Brain, Behavior, and Immunity(動物愛誤)(アニマルホーダー.動物囤積症.Animal Hoarding)(統合失調症.思覺失調症)(双極性障害.躁鬱症)(トキソプラズマ.弓形蟲感染症.Toxoplasma gondii)
Volume 79, July 2019, Pages 152-158
還要多少犧牲？毛寶不願面對的真相 トキソプラズマ感染と予防について解説 寄生蟲是如何改變生物體的行為(有字幕.中日字幕あり)
Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders
Highlights
•
T. gondii infection might be a contributing causal factor for schizophrenia.
•
CMV infection might be a contributing causal factor for any psychiatric disorder.
•
CMV infection was associated with attempting or committing suicide.
Abstract
Background
Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior.
Methods
This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N=2591), have attempted or committed suicide (N=655), or have had traffic accidents (N=2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants.
Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV).
Results
T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03–2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27–6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00–1·23, p=0.054) was found.
CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06–1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12–1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10–1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08–1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01–2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97–1·17) was found.
Conclusions
This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.
Keywords
Toxoplasma gondiiToxoplasmosisCytomegalovirusInfectionParasite, psychiatric disordersSuicideTraffic accidentsAntibodiesSerology
1. Introduction
In recent years there has been a growing interest in the influence of infectious agents on human behavior and mental disorders. Common infectious pathogens such as Toxoplasma gondii (T. gondii) and cytomegalovirus (CMV) have been associated with psychiatric disorders, cognitive deficits, suicidal behavior, and traffic accidents (Dickerson et al., 2018, Dickerson et al., 2017, Dickerson et al., 2014b, Flegr et al., 2002, Flegr and Horáček, 2018, Hamdani et al., 2017, Sutterland et al., 2015). The nature of these associations remains uncertain, but it is plausible that they reflect causality.
T. gondii is a protozoan parasite that causes the disease toxoplasmosis. Most exposed people experience a latent (asymptomatic) form of the disease. However, prenatal infection with T. gondii may cause abortion as well as a congenital syndrome that includes seizures and severe intellectual disability (Nissen et al., 2017). Studies have demonstrated that latent T. gondii infection may induce behavioral changes both in animal models and in humans, possibly as part of an evolutionary strategy dubbed the ‘parasite manipulation hypothesis’, but the results have been inconsistent (Flegr et al., 2011, Poirotte et al., 2016, Worth et al., 2014).
CMV is a common lifelong, latent beta herpes virus infection, and most healthy exposed people experience a latent form of the disease, with few or no symptoms. Congenital CMV infection may cause visual impairment, hearing loss or cognitive impairment (Dollard et al., 2007). Several studies have shown that infection with CMV is associated with increased risk of psychiatric disorders such as schizophrenia, bipolar disorder, and cognitive deficits (Dickerson et al., 2014b, Hamdani et al., 2017). Moreover, CMV may exacerbate existing psychiatric pathology through mechanisms including induction of pro-inflammatory cytokines (e.g., interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)) or directly via interactions with specific illness susceptibility genes (Prossin et al., 2015).
If T. gondii and CMV infections were causally associated with inexpedient behavior or psychiatric disorders it could have public health as well as clinical implications, since it could offer targets for both prevention and treatment. To this end, it is essential to establish the direction of the association between the infectious agents and the behavioral and psychiatric outcomes, i.e. the sequence of events. We therefore examined a large cohort of blood donors carefully assessed for both T. gondii and CMV infection exposures over time, and for behavioral and psychiatric outcomes.
2. Methods
2.1. Study population
The Danish Blood Donor Study (DBDS) is an ongoing national large-scale prospective cohort of Danish blood donors, previously described (Burgdorf et al., 2017). DBDS was initiated in March 2010 as a multicenter, public-health study and biobank (www.dbds.dk) and by 2018 included more than 110,000 individuals between 18 and 67years at day of inclusion (inclusive). Data collection in DBDS employs existing infrastructure for standardized data collection and for handling and storage of blood samples from all Danish blood centers. The DBDS biobank contains DNA and EDTA plasma samples, consecutive for all donors returning for blood donation after enrolment.
2.2. Overall design
We carried out a case-control study in DBDS and a case-control study nested in DBDS to account for temporality, i.e., the exposure should precede the outcome of interest. Specifically, we identified all individuals in the DBDS cohort registered with psychiatric disorders, suicidal behavior, or traffic accidents (N=5953). All cases with psychiatric disorders (1971–2013), suicidal behavior (1977–2011) and traffic accidents (2008–2012) were included. These were frequency matched with suitable controls (N=7101). For all identified individuals, sample immunological assays were used to provide information on past infection with T. gondii and CMV. Details follow below.
2.3. Psychiatric diagnoses
The Danish Psychiatric Central Research Register (Mors et al., 2011) is a nationwide computerized register. The register holds information on all admissions to Danish psychiatric inpatient facilities since 1969 and to outpatient facilities since 1995. Psychiatric diagnoses are coded according to the International Classification of Diseases − 8th Revision (WHO, 1965) between 1969 and 1993 and 10th Revision (WHO, 1994) since 1994.
