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AbstractAimsThe aim of this study was to determine possible differences in psychiatric care contact and the type of contact in the year prior to suicide by migrant status and region of origin compared to Swedish persons.MethodsA population-based open cohort design, using linked national registers, to study all individuals aged 20–64 years who died by suicide between 1 January 2006 and 31 December 2016 in Sweden (N= 12 474). The primary exposure was migrant status compared to the Swedish majority population in the following categories: non-refugee migrants, refugee migrants and children of migrants. The secondary exposure was region of origin in seven regions: Sweden, other Nordic countries, Europe, Sub-Saharan Africa, the Middle East and North Africa, Asia, the Americas and Oceania. The four outcomes were psychiatric in- and outpatient care, prescribed and purchased psychotropic medication and a variable composing the other variables, all measured the year before death. Logistic regression models adjusted for age, sex, income and marital status estimated the likelihood of psychiatric care utilisation by type of care within the year prior to death by migrant status and region of origin (individually and combined).ResultsOut of all who had died by suicide, 81% had had psychiatric care of any type in the year before death by suicide. Among refugees the prevalence of psychiatric care before death by suicide was 88%. Compared with the Swedish reference group, non-refugees and persons from Asia and Sub-Saharan Africa had a lower likelihood of utilising psychiatric care prior to suicide driven by a lower use of prescribed psychotropic medication. Persons from the Middle East and North Africa had a higher likelihood, driven by higher use of psychiatric outpatient care and prescribed psychotropic medication. Non-refugees' likelihood of utilising care before death by suicide was lower within the first 5 years of living in Sweden.ConclusionA large share of those who die by suicide use psychiatric care the year before they die. Non-refugee migrants and persons from Asia and Sub-Saharan Africa have a lower likelihood of utilising psychiatric care prior to suicide compared to Swedish, whereas persons from the Middle East and North Africa have a higher likelihood. Health care and policy makers should consider both migrant status, region of origin and time in the new country for further suicide prevention efforts.

ErbB4 is a member of the epidermal growth factor receptor (ErbB) family that mediates cellular responses activated by neuregulins (NRG) and other epidermal growth factor-like growth factors. Two naturally occurring ErbB4 isoforms, ErbB4 CYT-1 and ErbB4 CYT-2, have previously been identified. Unlike ErbB4 CYT-1, ErbB4 CYT-2 lacks a phosphoinositide 3-kinase (PI3-K)-binding site and is incapable of activating PI3-K. We have now examined the consequences of the inability of this isoform to activate PI3-K on cell proliferation, survival, and chemotaxis in response to NRG-1beta: (i) NRG-1beta stimulated proliferation of cells expressing either ErbB4 CYT-1 or ErbB4 CYT-2. Consistent with the mitogenic responsiveness, analysis of downstream signaling showed that Shc and MAPK were phosphorylated after stimulating either isoform with NRG-1beta. (ii) NRG-1beta protected cells expressing ErbB4 CYT-1 but not cells expressing ErbB4 CYT-2 from starvation-induced apoptosis as measured by effects on cell number and 4', 6-diamidino-2-phenylindole staining. Furthermore, in cells expressing ErbB4 CYT-2, Akt, a protein kinase that mediates cell survival, was not phosphorylated. (iii) NRG-1beta stimulated chemotaxis and membrane ruffling in cells expressing ErbB4 CYT-1 but not in cells expressing ErbB4 CYT-2. In summary, ErbB4 CYT-2 can mediate proliferation but not chemotaxis or survival. These results suggest a novel mechanism by which cellular responses such as chemotaxis and survival may be regulated by the expression of alternative receptor-tyrosine kinase isoforms that differ in their coupling to PI3-K signaling.

In a model of cerebral hypoxia-ischemia in the immature rat, widespread brain injury is produced in the ipsilateral hemisphere, whereas the contralateral hemisphere is left undamaged. Previously, we found that calpains were equally translocated to cellular membranes (a prerequisite for protease activation) in the ipsilateral and contralateral hemispheres. However, activation, as judged by degradation of fodrin, occurred only in the ipsilateral hemisphere. In this study we demonstrate that calpastatin, the specific, endogenous inhibitor protein to calpain, is up-regulated in response to hypoxia and may be responsible for the halted calpain activation in the contralateral hemisphere. Concomitantly, extensive degradation of calpastatin occurred in the ipsilateral hemisphere, as demonstrated by the appearance of a membrane-bound 50-kDa calpastatin breakdown product. The calpastatin breakdown product accumulated in the synaptosomal fraction, displaying a peak 24 h post-insult, but was not detectable in the cytosolic fraction. The degradation of calpastatin was blocked by administration of CX295, a calpain inhibitor, indicating that calpastatin acts as a suicide substrate to calpain during hypoxia-ischemia. In summary, calpastatin was up-regulated in areas that remain undamaged and degraded in areas where excessive activation of calpains and infarction occurs.

The Levene model in 7‐day‐old rats is the most often used model of hypoxia—ischaemia (HI) in immature animals. The rat central nervous system is immature at birth and corresponds neurodevelopmentally to the term human infant during the second postnatal week. The Levene model of HI differs from clinical asphyxia with respect to the unilateral distribution of brain injury and lack of multi‐organ dysfunction. Furthermore, it does not allow cardiovascular monitoring or repeated blood sampling. On the other hand, the progressive nature of HI bears many similarities to birth asphyxia with regard to blood flow changes and cellular metabolic derangements. The model is well characterized, easy to carry out and the low cost allows inclusion of a sufficient number of animals for dose‐response evaluation of neuroprotective agents. In addition, it provides the unique opportunity of long‐term evaluation of neuropathological and functional outcome.

