide in 16.4%, poisoning in 8.0% (over half of which involved agricultural or horticultural poisons) and other methods in 6.1%. There was a considerable excess of deaths due to firearms compared with the distribution of methods of suicide and open verdict deaths in males in the general population. Hanging was also somewhat more frequent. During the study period there was a reduction in firearm death rates, particularly after 1989 when there was national legislation on firearm ownership, registration and storage. There were also fewer farming suicides after this date. By the end of the study period hanging was more frequent than deaths involving firearms. CONCLUSIONS: Farmers who commit suicide tend to use methods to which they have easy access. Restriction of the ready availability of such methods, particularly in farmers known to be depressed or otherwise at risk, might prevent some suicides.

Adolescent↗
PubMed1997

A study of suicide in farmers in England and Wales.

The proportional mortality ratio for suicide is higher in farmers than in the general population. The reasons for this are likely to be complex, but may include easy availability of firearms, stress related to work, financial difficulties, and family problems. A psychological autopsy study of suicide in 84 farmers who died between 1991-1994 is presented and some preliminary findings are discussed.

Adolescent↗
PubMed1997

IQ and risk for schizophrenia: a population-based cohort study.

BACKGROUND: This study aimed to quantify the association between low IQ and the later development of psychosis in a population-based cohort study of 18-year-old conscripts. METHODS: Fifty thousand males conscripted into the Swedish army in 1969-1970 were followed by means of the Swedish National Register of Psychiatric Care up to 1983. Tests of verbal and visuospatial abilities, general and mechanical knowledge and several psychosocial variables were recorded at conscription. RESULTS: One hundred and ninety-five subjects were admitted to hospital with schizophrenia and 192 with a non-schizophrenic psychosis on ICD-8 criteria. The distribution of scores in those later diagnosed as suffering from schizophrenia was shifted in a downward direction, with a linear relationship between low IQ and risk. This remained after adjustment for potential confounders. The risk for non-schizophrenic disorders was also higher in those with lower IQ but the effect was less marked and non-linear. Only poorer performance on the verbal tasks and mechanical knowledge test conferred a significantly increased risk for schizophrenia after taking into account general intellectual ability. Low IQ at conscription was not related to age of onset. CONCLUSIONS: The results confirm the importance of low intellectual ability as a risk factor for schizophrenia and other psychoses. This is unlikely to be due to prodromal decline or known confounders. The association could be directly causal with cognitive impairment leading to false beliefs and perceptions, or could be indirect with any factors causing lower IQ, such as abnormal brain development increasing the risk for schizophrenia.

Adolescent↗
PubMed1996

Novel (R)-2-amino-5-fluorotetralins: dopaminergic antagonists and inverse agonists.

A series of secondary and tertiary N-alkyl derivatives of (R)-2-amino-5-fluorotetralin have been prepared. The affinities of the compounds for [3H]raclopride-labeled cloned human dopamine (DA) D2 and D3 receptors as well as [3H]-8-OH-DPAT-labeled rat hippocampal 5-HT1A receptors were determined. In order to selectively determine affinities for the high-affinity agonist binding site at DA D2 receptors, the agonist [3H]quinpirole was used. The intrinsic activities of the compounds at DA D2 and D3 receptors were evaluated in a [35S]GTP gamma S binding assay. The novel compounds were characterized as dopaminergic antagonists or inverse agonists. The antagonist (R)-2-(butylpropylamino)-5-fluorotetralin (16) bound with high affinity (Ki = 4.4 nM) to the DA D3 receptor and was the most D3-selective compound (10-fold). (R)-2-[[4-(8-Aza-7, 9-dioxospiro[4.5]decan-8-yl)butyl]propylamino]-5-fluorote tralin (18) bound with very high affinity to both DA D3 and 5-HT1A receptors (Ki = 0.2 nM) and was also characterized as a dopaminergic antagonist. (R)-2-(Benzylpropylamino)-5-fluorotetralin (10) behaved as an inverse agonist at both DA D2 and D3 receptors. It decreased the basal [35S]GTP gamma S binding and potently inhibited the DA-stimulated [35S]GTP gamma S binding. It is apparent that the intrinsic activity of a 2-aminotetralin derivative may be modified by varying the N-alkyl substituents.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Differential serotoninergic and dopaminergic activities of the (R)- and the (S)-enantiomers of 2-(di-n-propylamino)tetralin.

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenolic or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat body posture) behavioural responses. The present study shows that s.c. administration of (R)-DPAT induces typical 5-HT1A receptor agonist behaviours. These effects are blocked by the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administration of (S)-DPAT induces dopaminergic behaviours, which are fully antagonised by raclopride, a dopamine D2 receptor antagonist. Both enantiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-hydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxylase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytryptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT1A receptor agonist and (S)-DPAT as a dopamine D2 receptor agonist. Presynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S)-DPAT for dopamine D2 receptors. Receptor binding studies, utilizing [3H]8-hydroxy-2-(di-n-propylamino)tetralin and [3H]quinpirole as radioligands for 5-HT1A and dopamine D2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A receptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT for dopamine D2 receptors. Thus, the results from receptor binding studies support the conclusion that (R)- and (S)-DPAT are agonists showing selectivity for 5-HT1A and dopamine D2 receptors, respectively. Taken together, these findings may explain previous controversies with regard to the pharmacology of racemic DPAT and re-emphasise the necessity to study pure enantiomers of chiral compounds.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Critical reevaluation of spiperone and benzamide binding to dopamine D2 receptors: evidence for identical binding sites.

There are several inconsistencies in the literature as regards the characteristics of benzamide and butyrophenone binding to dopamine D2-like receptors. The variations observed in Bmax, Kd and Ki values have led to hypotheses, such as the existence of a specific "benzamide binding site' and that dopamine D2 receptors exist in a monomer-dimer equilibrium, where benzamides are supposed to bind receptor monomers and butyrophenones receptor dimers. We have previously suggested that the discrepant results may instead be related to methodological difficulties associated with the use of very high-affinity radioligands (e.g. ligand depletion and failure to achieve equilibrium). The present study was designed to reinvestigate and critically reevaluate the binding characteristics of [3H]spiperone, [3H]nemonapride, [125I](S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6- dimethylsalicylamide ([125I]NCQ-298) and [3H]raclopride to cloned human dopamine D2A and rat striatal dopamine D2 receptors in order to establish whether they label the same receptor population. We found that the Kd values of [3H]spiperone, [125I]NCQ-298 and [3H]nemonapride were about 20 pM and that of [3H]raclopride about 1 nM. We did not find any significant differences between the Bmax values determined with the various radioligands. Furthermore, the Ki values of spiperone and NCQ-298 (derived from cross-competition studies) for dopamine D2 receptors labelled with either [3H]spiperone or [125I]NCQ-298 were in good agreement with the corresponding Kd values. In conclusion, our results clearly demonstrate that when studied under correct experimental conditions, all four radioligands label an identical receptor population.

Animals↗