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Article ; Online: Programmed ageing: decline of stem cell renewal, immunosenescence, and Alzheimer's disease.

Lathe, Richard / St Clair, David

Biological reviews of the Cambridge Philosophical Society

2023 Volume 98, Issue 4, Page(s) 1424–1458

Abstract: The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. ... ...

Abstract	The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master 'clock of age' (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial - specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.
MeSH term(s)	Animals ; Humans ; Mice ; Aged ; Immunosenescence/physiology ; Alzheimer Disease/genetics ; Cell Self Renewal ; Aging ; Mammals ; Hormones
Chemical Substances	Hormones
Language	English
Publishing date	2023-04-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1423558-4
ISSN	1469-185X ; 0006-3231 ; 1464-7931
ISSN (online)	1469-185X
ISSN	0006-3231 ; 1464-7931
DOI	10.1111/brv.12959
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Article ; Online: Autoantibodies against acetylcholine receptors are increased in archived serum samples from patients with schizophrenia.

McLean, Ryan Thomas / Buist, Elizabeth / St Clair, David / Wei, Jun

Schizophrenia research

2024 Volume 267, Page(s) 8–13

Abstract: Previous studies have demonstrated that the levels of IgG against neurotransmitter receptors are increased in patients with schizophrenia. Genome-wide association (GWA) studies of schizophrenia confirmed that 108 loci harbouring over 300 genes were ... ...

Abstract	Previous studies have demonstrated that the levels of IgG against neurotransmitter receptors are increased in patients with schizophrenia. Genome-wide association (GWA) studies of schizophrenia confirmed that 108 loci harbouring over 300 genes were associated with schizophrenia. Although the functional implications of genetic variants are unclear, theoretical functional alterations of these genes could be replicated by the presence of autoantibodies. This study examined the levels of plasma IgG antibodies against four neurotransmitter receptors, CHRM4, GRM3, CHRNA4 and CHRNA5, using an in-house ELISA in 247 patients with schizophrenia and 344 non-psychiatric controls. Four peptides were designed based on in silico analysis with computational prediction of HLA-DRB1 restricted and B-cell epitopes. The relationship between plasma IgG levels and psychiatric symptoms, as defined by the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), were examined. The results showed that the levels of plasma IgG against peptides derived from CHRM4 and CHRNA4 were significantly increased in patients with schizophrenia compared with control subjects, but there was no significant association of plasma IgG levels with any symptom domain or any specific symptoms. These preliminary results suggest that CHRM4 and CHRNA4 may be novel targets for autoantibody responses in schizophrenia, although the pathogenic relationship between increased serum autoantibody levels and schizophrenia symptoms remains unclear.
MeSH term(s)	Humans ; Schizophrenia/blood ; Schizophrenia/immunology ; Autoantibodies/blood ; Female ; Male ; Adult ; Middle Aged ; Immunoglobulin G/blood ; Receptors, Cholinergic/immunology ; Enzyme-Linked Immunosorbent Assay
Language	English
Publishing date	2024-03-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	639422-x
ISSN	1573-2509 ; 0920-9964
ISSN (online)	1573-2509
ISSN	0920-9964
DOI	10.1016/j.schres.2024.03.012
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Article ; Online: From conifers to cognition: Microbes, brain and behavior.

Lathe, Richard / St Clair, David

Genes, brain, and behavior

2020 Volume 19, Issue 8, Page(s) e12680

Abstract: A diversity of bacteria, protozoans and viruses ("endozoites") were recently uncovered within healthy tissues including the human brain. By contrast, it was already recognized a century ago that healthy plants tissues contain abundant endogenous microbes ...

