<![CDATA[Orchid Advocacy - Translational Medicine Friday]]>Fri, 17 Jan 2025 10:34:57 -0800Weebly<![CDATA[Microglial TREM 2 Gene]]>Sat, 11 Jan 2025 08:51:35 GMThttps://orchidadvocacy.org/translational-medicine-friday/microglial-trem-2-gene​*Neuro-Degeneration
*Cancer
*Neuro-Developmental Disorders &
*Psychiatric Disorders
TREM2 in Neuro-Degeneration
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​TREM2 regulates BV2 microglia activation and influences corticosterone-induced neuroinflammation in depressive disorders (2024)
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​TREM2 improves microglia function and synaptic development in autism spectrum disorders by regulating P38 MAPK signaling pathway (2024)
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​A multi-omics study of brain tissue transcription and DNA methylation revealing the genetic pathogenesis of ADHD (2024) [includes TREM2]
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​Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development (2024)
]]><![CDATA[Engineered Microglia and More]]>Sat, 11 Jan 2025 07:54:32 GMThttps://orchidadvocacy.org/translational-medicine-friday/engineered-microglia-and-more
Val's Take/Conjecture
  • A collection of articles featuring:
    • ​Engineered Microglia as a Treatment
    • The Role of Glial Cells in Mental Illness
    • Maternal Immune Activation Generates "Anxiety" in Offspring.
    • ADHD as "Dysregulated not Deficit" and
    • Maternal Type-I interferon signaling adversely affects Microglia resulting in increased Sensitivity to Stress.

This new research requires significant modification of our paradigms.
​Taming microglia: the promise of engineered microglia in treating neurological diseases (2024)
​The role of glial cells in mental illness: a systematic review on astroglia and microglia as potential players in schizophrenia and its cognitive and emotional aspects (2024)
​Maternal immune activation generates anxiety in offspring (2021)
​“Dysregulated not deficit”: A qualitative study on symptomatology of ADHD in young adults (2023)
​Maternal Type-I interferon signaling adversely affects the microglia and the behavior of the offspring accompanied by increased sensitivity to stress (2019)
]]><![CDATA[Addiction]]>Sun, 05 Jan 2025 11:13:49 GMThttps://orchidadvocacy.org/translational-medicine-friday/addiction
​Val's Take:  U2's "Bad" is from 1984.  I actually didn't hear it until working on it this past year with the Ukulele and Percussion Ensemble at Swallow Hill Music in Denver.

It meant a lot more to me now than I think it would have meant to me in 1984.

It is about Addiction and how morally implicated and powerless the people witnessing that feel.  You know you're not helping or solving things --- but you don't know what to do and there is GUILT.

To make matters even more morally fraught, it is not just you or Bono who are lamenting, "If I could, yes I would. If I could, I would" --- it is often the person themselves.

Further, you are NOT PERFECT --- maybe you don't have an illegal substance problem -- as you're guzzling your 7th Diet Coke of the day.

Further, your intended recipient of this angst might be grateful they don't have some of your problems -- "There but for the grace of God go I."

At the end of the day, this is about IMPERFECT PEOPLE HELPING IMPERFECT PEOPLE.
Dr. Mizra talks about the connection between ADHD & Substance Use Issues.

Dr. Sulman Aziz Mirza, MD is Board Certified physician in Adult Psychiatry, Child & Adolescent Psychiatry and Addiction Medicine.

Val's Take:  Just as I think it is important to recognize the NEURO-DEVELOPMENTAL/PSYCHIATRIC CONTINUUM --- it is important to include SUBSTANCE USE ISSUES.

There are many aspects to that.  Two of those aspects seem to include:
  • having enough ENERGY to run the brain and the synapses; and
  • dealing with AFFECTIVE PAIN that may be HIGHLY DYSREGULATED.
​This is Neurobiologist David Anderson's 2013 TedTalk.  He has a lab at Caltech bearing his name.

He is an amazingly accomplished researcher.  

I've posted this video on Orchid several times for various purposes.