Cases with any diagnosis of psychiatric disorder (ICD-10: F00-F99 and eq. ICD-8) and subgroups of cases, including schizophrenia and related disorders (ICD-10: F20-F29 and eq. ICD-8 (Pedersen et al., 2014)), mood disorders (ICD10: F30-F39 and eq. ICD8) and neurotic, stress-related, and somatoform disorders (ICD-10: F40-F48 and eq. ICD-8) before the end of 2013 were obtained. For all participants, we obtained information on parental history of any psychiatric diagnosis.
2.4. Attempting and committing suicide
The Danish Register of Causes of Death (Juel and Helweg-Larsen, 1999) contains information concerning all residents who died in Denmark from 1970 through 2011. In Denmark, the legal regulation on death certification states that any case of sudden and unexpected death shall be reported to the police, and the death certificate may only be issued after a medico-legal examination.
The Danish National Patient Register (Lynge et al., 2011) was established in 1977 to prospectively record public hospital admissions, and obtained nationwide coverage regarding inpatient admissions. From 1995 it was expanded to include outpatient and emergency room contacts, and from 2002 it includes private hospitals and private specialty clinics. Diagnoses are based on the International Classification of Diseases 8th Revision between 1977 and 1993, and the International Classification of Diseases –10th Revision from 1994 onward.
First episode of deliberate self‐violence and suicide were defined by inclusion in the Danish National Patient Register (1977–2012), the Psychiatric Central Research Register (1969–2013) or the Danish Register of Causes of Death (1970–2011), which has previously been used in Danish register studies (Nordentoft, 2011). In this study we restricted the definition criteria to episodes registered after the age of 15.
2.5. Traffic accidents
Participants who had been involved in a traffic accident in the period 2008–2012 were identified in the Danish National Patient Register or in the Danish Register of Causes of Death.
Participants registered with accident as a cause of contact in the Danish National Patient Register were defined as a case if they had one or more cause of contact that indicated involvement in a traffic accident (diagnosis ICD-10: Z041, accident-code: EUK0, EUG0 plus EUA0 or EUA2 or EUHD01). Cases registered as a pedestrian (EUP1) or passenger (EUHD02, EUT2-EUT5) were excluded. Participants with transport accidents (ICD-10: V01-V99) as an underlying cause of death from the Danish Register of Causes of Death were also defined as cases.
2.6. Controls
Frequency matched controls were selected among the 81,912 DBDS participants and matched for age (age at time of blood sampling in completed years) and sex for the 5953 cases. For each sex and age matched group, 20% more controls than cases were chosen (N=7101, of whom 554 were also a case) giving a total number of 12,500 cases and controls. To allow using controls between different outcomes, controls were not conditioned to be healthy. This was handled in the specific analyses for each outcome.
2.7. Immunological assays
Plasma samples from blood donations were initially collected in 5ml plasma preparation tubes (K2EDTA/Gel), centrifuged and frozen within 6h after blood collection. For this study all 81,912 plasma samples were thawed and transferred to Thermo Scientific Matrix tubes with 2D Codes on the bottom, before selection of cases and controls.
The 12,500 selected plasma samples for cases and controls were randomized into three batches and transferred to the Stanley Neurovirology Laboratory for analysis of specific enzyme-based immunoassays for immunoglobulin (IgG) class antibodies against T. gondii and CMV, previously described (Dickerson et al., 2003). The raw IgG antibody titer values were standardized across plates and the distribution of this standardized z-score was fitted with two normal distributions to determine the cut-off value for each batch and each infectious agent (Supplemental Figs. 1 and 2). The cut-off was determined to match the area under the tails in the two normal distributions. If the individual had a value above this cut-off, it was considered that the person had been exposed to the infectious agent.
2.8. Statistical methods
After sample-analysis and quality control, statistical analysis was conducted on 11,546 cases and controls.
A conditional logistic regression model was used to analyze the associations between T. gondii and CMV and the risk of psychiatric disorders, suicidal behavior, and traffic accidents forming strata for frequency matched sets. By design, we controlled for sex and age at time of blood sampling, therefore age and sex are not directly included in the conditional logistic regression. Additionally, we conducted an analysis where toxoplasmosis and CMV were mutually adjusted, and all analyses were adjusted for parental history of psychiatric disorder before time of blood collection, as previously described (Pedersen et al., 2011). Odds ratios (ORs) and 95% likelihood ratio confidence intervals (95% CIs) were calculated. A two-sided P value of less than 0·05 was considered to be statistically significant. Statistical analyses were performed using the PHREG procedure in SAS 9·3 (SAS Institute, Cary, North Carolina). We also calculated the batch specific estimates (Supplemental Figs. 3 and 4).
The nested case-control study was conducted to account for temporality, i.e., the exposure should precede the outcome of interest to fulfill Hills viewpoints of causality (Rothman et al., 2008). For each outcome of interest, we included only individuals with onset after the date of blood sample collection and conducted conditional logistic regression for these cases and their time-, age- and sex-matched controls. The estimates thus obtained are informative for the risk of developing the outcomes of interest following exposure to T. gondii or CMV i.e., incidence rate ratios (Pearce, 1993, Vandenbroucke and Pearce, 2012).
2.9. Ethics
The Ethics Committee of Central Denmark (M-20090237) and The Danish Data Protection Agency (2007-58-0015) have previously approved the study. The Danish Data Protection Agency approved the transport and analysis of plasma samples to the Stanley Neurovirology Laboratory. The National Board of Health approved the use of registry data. Data will be kept confidential under the law concerning processing of personal data. Written informed consent was obtained from all participants.