Abstract	A diversity of bacteria, protozoans and viruses ("endozoites") were recently uncovered within healthy tissues including the human brain. By contrast, it was already recognized a century ago that healthy plants tissues contain abundant endogenous microbes ("endophytes"). Taking endophytes as an informative precedent, we overview the nature, prevalence, and role of endozoites in mammalian tissues, centrally focusing on the brain, concluding that endozoites are ubiquitous in diverse tissues. These passengers often remain subclinical, but they are not silent. We address their routes of entry, mechanisms of persistence, tissue specificity, and potential to cause long-term behavioral changes and/or immunosuppression in mammals, where rabies virus is the exemplar. We extend the discussion to Herpesviridae, Coronaviridae, and Toxoplasma, as well as to diverse bacteria and yeasts, and debate the advantages and disadvantages that endozoite infection might afford to the host and to the ecosystem. We provide a clinical perspective in which endozoites are implicated in neurodegenerative disease, anxiety/depression, and schizophrenia. We conclude that endozoites are instrumental in the delicate balance between health and disease, including age-related brain disease, and that endozoites have played an important role in the evolution of brain function and human behavior.
MeSH term(s)	Animals ; Brain/microbiology ; Brain/parasitology ; Brain/physiology ; Brain/virology ; Cognition ; Humans ; Microbiota
Keywords	covid19
Language	English
Publishing date	2020-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2075819-4
ISSN	1601-183X ; 1601-1848
ISSN (online)	1601-183X
ISSN	1601-1848
DOI	10.1111/gbb.12680
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Article ; Online: An examination of plasma autoantibodies against voltage gated calcium channels in schizophrenia.

McLean, Ryan Thomas / Buist, Elizabeth / St Clair, David / Wei, Jun

Brain, behavior, & immunity - health

2023 Volume 28, Page(s) 100603

Abstract: Autoantibodies targeting the central nervous system have been shown to induce psychiatric symptoms resembling schizophrenia. Concurrently, genetic studies have characterised a number of risk variants associated with schizophrenia although their ... ...

Abstract	Autoantibodies targeting the central nervous system have been shown to induce psychiatric symptoms resembling schizophrenia. Concurrently, genetic studies have characterised a number of risk variants associated with schizophrenia although their functional implications are largely unknown. Any biological effects of functional variants on protein function may potentially be replicated by the presence of autoantibodies against such proteins. Recent research has demonstrated that the R1346H variant in the CACNA1I gene coding for the Cav 3.3 protein results in a synaptic reduction of Cav3.3 voltage gated calcium channels and, consequently, sleep spindles, which have been shown to correlate with several symptom domains in patients with schizophrenia. The present study measured plasma levels of IgG against two peptides derived from CACNA1I and CACNA1C, respectively, in patients with schizophrenia and healthy controls. The results demonstrated that increased anti-CACNA1I IgG levels were associated with schizophrenia but not associated with any symptom domain related to the reduction of sleep spindles. In contrast to previously published work indicating that inflammation may be a marker for a depressive phenotype, plasma levels of IgG against either CACNA1I or CACNA1C peptides were not associated with depressive symptoms, suggesting that anti-Cav3.3 autoantibodies may function independently of pro-inflammatory processes.
Language	English
Publishing date	2023-02-13
Publishing country	United States
Document type	Journal Article
ISSN	2666-3546
ISSN (online)	2666-3546
DOI	10.1016/j.bbih.2023.100603
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Article ; Online: Intradural cervical herniated nucleus pulposus presentation and management: a case report.

Yen, Tzu Chuan / Worley, John R / St Clair, Devin / Crim, Julia R / Moore, Don K

AME case reports

2023 Volume 7, Page(s) 28

Abstract: Background: Intradural disc herniations (IDH) are uncommon and can be found in the cervical spine. It is commonly associated with Brown-Sequard syndrome (BSS). The case report describes cervical spine magnetic resonance imaging (MRI) findings that ... ...