Here, he makes many salient points, including:
  • we need psychiatric medications that are precise and do not affect the brain globally.
  • Additionally, we need to understand the specific biology of various components of these disorders --- because they don't always go together.
]]><![CDATA[Translational medicine in Glial protection]]>Wed, 01 Jan 2025 02:13:22 GMThttps://orchidadvocacy.org/translational-medicine-friday/translational-medicine-in-glial-protection
Val's Take/Conjecture
  • In 2013, the National Institute of Mental Health (NIMH) proclaimed the DSM 5 "lacked validity"  because it was based on clusters of symptoms and not the underlying biology.
  • The American Psychiatric Association said, "Well, what is your alternative?"
  • NIMH said, "We'll get back to you on that."
  • Since then the basic research has exploded.
  • On the other hand, the Translational Research and Medicine perhaps predictably has lagged behind.
  • That is slowly starting to change.
  • Part of that is recognizing the glial protective aspects of current medications (which may not work for everyone) and
  • Pursuing Novel Therapeutic Medications and Approaches.
​Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice (2024)
​The Janus face of antipsychotics in glial cells: Focus on glioprotection (2023).
"[C]onverging lines of evidence indicate that psychiatric disorders are commonly associated with the triad
  • neuroinflammation,
  • oxidative stress, and
  • excitotoxicity, and

that glial cells may contribute to the gliotoxicity process.

"Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning.

"In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism."
 "[C]onverging lines of evidence indicate that psychiatric disorders are commonly associated with the triad
  • neuroinflammation,
  • oxidative stress, and
  • excitotoxicity, and

that glial cells may contribute to the gliotoxicity process.

"Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning.

"In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism." "[C]onverging lines of evidence indicate that psychiatric disorders are commonly associated with the triad
  • neuroinflammation,
  • oxidative stress, and
  • excitotoxicity, and

that glial cells may contribute to the gliotoxicity process.

"Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning.

"In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism."
​Microglia and cognitive impairment in schizophrenia: translating scientific progress into novel therapeutic interventions (2023).
​Suicide in bipolar disorder patients is associated with hippocampal microglia activation and reduction of lymphocytes-activation gene 3 (LAG3) microglial checkpoint expression (2023).
​Role of Microglial Modulation in Therapies for Perinatal Brain Injuries Leading to Neurodevelopmental Disorders (2024).
​Editorial

Special Issue "Microglia Heterogeneity and Its Relevance for Translational Research" (2021)
Val's Take:  One of the things that happened with NIMH and Researchers around the world:  They started saying these neuro-developmental & psychiatric disorders are "BLURRED."
​Since that time, it has become more obvious that there are common mechanisms in a range of CHRONIC DISEASE --- the actual "dysregulation" may be different --- but those new understandings are multiplying to benefit a range of illnesses.
]]><![CDATA[Lead and Psychiatric Disorders]]>Tue, 17 Dec 2024 01:11:59 GMThttps://orchidadvocacy.org/translational-medicine-friday/lead-and-psychiatric-disorders
Val's Take/Conjecture
  • "Lead" in gasoline in the 20th Century is currently being identified as a "CAUSE" of poor mental health.
  • At least at one point, Lead was identified with the Fall of the Roman Empire.
    • ​I think most historians would identify a range of factors --- but "Lead" may come back in popularity as a factor with regard to the fall of ancient Rome.
To me when people say --- "Hey, I think this is a factor in mental health" ---- I think they are generally right.​
  • To me, this is really about Developmental and After Acquired INFLAMMATION --- so it can be a lot of things and a lot of combinations of things.
​There's realization in Medicine and Psychiatry for the need for INDIVIDUALIZED PRECISION MEDICINE.
20th Century Lead Exposure Damaged American Mental Health
Dec. 4, 2024
​IT IS NOT JUST LEAD
The exposomeThe role of the exposome is to understand how the totality of an individual's exposures throughout the lifetime can impact human health.
]]><![CDATA[Immune System Gene and Neurodevelopmental Disorders]]>Sat, 30 Nov 2024 01:56:29 GMThttps://orchidadvocacy.org/translational-medicine-friday/immune-system-gene-and-neurodevelopmental-disorders
It's not intuitive, but the Immune System plays critical roles in Neuro-Developmental and Psychiatric Disorders.  That has been highlighted in the last 10 to 15 years, and it is continuing to be corroborated.