The aim of this study was to investigate the possible role of excitatory amino acids (EAAs) and cysteine in the development of brain damage after hypoxia-ischemia (HI) in neonates. In a rat model of neonatal HI, changes in extracellular (ec) amino acids in cerebral cortex were measured with microdialysis and correlated with the extent of brain damage at the site of probe placement. Extracellular concentrations of glutamate, aspartate and cysteine increased during HI and remained elevated during reperfusion. During HI the pattern of EAA changes was the same in the infarcted, undamaged and border zone regions. During reperfusion, however, the ec concentrations of glutamate, aspartate and cysteine were higher in infarcted and border zone areas compared to undamaged tissue. HI also produced a slight increase of tissue concentration of cysteine and decrease of tissue concentration of glutamate in parietal cortex of the HI hemisphere. The effect of cysteine on brain damage induced by HI and glutamate was also investigated. A subtoxic dose of cysteine potentiated glutamate toxicity in the arcuate nucleus and enhanced brain infarction after HI in neonatal rats. The results show that in neonatal HI the extracellular levels of EAAs during HI are not directly related to brain injury but the EAA levels during reflow predict the extent of infarction. Cysteine increases HI-induced brain injury and potentiates glutamate toxicity in neonatal rats. Speculatively, elevated level of cysteine during reperfusion may participate in the excitotoxic cascade leading to brain injury.

The loci encoding the class II cell surface antigens HLA-DR, -DQ, and -DP exhibit a remarkable degree of allelic polymorphism. Most of the class II allelic diversity is localized to the second exon, which encodes a beta-pleated sheet followed by an alpha-helical domain. Here, phylogenetic analysis of 39 human DRB1 alleles and 21 DRB1 alleles obtained by polymerase chain reaction (PCR) amplification from a set of closely related primates reveals that sequences encoding the beta-pleated sheet and those encoding the alpha-helix of the second domain have different evolutionary histories. The polymorphisms in the beta-pleated sheet have been conserved between species and appear to reflect the ancestral relationships among haplotypes, whereas polymorphic segments encoding the alpha-helical domain appear to have been inserted by interallelic sequence exchange into the framework of different ancestral DRB1 sequences. Allelic polymorphism at the DRB1 locus may thus have been generated in part by combining different variants of the two structural domains.

A genomic DNA fragment that encodes a Plasmodium falciparum antigen has been isolated by using human antibodies eluted from the membrane of infected erythrocytes. The antigen has a very unusual primary structure; it is exceptionally rich in asparagine residues, many of which are distributed in clusters (2-15 residues) along the polypeptide chain. Unlike many P. falciparum antigens, this protein lacks tandemly repeated sequences. The antigen is distinct from Pf 155, a merozoite-derived antigen deposited in the membrane of infected erythrocytes, but contains epitopes that crossreact with anti-Pf 155 antibodies. Antisera prepared in mice against the asparagine-rich protein react with late-stage parasites in indirect immunofluorescence. In an in vitro merozoite reinvasion assay, the IgG fraction of a mouse polyclonal antiserum, as well as a mouse monoclonal antibody, gave significant inhibition. Three polypeptides (Mr 36,000, 30,000, and 15,000) were recognized by these antibodies on immunoblots of P. falciparum extracts.

l-Cysteine produces excitotoxic brain damage but its chemical structure differs from that of other excitotoxins. Although it is an NMDAmimetic, its mode of action is complex and may encompass antiexcitotoxic components. The purpose of the present study was to investigate whether cysteine kills neurons by potentiating the effects of glutamate and/or by releasing glutamate. In primary cultures of cortical neurons, 24 h of exposure to glutamate caused a concentration-dependent, dizocilpine-sensitive cell death as measured by release of lactate dehydrogenase. Cysteine was also toxic but higher concentrations were required. In addition, N-acetylcysteine produced mild toxicity at 1 mM. There was no general potentiation between either glutamate and cysteine or glutamate and N-acetylcysteine although some combinations acted synergistically. In no case did the thiols inhibit glutamate toxicity. The interaction between glutamate and cysteine toxicity was also assessed in the immature rat arcuate nucleus in vivo. When given at a dose (0.5 mg/g) that did not cause any toxicity per se, cysteine enhanced the toxicity of glutamate (0.3–0.8 mg/g). Cortical microdialysis was carried out in anesthetized rats (8–10 days old) administered a toxic dose of cysteine (1 mg/g). The levels of taurine were elevated 15-fold, phosphoethanolamine 3-fold and alanine 2-fold. Despite the observation that glutamine decreased markedly and rapidly, there was only a delayed doubling of glutamate concentrations. It is therefore unlikely that cysteine induces neurotoxicity by releasing glutamate. Taken together, the results suggest that there is a synergistic effect between cysteine and glutamate. Speculatively, this potentiation may be produced by reduction by cysteine of the redox site of the glutamate-activated NMDA receptor-ionophore complex.