3. Results
Register data on 81,912 individuals were reviewed to find individuals who had been diagnosed with psychiatric disorders, had attempted or committed suicide, and/or had been involved in traffic accidents, resulting in a total of 12,500 cases and controls. After sample analysis and quality control, statistical analysis was conducted on 11,546 cases and controls, see distribution of cases and controls (non-exclusive) in Table 1. A total of 5492 individuals (2807 women) were registered with a psychiatric disorder, suicide or suicide attempt, or traffic accident. Overall, 2591 individuals (1314 women) were registered in the Danish Psychiatric Central Research Register with a psychiatric diagnosis, 655 (377 women) had attempted or committed suicide, and 2724 individuals (1233 women) had been involved in a traffic accident. The average age at blood donation was 37.4years in the study population; age distribution is shown in Supplemental Fig. 5.
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3.1. Infection with T. gondii and CMV
Of the 11,546 studied individuals, 2990 and 7020 individuals, respectively, tested positive for IgG class antibodies against T. gondii (25·9%) or CMV (60·8%). For a more detailed overview of the number of infected/non-infected cases and controls for each health outcome, see Supplemental Table 1.
We found that individuals with a T. gondii infection had increased odds of being diagnosed with schizophrenia disorders compared to those without infection (OR, 1·47; 95% CI, 1·03–2·09) (Table 1). The association was even stronger when accounting for temporality and considering only the 28 cases who were diagnosed with a schizophrenia disorder after the date of blood collection (IRR, 2·78; 95% CI, 1·27–6·09) (Table 1). A very weak association between toxoplasmosis and involvement in traffic accidents was observed in 9018 individuals (OR, 1·11; 95% CI, 1·00–1·23) also when including only individuals with traffic accident after blood donation (IRR, 1·18; 95% CI, 0·99–1·41) (Table 1). Besides schizophrenia, T. gondii infection was not statistically significantly associated with any other psychiatric disorder, whether overall (OR, 1·03; 95% CI, 0·93–1·15), or more specifically, i.e. mood disorders (OR, 0·89; 95% CI, 0·73–1·07), neurotic, stress-related, and somatoform disorders (OR, 1·05; 95% CI, 0·92–1·21), or attempting or committing suicide (OR, 1·13; 95% CI, 0·94–1·36) (Table 1).
CMV infection was associated with increased risk of: any psychiatric disorder (OR, 1·17; 95% CI, 1·06–1·29), neurotic, stress-related and somatoform disorders (OR, 1·27; 95% CI, 1·12–1·44) and attempting or committing suicide (OR, 1·31; 95% CI, 1·10–1·56) (Table 1). Considering only cases with an outcome after the date of blood donation, CMV infection was still statistically significantly associated with any psychiatric disorder (IRR, 1·37; 95% CI, 1·08–1·74) but not with attempting or committing suicide (IRR, 1·18; 95% CI, 0·50–2·82). In addition, CMV infection was found only to be associated with mood disorders (IRR, 1·43; 95% CI, 1·01–2·04) after excluding individuals with onset pre-dating blood sample collection (Table 1). CMV infection was not statistically significantly associated with schizophrenia and related disorders (OR, 1·25; 95% CI, 0·89–1·77) or with traffic accidents (OR, 1·06; 95% CI, 0·97–117) (Table 1). Mutual adjustment of CMV and toxoplasmosis did not change the overall findings (Supplemental Table 2).
4. Discussion
This largest to date serological study provides evidence that exposure to T. gondii might be a contributing causal factor for developing schizophrenia and that exposure to CMV might be a contributing causal factor for developing serious psychiatric disorders.
Research suggests that changes in dopamine levels are involved in the pathogenesis of toxoplasmosis-associated behavior changes in humans. These include prolongation of reaction time, decreased long-term concentration, decreased cognition and specific changes in neurodegenerative- and psychiatric disorders (Flegr et al., 2003).
The Toxoplasma genome carries two genes encoding dopamine-synthesizing enzymes (tyrosine hydroxylase) (Gaskell et al., 2009, Henriquez et al., 2009). Dopamine is produced and secreted in large amounts in Toxoplasma cysts in the brain tissue of infected rodents (Martin et al., 2015, Prandovszky et al., 2011) and most likely in humans as well (Flegr et al., 2003, Henriquez et al., 2009, McConkey et al., 2013, Skallová et al., 2005). It has been shown that latent (but not acute) T. gondii infection in mice elevates the local brain dopamine concentrations, as observed in individuals with schizophrenia (Eyles et al., 2012, Henriquez et al., 2009). This increased dopamine level may be responsible for toxoplasmosis-associated behavior changes.
Human cognition may be affected by exposure to T. gondii, as severe congenital toxoplasmosis can lead to mental retardation (Nissen et al., 2017). Even among “unaffected” children with congenital toxoplasmosis, high maternal antibody titres during pregnancy are associated with delayed mental development in their first year and an increased risk of having an IQ less than 70 at 7years (Sever et al., 1988). Human cognition and behavior may also be affected by postnatal T. gondii infection. In schoolchildren, Toxoplasma seropositivity has been associated with lower mathematics (Ferreira et al., 2013) and reading skills but also poorer memory capacity (Mendy et al., 2015a, Mendy et al., 2015b). Several studies have also shown a negative effect of T. gondii on cognition in adults and the elderly (Dickerson et al., 2014a, Gajewski et al., 2014, Hamdani et al., 2017, Mendy et al., 2015a, Mendy et al., 2015b, Nimgaonkar et al., 2016, Wyman et al., 2017).