Abstract	Background: Intradural disc herniations (IDH) are uncommon and can be found in the cervical spine. It is commonly associated with Brown-Sequard syndrome (BSS). The case report describes cervical spine magnetic resonance imaging (MRI) findings that assists in identifying IDH pre-operatively and discusses surgical management. Case description: This is a case report regarding a 42-year-old obese male who developed atraumatic spontaneous bilateral upper extremity numbness, right upper extremity weakness and right lower extremity weakness. MRI showed a C6-7 herniated nucleus pulposus that focally protruded through the posterior longitudinal ligament with a beak-like projection similar to what has been described in previous reports. Clinical exam revealed an incomplete spinal cord injury (SCI) most consistent with BSS. He underwent anterior cervical discectomy and fusion at the level of C6-7. Intra-operatively, a disc fragment was found to be embedded in the dura. Three months post-operatively, the patient had persistent weakness in his right lower extremity but no longer had any bilateral upper extremity weakness. Conclusions: An anterior cervical decompression and fusion was performed shortly after the patient presented, with adequate neurological recovery after 3 months. Advanced imaging with an MRI could lead to the diagnosis of an IDH and surgical intervention via the anterior approach could facilitate removal of the disc and adequate dura repair.
Language	English
Publishing date	2023-04-20
Publishing country	China
Document type	Case Reports
ISSN	2523-1995
ISSN (online)	2523-1995
DOI	10.21037/acr-22-82
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Article: From conifers to cognition: Microbes, brain and behavior

Lathe, Richard / St Clair, David

Genes Brain Behav

Abstract	A diversity of bacteria, protozoans and viruses ("endozoites") were recently uncovered within healthy tissues including the human brain. By contrast, it was already recognized a century ago that healthy plants tissues contain abundant endogenous microbes ("endophytes"). Taking endophytes as an informative precedent, we overview the nature, prevalence, and role of endozoites in mammalian tissues, centrally focusing on the brain, concluding that endozoites are ubiquitous in diverse tissues. These passengers often remain subclinical, but they are not silent. We address their routes of entry, mechanisms of persistence, tissue specificity, and potential to cause long-term behavioral changes and/or immunosuppression in mammals, where rabies virus is the exemplar. We extend the discussion to Herpesviridae, Coronaviridae, and Toxoplasma, as well as to diverse bacteria and yeasts, and debate the advantages and disadvantages that endozoite infection might afford to the host and to the ecosystem. We provide a clinical perspective in which endozoites are implicated in neurodegenerative disease, anxiety/depression, and schizophrenia. We conclude that endozoites are instrumental in the delicate balance between health and disease, including age-related brain disease, and that endozoites have played an important role in the evolution of brain function and human behavior.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #827501
Database	COVID19

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Article ; Online: Using mouse transgenic and human stem cell technologies to model genetic mutations associated with schizophrenia and autism.

St Clair, David / Johnstone, Mandy

Philosophical transactions of the Royal Society of London. Series B, Biological sciences

2018 Volume 373, Issue 1742

Abstract: Solid progress has occurred over the last decade in our understanding of the molecular genetic basis of neurodevelopmental disorders, and of schizophrenia and autism in particular. Although the genetic architecture of both disorders is far more complex ... ...

Abstract	Solid progress has occurred over the last decade in our understanding of the molecular genetic basis of neurodevelopmental disorders, and of schizophrenia and autism in particular. Although the genetic architecture of both disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed
MeSH term(s)	Animals ; Animals, Genetically Modified ; Autistic Disorder/genetics ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/physiology ; Mice ; Mutation ; Schizophrenia/genetics
Language	English
Publishing date	2018-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	208382-6
ISSN	1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
ISSN (online)	1471-2970
ISSN	0080-4622 ; 0264-3839 ; 0962-8436
DOI	10.1098/rstb.2017.0037
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Article: How can emerging disinfection technologies gain a foothold in the current culture of hospitals?

St Clair, David

World hospitals and health services : the official journal of the International Hospital Federation

2014 Volume 50, Issue 2, Page(s) 20–22

Abstract: In the United States, more than 90% of hospitals still use only the traditional "spray and wipe" disinfection methods initiated over a century ago to protect patients from their environment; international adoption of new methods is even lower. Innovative ...

