Technology situation

Technical situation

Summary

In this page we review the proximate technology situation. 

Technology has been a key driver of consumer interest in health care since the 1940s.  Significant current developments are reviewed.
Health Information Technology policy is discussed. 

Introduction

Heath care markets are deeply affected by technology developments and constraints.  Since the 1940s deployment of penicillin Americans have been convinced that their health issues have technological solutions.  The health care VDS has formed around this view, supporting and leveraging it. 


Expected technological advances, some discussed by NIH is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   director Francis Collins, suggest major transformations & powerful justification of health care:







Technology contents
  • AI & Robotics
  • Application development
  • Biotechnology research
  • Circuits
  • Epidemiology studies patterns, causes and effects of health and disease in populations.  It identifies risk factors for disease and focuses on preventative health care.  Being observational it suffers from a core limitation.  It can only show association, not causation.  It can suggest hypothesis but it can not disprove them.  
  • Epigenetics
  • Financial services
  • Obitiary of emergent force in venture capital (Jun 2016)
  • Distributed ledgers: bitcoin is a set of open-source software, used to provide infrastructure that supports a distributed cryptocurrency and payment system, based on the blockchain.   All transaction inputs are unspent outputs from previous transactions.  All transaction inputs are signed.  Change is provided in an additional output to the transaction. 
    's blockchain is a bitcoin distributed database technology that allows several bitcoin operators to keep a shared, cryptographically verified, ledger and consensus mechanism to allow agreement on what transactions have happened and in what order.  It implements a Merkle tree.  Six times an hour on average, a new group of validated transactions, a block, is created, added to the local block chain and published to all nodes.  Paraphrasing breadwallet's Aaron Voisine, publishing is robust because: Each operator has connected via references from its initial peers to a random subset of all the other operators; and the new block is offered to the connected peers who can both ask for it if they have not seen it previously from some other source and pass it on to their other peers in a cascade (a gossip network).  To build new blocks an operator must have all the prior blocks in the chain.  All unspent bitcoins are represented [only] in the blockchain.  Miners keep the blockchain consistent by verifying that a new block has a proof-of-work.  This requires that miners find a nonce that multiplied by the block hash is smaller than the network's difficulty target.   (Oct 2016)
  • Genomics
  • Microbiology
  • Modeling
  • Neuroscience
  • Payments
  • Process engines
    • Business process management
  • Proteomics
  • Quality
  • Robotics
  • Scientific method
  • Screening
  • Search
  • Servers
  • 200 prescription drugs including: beta blockers stop the action of beta-adrenergic signals and hence slow the heart.  , P.P.I. is proton pump inhibitor, which irreversibly block operation of gastric parietal cells' hydrogen/potassium ATPase, used as a medication: esomeprazole; to treat GERD.  They are among the most widely prescribed drugs in the world. 
    s, birth control pills, corticosteroids, anticonvulsants, prescription-strength ibuprofen, interferon; have depression is a debilitating state which is facilitated by genetic predisposition - for example genes coding for relatively low serotonin levels; and an accumulation of traumatic events.  There is evidence of shifts in the sleep/wake cycle in affected individuals (Dec 2015).  The affected person will experience a pathological sense of loss of control, prolonged sadness, irritability, sleep disturbances, loss of appetite, and inability to experience pleasure.  Michael Pollan concludes depression is fear of the past.  It affects 12% of men and 20% of women.  It appears to be associated with androgen deprivation therapy treatment for prostate cancer (Apr 2016).  Chronic stress depletes the nucleus accumbens of dopamine, biasing humans towards depression.  Depression easily leads to following unhealthy pathways: drinking, overeating; which increase the risk of heart disease.   It has been associated with an aging related B12 deficiency (Sep 2016).  During depression, stress mediates inhibition of dopamine signalling.  There is an association between depression and particular brain regions: Hippocampal dendrite and spine number reductions, Dorsal raphe nucleus linked to loneliness, Abnormalities of the ACC.  Childhood adversity can increase depression risk by linking recollections of uncontrollable situations to overgeneralizations that life will always be terrible and uncontrollable.  Treatments include: CBT, UMHS depression management.  As of 2010 drug treatments take weeks to facilitate a response & many patients do not respond to the first drug applied, often prolonging the agony.   Genomic predictions of which treatment will be effective have not been possible because: Not all clinical depressions are the same, a standard definition of drug response is difficult; as a side effect, drugs which one-third of American's take (Jun 2018)
  • MIS


  • Neuroscience reveals how we develop and operate.  It is highlighting changes in health care practice that can optimize treatments.