Infections have been associated with cognitive and behavior changes in humans. Prenatal exposure to a range of infections and inflammatory responses may be associated with increased risk of adult schizophrenia (Khandaker et al., 2013). Infections in early childhood have been found to have negative effects on human cognition and increased risk of nonaffective psychosis. The association between infection and non-affective psychosis is mediated and moderated by IQ (Khandaker et al., 2018).
The immunological reaction to a parasite infestation may disrupt tryptophan metabolism, as parasite-infected cells secrete large amounts of kynurenic acid (KYNA) via indoleamine-2,3-dioxygenase (IDO)-mediated tryptophan degradation (Henriquez et al., 2009, McConkey et al., 2013). Latent T. gondii infection leads to the production of the rate-limiting enzyme IDO and tryptophan dioxygenase (TDO) in astrocytes (Campbell et al., 2014, Henriquez et al., 2009, McConkey et al., 2013, Nagineni et al., 1996). This leads to decreased levels of tryptophan, necessary for the growth and replication of T. gondii, but moreover, leads to the production of some harmful metabolites such as KYNA. Tryptophan is degraded by IDO to kynurenine, which is either metabolized to KYNA, an antagonist of the glutamate N-methyl-d-aspartate (NMDA) and nicotinic receptors (Campbell et al., 2014, Henriquez et al., 2009, Kessler et al., 1989) or hydroxylated to quinolinate, a potent NMDA neurotoxic agent (El-Defrawy et al., 1986). High levels of KYNA are found in the cerebrospinal fluid of schizophrenic individuals, and may plausibly cause cognitive disorders in schizophrenia (Henriquez et al., 2009). Tryptophan is also the essential precursor of serotonin, which is involved in depressive disorders. Hence, both dopaminergic and glutamatergic systems are affected by T. gondii and could represent the mediating factors between toxoplasmosis and psychiatric disease.
A causal relationship between serological evidence of exposure to Toxoplasma and psychiatric disorders has been well studied in individuals with schizophrenia (Flegr and Horáček, 2018, Hamdani et al., 2017, Sutterland et al., 2015, Torrey et al., 2012, Torrey et al., 2007). We found a statistically significant association between serological evidence of exposure to Toxoplasma and schizophrenia or related disorders, compared to controls. An even stronger statistically significant association was observed between serological evidence of exposure to Toxoplasma and schizophrenia after excluding participants whose diagnosis preceded blood sample collection. This corroborates that Toxoplasma has a positive effect on the rate of schizophrenia and that T. gondii infection might be a contributing causal factor for schizophrenia. Similarly, a meta-analysis including all available studies analyzing the association between T. gondii infection and schizophrenia reported an increased odds ratio of 2·73 (Torrey et al., 2007). This level of association exceeds both the genetic and most other environmental risk factors for schizophrenia to date (Torrey et al., 2012), supporting the close relation between T. gondii infection and schizophrenia.
It has been found that individuals with higher titers of IgG class antibodies on T. gondii often show more severe symptoms of psychosis and a correlation between toxoplasmosis and increased mortality in schizophrenic patients has been observed (Dickerson et al., 2007, Torrey et al., 2007). Interestingly, many anti-psychotic drugs commonly used in the treatment of schizophrenic patients have anti-T. gondii activity and may inhibit the replication and invasion of T. gondii in infected individuals (Gutiérrez-Fernández et al., 2015). It has been shown that schizophrenic patients treated with anti-psychotic drugs have lower levels of antibodies to T. gondii compared to untreated schizophrenic patients (Leweke et al., 2004). One could argue that the effect of anti-psychotic drugs in schizophrenic patients may be partly due to the inhibition of T. gondii activity.
Toxoplasma-associated behavior changes could result in decreased concentration and prolonged reaction time, which could increase the risk of traffic accidents. We found a very weak statistical association between T. gondii infection and risk of traffic accidents. Previous studies have found a 2–4 times higher risk of traffic accidents in individuals with T. gondii infection compared to non-infected individuals (Flegr et al., 2002, Flegr and Dama, 2014, Stepanova et al., 2017). Interesting, the only existing prospective cohort study on traffic accidents and toxoplasmosis found a significant association between traffic accidents and toxoplasmosis only in RhD-negative individuals, and not in RhD-positive individuals or in the non-sorted population (Flegr et al., 2009). The difference in RhD status could also apply to our study and may explain why we only found a very weak association between toxoplasmosis and traffic accidents. A recent systematic review and meta-analysis concluded that exposure to T. gondii significantly increases the risk of having traffic accidents (Gohardehi et al., 2018) which our results also supports. In addition, T. gondii infected individuals have been found also to have an increased risk of workplace accidents (perhaps due to decreased concentration and prolonged reaction times) (Alvarado-Esquivel et al., 2012) and of starting their own business (Johnson et al., 2018), but not of increased financial risk-taking (Lanchava et al., 2015).