This is transforming our understerstanding of Neuro-Developmental and Psychiatric Disorders.
Immune System Gene Linked to Hyperactivity, ADHD and Autism
​
​Nov. 21, 2024
Duke University Study
]]><![CDATA[from the one-man show of genetics to lots of cross-talk & a Cast of Thousands -----(actually a cast of Trillions)]]>Sat, 30 Nov 2024 00:07:54 GMThttps://orchidadvocacy.org/translational-medicine-friday/from-the-one-man-show-of-genetics-to-lots-of-cross-talk-a-cast-of-thousands-actually-a-cast-of-trillions
​Val's Take/Conjecture
  • The Ancient Greeks had the "Four Humors" and Chinese Medicine has the "Five Elements."
    • These conceptualizations are not necessarily stictly accurate.
    • BUT they give people a way of understanding a monumentally complex biology --- that is within their grasp.
  • In 2013, Thomas Insel, head of the National Institute of Mental Health, said the DSM "lacks validity" --- and we'll be using it as our "DICTIONARY" --- until we can get something better. --- Hmmm . . . BUT it probably is going to take 20 to 30 years to flesh out something better that it based on the underlying biology rather than clusters of symtoms.
  • That is happening.
​Professor Graham Rook
​"We Are Ecosystems"
​We are conceptualizing neurodevelopmental and psychiatric disorders as:
  • Developmental, in many cases as a result of Maternal Immune Activation
  • Involving:
    • the Immune System
    • the Central Nervous System
    • the Endocrine System
    • the Metabolism, and
    • the Microbiome
  • It is a form of premature aging
  • Individuals often have processings differences that can confer benefits and challenges.
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Endocrine cross-talk between the gut microbiome and glial cells in development and disease. 2021)

"Glial cells make up the major cellular component of the nervous system. Glial development is usually investigated through perturbations of host genetics, although non-host-derived signalling molecules can also regulate glial cells. ..."
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​Investigating the “two-hit hypothesis”: Effects of prenatal maternal immune activation and adolescent cannabis use on neurodevelopment in mice (2023)
Val's Take/Conjecture:  I think Cannabis Use is an issue, BUT to me the larger issue is Secondary Inflammatory Hits during the lifetime.

People with psychiatric disorders are much more vulnerable to Long Haul Covid.

We know that childhood illnesses can be much more serious in Adults.  For some people, that period in utero led to perhaps years worth of inflammation as compared to someone who did not experience Maternal Immune Activation.

The lifespan for people with psychiatric disorders is reduced.
​Life expectancy and years of potential life lost in people with mental disorders: a systematic review and meta-analysis (2023)
]]><![CDATA[Major Paradigm shifts:  ​Maternal immune Activation, Microglia (& other glia) & Human Endogenous Retro Viruses]]>Wed, 27 Nov 2024 23:00:49 GMThttps://orchidadvocacy.org/translational-medicine-friday/major-paradigm-shifts-maternal-immune-activation-microglia-other-glia-human-endogenous-retro-viruses
Val's Take/Conjecture
  • The Immune Connection to the Neuro-Developmental/Psychiatric Disorder Continuum is HUGE.
  • It is also COMPLICATED --- we're talking about something that begins IN UTERO and continues with:
    • ​molecular "CROSSTALK", as well as
    • DYSREGULATION of MOLECULAR PATHWAYS
  • ​"Microglia" --- immune cells in the brain are also associated with "emotional regulation."
​Ancient Viruses Linked to Mental Illness (2024)​

New research led by King's College London has found that thousands of DNA sequences originating from ancient viral infections are expressed in the brain, with some contributing to susceptibility for psychiatric disorders such as schizophrenia, bipolar disorder, and depression.  
Endogenous Retroviruses Activity as a Molecular Signature of Neurodevelopmental Disorders (2019)

​Moreover, growing evidence supports the involvement of HERVs (Human Endogenous Retro Viruses) in neurodevelopmental disorders, such as autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia (SCZ) .

Susceptibility and resilience to maternal immune activation are associated with differential expression of endogenous retroviral elements (2023)
​
​"MIA alters placental and fetal expression of endogenous retroviral elements. MIA-induced alterations in endogenous retrovirus expression persist into adulthood. Differential expression of endogenous retroviruses defines MIA subgroups."
​Val's Take:  There is a gulf between Researchers and US Clinicians.

I think that had been there for awhile but the 2013  "invalid" DSM 5 sanctioned gross incompetence in a public way.

England is probably 10 or 20 years ahead of us in understanding the Immune Connection to Psychiatric Disorders.

I do think the proprietary nature of the American Psychiatric Association is in part to blame for incompetence in the US Mental Health Profession.
]]><![CDATA[The complicated domino effects of Maternal Immune Activation]]>Wed, 27 Nov 2024 20:27:04 GMThttps://orchidadvocacy.org/translational-medicine-friday/the-complicated-domino-effects-of-maternal-immune-activation
Val's Take/Conjecture
  • There are several factors that can result in Maternal Immune Activation (MIA).
  • MIA is associated with Neuro-Developmental and Psychiatric Disorders in the Child.
    • Why is that?
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​Influence of Immune System Abnormalities Caused by Maternal Immune Activation in the Postnatal Period  (2023)