Abstract	In the United States, more than 90% of hospitals still use only the traditional "spray and wipe" disinfection methods initiated over a century ago to protect patients from their environment; international adoption of new methods is even lower. Innovative approaches like whole room disinfection find an inhospitable reception in spite of clearly superior reductions in health care-acquired infections. Much of the resistance is due to a lack of true accountability for patient safety in hospital organizations and to perverse incentive structures in historical reimbursement policies. But all of that may change in the coming years as hospitals and doctors become more responsible for the health outcomes of their patients.
MeSH term(s)	Cross Infection/prevention & control ; Disinfection/instrumentation ; Hospital Administration ; Humans ; Organizational Culture ; Safety Management
Language	English
Publishing date	2014
Publishing country	England
Document type	Journal Article
ZDB-ID	1287212-x
ISSN	1029-0540
ISSN	1029-0540
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Article ; Online: Prefrontal cortical dopamine deficit may cause impaired glucose metabolism in schizophrenia.

Wu, Qiongqiong / Long, Yujun / Peng, Xingjie / Song, Chuhan / Xiao, Jingmei / Wang, Xiaoyi / Liu, Furu / Xie, Peng / Yang, Jinqing / Shi, Zhe / Hu, Zhonghua / McCaig, Colin / St Clair, David / Lang, Bing / Wu, Renrong

Translational psychiatry

2024 Volume 14, Issue 1, Page(s) 79

Abstract: The brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between ... ...

Abstract	The brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between negative symptoms of schizophrenia and high fasting blood glucose. We then show that glucose metabolism and negative symptoms are improved when intermittent theta burst stimulation (iTBS) on prefrontal cortex (PFC) is performed in patients with predominantly negative symptoms of schizophrenia. These findings led us to hypothesize that the prefrontal cortical dopamine deficit, which is known to be associated with negative symptoms, may be responsible for abnormal glucose metabolism in schizophrenia. To explore this, we optogenetically and chemogenetically inhibited the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine projection in mice and found both procedures caused glucose intolerance. Moreover, microinjection of dopamine two receptor (D2R) neuron antagonists into mPFC in mice significantly impaired glucose tolerance. Finally, a transgenic mouse model of psychosis named Disc1
MeSH term(s)	Mice ; Humans ; Animals ; Dopamine/metabolism ; Schizophrenia/metabolism ; Ventral Tegmental Area/metabolism ; Mice, Transgenic ; Prefrontal Cortex/metabolism ; Glucose/metabolism ; Nerve Tissue Proteins/metabolism
Chemical Substances	Dopamine (VTD58H1Z2X) ; Glucose (IY9XDZ35W2) ; Disc1 protein, mouse ; Nerve Tissue Proteins
Language	English
Publishing date	2024-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-024-02800-7
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Article ; Online: Structural and copy number variants in the human genome: implications for psychiatry.

St Clair, David

The British journal of psychiatry : the journal of mental science

2013 Volume 202, Issue 1, Page(s) 5–6

Abstract: Copy number variants are small chromosomal deletions and duplications. When they alter the dose of genes critical for normal brain development and adult brain functioning they may cause severe disorders such as autism and schizophrenia. Numerous such ... ...

Abstract	Copy number variants are small chromosomal deletions and duplications. When they alter the dose of genes critical for normal brain development and adult brain functioning they may cause severe disorders such as autism and schizophrenia. Numerous such loci have recently been identified. They are offering amazing leads for neuropsychiatric research.
MeSH term(s)	Adult ; DNA Copy Number Variations/genetics ; Genome, Human/genetics ; Humans ; Mental Disorders/genetics ; Psychiatry
Language	English
Publishing date	2013-01
Publishing country	England
Document type	Editorial
ZDB-ID	218103-4
ISSN	1472-1465 ; 0007-1250
ISSN (online)	1472-1465
ISSN	0007-1250
DOI	10.1192/bjp.bp.112.109579
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