Besides T. gondii infection, herpesvirus, such as CMV, infection has also been associated with psychiatric disorders, schizophrenia, mood disorders, decreased cognitive functioning, and suicide in seriously mentally ill individuals (Dickerson et al., 2017, Dickerson et al., 2014b, Hamdani et al., 2017, Prossin et al., 2015). Infections like CMV may cause alterations in the immune inflammatory cascades and have an impact on brain function through neuroinflammation (Tanaka et al., 2017).
In our study, CMV was statistically significantly associated with having any psychiatric disorder. An even stronger association was observed when including only individuals diagnosed after blood collection. CMV was more strongly associated with a more selected group of neurotic, stress-related, and somatoform disorders. This group might drive the observed effect in any psychiatric disorder, and a post hoc analysis showed that CMV infection had no impact on the risk of any psychiatry excluding F40-F48 (OR=1·06, 95% CI 0·94–1·21, IRR=1·41, 95%CI 0·99–2·00). Studies have showed that higher CMV-IgG levels are associated with increased anxiety, depression, vital exhaustion (lack of energy, increased irritability, and feelings of demoralization) and decreased SF-12 mental health (Phillips et al., 2008, Rector et al., 2014, Trzonkowski et al., 2004). Higher CMV-IgG levels reflect poorer immune control and reactivation of the virus (Glaser and Kiecolt-Glaser, 1994, Kuo et al., 2008, van Zanten et al., 1995), which may be triggered by psychological stress, representing a potential mechanism linking stress and immunity (Bosch et al., 2013).
Prossin et al. also found that a higher IgG concentration against CMV was associated with elevated mood states in bipolar disorders compared to healthy controls. In addition, CMV IgG was higher in individuals with bipolar disorder with elevated moods but not different in depressed moods when compared with euthymic bipolar disorder individuals (Prossin et al., 2015). We found a statistically significant association between CMV and mood disorder, but only in individuals diagnosed after the date of blood collection. In our analysis, we combined all diagnoses of mood disorders (ICD-10: F30-F39) into one category, whereas Prossin et al. focused only on bipolar disorder (ICD-10: F30-31) (Prossin et al., 2015). Our analysis was based on a more diverse group of mood disorders and is not suitable for demonstration of a statistically significant association between CMV and a specific mood disorder, such as bipolar disorder, due to the small numbers of cases (N=57).
Previous studies have reported an association between inflammatory processes, such as infectious agents, and suicide. We found that CMV infection was statistically significantly associated with attempting or committing suicide. Taking only suicide or suicide attempts after blood donation into account, no association was observed, which might be due to the small number of individuals with suicide or suicide attempts after blood collection. Only two studies to date have addressed the association between CMV and suicide, and found an association between CMV and suicide attempts in individuals with serious mental illness (Dickerson et al., 2018, Dickerson et al., 2007). The observed association between CMV and suicide attempt may be due to the direct effect of the microorganisms altering the level of dopamine and other neurotransmitters, or due to the immune response altering the activity of toll-like receptors in response to CMV, which has also been shown to be altered in brains of individuals with completed suicide attempts (Pandey et al., 2014).
The effect of coinfection with T. gondii and CMV and the association with psychiatric disorders, suicidal behavior or traffic accidents did not influence the overall results.
Our study has several strengths. This case-control study is the largest serological study to date of T. gondii and CMV infection in relation to psychiatric disorders, self-violence and risk-taking behavior in a nation-wide population. Another strength of this study was that we accounted for temporality in the nested case-control study, i.e., the pathogen exposure should precede the outcome of interest to show possible causality. A limitation of this study was that we did not control for socio-economic factors, which may influence the probability of pathogen infection, development of psychiatric disorders, suicidal behavior, or involvement in traffic accidents. A study of the socio-demographic characteristics of the DBDS population showed that the middle to high income groups, but not the highest income group, had fourfold higher donor prevalence than the lowest income group (6.7% compared to 1.7%) and that social marginalization, as indicated by low income and being a male living without a woman, was associated with lower prevalence of blood donation (Burgdorf et al., 2017). We cannot rule out that socio-economic factors could potentially account for part or all of the observed causaleffect. The link between family history of psychiatric disorder and psychiatric disorders or suicidal behavior is well established (Dean et al., 2010). However, adjusting for parental history of psychiatric disorders did not influence the overall results. In this study, the prevalence of any psychiatric disorders was lower than the national lifetime risk of mental disorders (Pedersen et al., 2014). This may be due to the fact that the blood donor population is a highly selected population who are healthier than the general population, and since older blood donors are a highly selected group of individuals (the healthy donor effect), the generalizability to other settings may be limited.
In conclusion, our study finds that T. gondii infection might be a contributing causal factor for schizophrenia. Moreover, T. gondii infection was borderline significantly associated with traffic accidents. CMV infection may be a risk factor for developing any psychiatric disorder, especially neurotic, stress-related, and somatoform disorders, or for experiencing self-violence in the form of attempting or committing suicide. Although we did not control for socio-economic factors, which may have an effect on health outcome, we were able to account for temporality of pathogen exposure. Our findings support the growing scientific evidence linking pathogenic infection with serious psychiatric disorders. Routinely screening for T. gondii and CMV in populations with psychiatric disorders may identify novel stratification groups, which can be used to target treatment e.g. in combination with analysis of genetic risk factors. Likewise, targeting T. gondii or CMV infections can provide novel therapeutic approaches as well as potential biomarkers to identify individuals at increased risk. A detailed understanding of the origin, mechanisms and outcomes of these pathogenic infections in relation to psychiatric disorders, self-violence and risk-taking behavior is necessary in order to improve detection and treatment.