"The developmental origins of health and disease (DOHaD) indicate that fetal tissues and organs in critical and sensitive periods of development are susceptible to structural and functional changes due to the adverse environment in utero. Maternal immune activatio …"
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​Maternal immune activation induces sustained changes in fetal microglia motility (2020)
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​Maternal immune activation and neuroinflammation in human neurodevelopmental disorders (2021)
"Evidence from human and animal studies indicates that maternal immune activation programmes the
fetal brain and immune system through inflammatory and
epigenetic mechanisms during key periods
  • of CNS [Central Nervous System],
  • microglial and
  • immune system development, and
  • colonization of gut microbiota."
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Mid-pregnancy maternal immune activation increases Pax6-positive and Tbr2-positive neural progenitor cells and causes integrated stress response in the fetal brain in a mouse model of maternal viral infection (2021)

​"Mid-pregancy maternal immune activation increases Pax6-positive and Tbr2-positive neural progenitor cells and causes integrated stress response in the fetal brain in a mouse model of . . ."
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Paliperidone Reversion of Maternal Immune
Activation-Induced Changes on Brain Serotonin and Kynurenine Pathways 
​(2021)

"Inflammation can alter the metabolism of tryptophan through the oxidative kynurenine pathway to compounds with neurotoxic and neuroprotective activity and compromise serotonin (5-HT) synthesis. Here we investigate the role of serotonergic and kynurenine …"
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Lasting and Sex-Dependent Impact of Maternal Immune Activation on Molecular Pathways of the Amygdala (2020)
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Maternal Immune Activation Disrupts Dopamine System in the Offspring (2016) 

"Our study, the first to combine electrophysiological and microdialysis experiments on the dopamine system in a maternal immune activation model of schizophrenia, reveals that . . ."
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Dysregulation of immune and metabolism pathways in maternal  (2023)

"Maternal immune activation regulates the dysregulation of four key risk KEGG pathways related to immunity, metabolism, and nervous system leading to abnormal embryonic . . ."
​Val's Take
  • Compared to where we have been in our knowledge of the Neuro-Developmental/Psychiatric Continuum ---
  • Researchers around the world are providing a COHERENT UNDERSTANDING with a LEVEL of DETAIL that is MIND-BLOWING.
  • Neuro-Transmitters like Serotonin and Dopamine are still there ---- BUT the Context and Complexity has been expanded Exponentially.
]]><![CDATA[Astrocytes -- Another Glial Cell involved with the Neuro-Developmental / Psychiatric Continuum]]>Wed, 27 Nov 2024 19:29:14 GMThttps://orchidadvocacy.org/translational-medicine-friday/astrocytes-another-glial-cell-involved-with-the-neuro-developmental-psychiatric-continuum
Val's Take/Conjecture
  • ​introducing "ASTROCYTES." -- another Glial Cell associated with the Immune response and Neuro-Developmental & Psychiatric Disorders.
​Astrocyte regulation of synaptic signaling in psychiatric disorders  (2022)
​Affective Immunology: The Crosstalk Between Microglia and Astrocytes Plays Key Role?  (2020)
Almost a century ago, Julius Wagner-Jauregg first reported the impact of immunological disturbance on psychological function.

This finding stirred up researchers' enthusiasm about bidirectional communication between immunological dysfunction and mental disorders.

To date, understanding the etiology of mental disorders, such as schizophrenia, autism spectrum disorder, anxiety disorder, as well as mood disorders, is one of the most actively explored topics in immunology.
We're starting to get more than a rough idea about what is going on with the Neuro-Developmental/Psychiatric Continuum:
  • It often starts in utero with Maternal Immune Activation (MIA).
  • That MIA dysregulates Microglia in the yok-sak in the placenta.
    • Microglia are innate immune cells in the brain.
  • This ultimately leads to abnormal development of neurons.
  • Additionally, other glial cells seem to create abnormal "myelation" of the neurons.
    • To me that sounds very much like Multiple Sclerosis.
    • One of the things I heard a researcher say a few years ---- the Immune System seemed to be involved with psychiatric disorders but it wasn't a classic autoimmune disease.
    • On the other hand, some MIA is the result of mom's auto-immune disease and people on the Neuro-Developmental/Psychiatric Continuum do have autoimmune diseases such as Thyroid Disorders.
  • Really understanding that we are talking about Developmental Disorders that involve multiple systems of the body and a BIG DRIVER is the IMMUNE SYSTEM is the key to real PROGRESS.
​Verywell Health
​Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders (2022)
Astrocyte involvement in metabolic regulation and disease (2024)

​Val's Take:  Astrocytes are involved with thyroid disorders --- and those are very common among people with psychiatric disorders.
​See Also:
​Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders (2024)
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