Acknowledgments
We acknowledge and thank the Danish blood donors and the staff at the Danish blood centers who were involved in the present study. A special thanks to Medical Laboratory Technologist Janne Amstrup Møller for her help with handling the samples.
Declaration of interests
The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.
Funding
This work was supported by The Lundbeck Foundation [R209-2015-3500]; The Danish Administrative Regions; The Danish Administrative Regions’ Bio- and Genome Bank; The Novo Nordisk Foundation [NNF14CC0001]; and The Stanley Medical Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
https://www.sciencedirect.com/science/article/pii/S0889159118306998
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大阪市の住宅街でハトや猫に大量の餌を与え続ける女性たち(鳥インフルエンザ.禽流感)(新型隱球菌.クリプトコックス症)(トキソプラズマ.弓形蟲感染症.Toxoplasma gondii)
トキソプラズマ症はアメリカでの食中毒関連の死因の第2位(動物愛誤)(トキソプラズマ.弓形蟲感染症.Toxoplasma gondii)①
USDA is turning lab cats into cannibals by forcing them to eat feline meat, watchdog says(動物愛誤)(トキソプラズマ.弓形蟲感染症.Toxoplasma gondii)②
US government 'killed thousands of kittens' as part of secretive decades-long experiments(動物愛誤)(トキソプラズマ.弓形蟲感染症.Toxoplasma gondii)③
The US government has agreed to stop killing thousands of kittens, which were being purposely infected with parasites for research(動物愛誤)(トキソプラズマ.弓形蟲感染症.Toxoplasma gondii)④
ネコは生態系の脅威か 約32億羽の鳥類を殺す(動物愛誤)(アニマルホーダー.動物囤積症.Animal Hoarding)(自然破壊.生態破壞)(製造車禍.傷人)(トキソプラズマ.弓形蟲感染症.Toxoplasma gondii)
【猫による被害まとめ】
１．糞尿・スプレーによる悪臭。
２．駐車中の車への傷つけ・スプレー。
３．悪戯・喧嘩による庭の破壊。
４．ペットへの加害・捕食。
５．網戸等の破壊。
６．ゴミ漁りによる散らかし。
７．蚤・トキソプラズマ等の、寄生虫・菌・ウィルスの感染媒体となり人に感染、若しくは中継。
※公園で野良猫に餌やりをされた為に野良猫が集まり、砂場が猫のトイレと化し子供達が遊べなくなるケースも発生しています。
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住民「ちゃんとクソの始末もしろよ」 ※
猫狂「どんどん窮屈な世の中になった」
住民「だからちゃんとクソの始末もしろよ」
猫狂「猫嫌いはキチガイ。みんな死ねばいい」
住民「そうじゃなくてクソの始末しろよ」
猫狂「ちゃんと去勢だってしてるし地域猫はいてもいい」
住民「だからクソの始末しろよ」
猫狂「ネズミとか・・・」
住民「クソの始末のハナシしてんだよ」
猫狂「ペストとか・・・」
住民「平成の世にペストがなんだって？クソさせるなよ」
猫狂「猫嫌いは猟奇殺人予備軍」
住民「クソの始末はどうした？」
猫狂「猫嫌いは人間同士の排除までやって最後は滅びる」
住民「クソの始末は誰がやるんだよ」
猫狂「猫嫌いはモンスターペアレンツ」
住民「猫のクソの話をしてるんだよクソの」
猫狂「猫嫌いは精神病質を抱えたファシスト」
住民「そうじゃないだろクソの始末の話だよ」
猫狂「犬の鳴き声とか・・・」
住民「クソの話をしてるんだよ猫の」
猫狂「猫嫌いは自分の子供も家に閉じ込める」
住民「人間の子は他所の庭でクソしないだろ」
※くりかえし
Toxoplasma. Mind controlling parasite Must watch
A Brain Parasite Might Be Making Us Angrier
映画『スリザー』予告
-------------------------------------------------------猫様に奉仕するため社会と戦った、猫真理教の聖戦士たちを紹介します。●2009/08/27 「猫に餌」を注意され、隣家女性を刺殺 ７０歳の男を逮捕
２７日午後１時４０分ごろ、千葉県船橋市習志野台で「包丁を持った男が女性を追いかけている」と１１０番通報があった。船橋東署員が現場にかけつけると、女性が自宅付近で腹部から血を流して倒れており、同署は殺人未遂の現行犯で、女性の脇に包丁を持って立っていた、近くに住む無職、林喜市容疑者（７０）を逮捕した。
女性は病院に搬送されたが、間もなく死亡。同署は殺人容疑に切り替えて捜査している。
同署の調べによると、林容疑者は同日午後１時４０分ごろ、隣に住む無職の女性（６４）の腹部を包丁で２回刺して殺害した疑いが持たれている。
林容疑者が２年ほど前から野良猫の餌付けをしていたことを巡り、女性とトラブルになっていた。同署の調べに林容疑者は「猫のことで注意され頭にきてやった」と供述しているという。-------------------------------------------------------●2009/05/25 野良猫に餌をやらないよう注意されたことを逆恨み 大家刺殺に懲役２２年判決 横浜地裁
川崎市のアパートで昨年６月、野良猫に餌をやらないよう注意されたことを発端に大家の男性（当時７６）を刺殺、その長男の妻にもけがを負わせたとして殺人と傷害の罪に問われた同市川崎区浜町３丁目、無職高田正雄被告（７０）に対する判決公判が２５日、横浜地裁川崎支部であり、加登屋健治裁判長は懲役２２年（求刑懲役２５年）の有罪判決を言い渡した。
判決などによると、昨年６月５日午後、高田被告は前日に大家の妻から猫に餌をやらないよう注意されたことに不満を持って自室で騒ぎ、注意しに来た大家の首をナイフで刺すなどして失血死させた。さらに大家の長男の妻の顔をバールで殴って２カ月のけがを負わせた。-------------------------------------------------------●2007/07/27 飼い猫トラブルで隣人刺す ７０歳男逮捕…大阪
飼い猫を巡るトラブルで苦情を言いに来た男性を包丁で刺し、全治２週間のけがを負わせたとして、大阪府警は２６日、東大阪市、無職、中田光一容疑者（７０）を殺人未遂容疑で逮捕した。
調べによると、中田容疑者は同日午後１０時半ごろ、同じアパートに住む男性（５４）の右胸を、自宅にあった包丁で刺した疑い。-------------------------------------------------------●2003/12/08 猫の仕返しと線路に石 電車妨害の男逮捕
8日午後3時10分ごろ、大阪府貝塚市のJR阪和線和泉橋本-東貝塚間で、線路に自転車の車輪や石などがあるのを白浜発新大阪行き特急「くろしお16号」の運転士が発見緊急停車した。運転士が線路脇に除き、約5分後に運転を再開。 けが人はなかった。
線路脇にいた男が投げ入れたと認め、貝塚署は往来危険の疑いで住所不定、無職藤田英久容疑者(52)を 逮捕した。「飼っていた猫が電車にはねられて死に、仕返ししようと思った」と供述したという。
調べでは、藤田容疑者は自転車の車輪2つと段ボール箱、重さ5キロの石を線路に投げ入れた疑い。
JR西日本によると、上下計2本が運休、上下計13本が最大8分遅れ、約2900人に影響した。-------------------------------------------------------名須川早苗(51)2014.4.30 札幌市北区警察施設や大型店で5件のガスボンベ爆発を起こし、激発物破裂の容疑で逮捕。野良猫の餌やりで周囲住民とトラブルを起こし、警察ともめていた模様（現在捜査中）。
-------------------------------------------------------藤井ミヤ子(62)2014.4.20 大阪市阿倍野区民家に置かれていた猫よけシートに放火し、現住建造物等放火未遂の容疑で逮捕。
------------------------------------------------------- 出水衛（48）2013.12.11 大阪府和泉市飼い猫約20匹と野良猫約100匹の餌代のため、民家など32件、被害額約1920万円相当の空き巣を繰り返し、窃盗容疑などで逮捕。「猫を抱きしめているのが至福の時間」と供述。-------------------------------------------------------
片山祐輔(30)2013.2.10 東京都江東区遠隔操作ウィルスで他人のパソコンを乗っ取って犯罪予告をし、パソコン所有者4人の誤認逮捕を引き起こし社会を震撼させた。4人は濡れ衣だとの犯行声明をマスコミに送るなど、警察を挑発し続けたが、ウィルスのソースコード入り記録媒体を江ノ島で猫の首輪に付けたことで身元を特定され、威力業務妨害容疑で逮捕。2006年に「のまネコ」を巡りエイベックスグループを脅迫し、懲役1年6ヶ月の実刑判決を受けるなど、猫への執着心が犯行や逮捕のきっかけとなっている。-------------------------------------------------------
早川充益（39）2013.1.12 名古屋市西区父経営の不動産会社に勤めていたが、「東日本大震災の原発事故で置き去りにされた動物を救う」と被災地に入り、会社が契約者から預かった数千万円の金を横領して犬猫の飼育費などに流用。横領が発覚したため、両親と義理の祖母を絞殺し、小牧市の山中で自殺。-------------------------------------------------------
動物愛護団体ら15人 2012.1～9月 福島県双葉市福島県警双葉署は、福島第一原発事故の警戒区域に無許可で立ち入ったとして、災害対策基本法違反容疑で15人を摘発していたことを2012年9月24日に報告。-------------------------------------------------------
高田光弘（74）2012.1.24 埼玉県毛呂山町息子が飼い猫を虐めていると思い込み、口論の末首を閉めて殺害。殺人容疑で現行犯逮捕。-------------------------------------------------------
西原康太（26）奈奈（30）2011.10.31 広島県東広島市猫の尿や毛などが散乱した不潔な部屋に生後2ヶ月の次男を置き、皮膚炎を発症させ死亡させた。保護責任者遺棄致傷の容疑で逮捕。-------------------------------------------------------
小坂雄造（39）里美（27）2011.5.26 千葉県柏市長男（2）に食事を与えず餓死させ、保護責任者遺棄致死の疑いで逮捕。「子どもより猫の方がかわいかった」と供述。-------------------------------------------------------
宍井良夫（65）2011.3.30 静岡県湖西市野良猫に餌やりしていた公園で、市の職員と共に野良猫を駆除していた男性にカッターナイフを突きつけて脅し、暴力行為容疑で逮捕。逮捕するため自宅に訪れた警察官も殴りつけ、傷害の現行犯。-------------------------------------------------------
坂本とし子（58）2011.3.4 千葉県勝浦市猫の飼育方法を指導しに来た保健所職員の顔をひっかいたとして、公務執行妨害と傷害容疑で現行犯逮捕。-------------------------------------------------------
佐々木祐一（65）2010.11.13 埼玉県寄居町猫同士の喧嘩が元で相手の飼い主の頭や顔を木刀で殴り、重傷を負わせた。殺人未遂容疑で逮捕。-------------------------------------------------------
水元努（31）2010.9.1 北海道留萌市「ペットの猫が死んでむなしくなった」と高速道路を約100km逆走し、道路交通法違反の疑いで現行犯逮捕。-------------------------------------------------------
会社役員の女（48）2010.4.27 岐阜市米国に残したペットの猫に会うため、偽造パスポートで米国へ渡航を繰り返したとして、旅券法違反の罪で懲役１年６カ月の判決。-------------------------------------------------------
板橋静男（72）2010.4.24 埼玉県川口市団地で猫を追いかけていた男児（9）のあごを締め上げるなどし、暴行容疑で逮捕。段ボールで野良猫の家を作り餌を与えるなど、団地内で有名。-------------------------------------------------------
林喜市（70）2009.8.27 千葉県船橋市女性から野良猫の餌やりを注意され、その帰宅を待ち伏せして包丁で刺殺。殺人罪で懲役17年の判決。-------------------------------------------------------
平野幸男（73）2008.10.22 長崎市犬の散歩に通りかかった男性を、餌やり中の野良猫が逃げたからと木刀で脅し、暴力行為容疑で逮捕。-------------------------------------------------------
永吉教幸（72）2008.7.5 栃木県小山市（ホームレス）寝泊まりしている公園で野良猫を抱いた人を、猫を虐めていると勘違いし鉄パイプで殴り、現行犯逮捕。-------------------------------------------------------
20歳の夫婦 2008.7.3 福岡市生後１ヶ月の乳児に食事を与えず、育児放棄で虐待死させる。保護責任者遺棄致死容疑で逮捕。乳児は猫のトイレにしていた段ボールに寝かせていた。「子供より猫の方が可愛かった」と供述。-------------------------------------------------------
河田教晴（28）2008.6.19 大阪市無職・生活保護受給者で猫5匹飼う。餌代に困り何度もコンビニに押し入り、強盗容疑で逮捕。-------------------------------------------------------
高田正雄（69）2008.6.5 神奈川県川崎市アパートの大家に餌やりを注意されて逆上し、サバイバルナイフで大家を刺殺、大家の義理の娘にも重傷を負わせ、殺人及び傷害罪で懲役22年の判決。-------------------------------------------------------
中田光一（70）2007.7.27 大阪市猫被害の苦情を言いに来たアパートの隣人を包丁で刺し、殺人未遂容疑で逮捕。-------------------------------------------------------
静岡県伊東市の老人（81）2006.8.24ペット禁止の市営住宅で猫を放し飼いしていることを市に告げ口されたと妄想、上の階に住む姉妹に言い掛かりを付けた挙げ句にノコギリで殴り、傷害容疑で逮捕。-------------------------------------------------------
中島数男（73）2005.4.24 兵庫県尼崎市猫の餌付けに苦情を言った人の部屋へ包丁を持って押し込み乱闘に。暴力行為(脅迫)容疑で逮捕。-------------------------------------------------------
荒木正道（60）2005.8.29 埼玉県吹上町猫糞で迷惑していた隣人を金属バットで小突くなどして、傷害容疑で逮捕。-------------------------------------------------------
藤田英久（52）2003.12.8 大阪府貝塚市電車に轢かれた猫の仕返しに、線路に自転車のタイヤや段ボール、石などを置き、往来危険容疑で逮捕。----------------------------------------------------------------
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脳をあやつる虫(トキソプラズマ)(弓形蟲感染症)(狂犬病)
http://www.nikkei-science.com/page/magazine/0306/parasite.html
トキソプラズマが人の脳を操る仕組み
http://natgeo.nikkeibp.co.jp/nng/article/news/14/7449/-----------------------------------------------------------------------------
起業したい人は猫のウ●コ食べればできるかも！（良い子は真似しないように、危険です）-----------------------------------------------------------------------------
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狂犬病どんな病気か？(狂犬病)
狂犬病～もし咬まれたら，すぐに医療機関へ(狂犬病)
犬・猫回虫症(イヌ回虫.犬蛔蟲.Toxocara canis)(猫回虫.貓蛔蟲.Toxocara cati)⑥
回虫症(イヌ回虫.犬蛔蟲.Toxocara canis)(猫回虫.貓蛔蟲.Toxocara cati)⑦
消化管内の寄生虫(イヌ回虫.犬蛔蟲.Toxocara canis)(猫回虫.貓蛔蟲.Toxocara cati)⑧
イヌ・ネコ回虫感染症(イヌ回虫.犬蛔蟲.Toxocara canis)(猫回虫.貓蛔蟲.Toxocara cati)⑨
成人肺トキソカラ症8例(イヌ回虫.犬蛔蟲.Toxocara canis)(猫回虫.貓蛔蟲.Toxocara cati)⑩
創作內容
Brain, Behavior, and Immunity(Animal Hoarding)(Toxoplasma gondii)
人と動物の共通感染症 (165)