    Neuroscience

  • Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    as a behavioral disorder (Jul 2016)
  • Boston University SOM's Matthew Pase finds sugary drinks tied to rapid brain aging and Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    markers (Apr 2017)
  • Mount Sinai Icahn SOM's Dr. Joel Dudley's precision medicine is the integration of molecular research and clinical data through a taxonomy based on a knowledge network overlaid on an information commons.  It aims to support treatment of disease and remove the organ and symptom based methodological flaws in the ICD.  Supporters of the D.S.M. note the aggressive shift to precision medicine at the NIMH under Dr. Insel, constrained useful clinical research (Nov 2015). 
    (Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
    • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    • Analytics tools (BI) for PHM will be hard to develop.  
      • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
      • A key aspect is providing clear signals about the nature of the data using data visualization. 
    • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    ) study associates Roseoloviruses is a subset: HHV6 (HHV-6A, HHV-6B), HHV7; of Herpes viruses.  HHV6 typically infects human infants before age two, with symptoms of fever, diarrhea, and a rash known as roseola.  : HHV-6A is a double stranded DNA Roseolovirus.  It infects all tested humans and is neuroinflammatory, being seen in diseases such as MS. 
    , HHV7 is a double stranded DNA Roseolovirus. 
    ; with Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    , judged by changes in the entorinal cortex is a main limbic association area between the hippocampus and the neocortex, in the medial temporal lobe.  It is a hub for memory and navigation. 
    , hippocampus is a part of the brain involved in the temporary storage or coding of long-term episodic memory.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different. 
    , promoter enrichments for C2H2 zink finger is a large set of finger like binding domains in mammalian transcription factors with a Cys2-His2 (C2H2) fold group, which can bind in the major groove of DNA. 
    transcription factor are enzymes which associate with a transcription complex to bind to the DNA and control its transcription and hence translation into proteins.  The regulation of DNA transcription and protein synthesis are reviewed by Tsonis.  Transcription factors allow environmental state to become reflected in the control of DNA transcription.  Transcription factors can regulate multiple genes, allowing network effects & multiple transcription factors can regulate a gene allowing sophisticated control processes.  In AWF the transcription, translation and deployment infrastructure of the eukaryotic cell has been abstracted in a codelet based implementation. 
    binding motifs and signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
    links with ApoE4 is a gene variant which produces the E4 variant of APOE.  It is a risk-factor for late-onset sporadic Alzheimer's disease.  Being homozygote for E4 does not imply getting Alzheimer's but does increase the risk 20 fold.  ApoE2 may reduce the risk of Alzheimer's.  It appears that ApoE4 differentially affects women.  Apoe4 is known to be broken down into fragments which impare mitochondrial operation.  It also promotes amyloid plaque buildup.  Therapies are being developed based on small molecules which reshape ApoE4 to be more like ApoE3 reducing the breakdown.   
    . It seems likely that after remaining dormant for years the virus is a relatively small capsule containing genetic material which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  The relationship with the host is short term, relative to parasites, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it. 
    activates (stressor is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
    • The short term response to the stressor
      • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  But when the stressor is
    • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
      • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
      • Activates the integration between the thalamus and amygdala. 
        • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
        • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
      • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
      • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
      • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
      • Increases the risk of autoimmune disease (Jan 2017) 
    • During depression, stress inhibits dopamine signalling.  
    • Strategies for stress reduction include: Mindfulness. 
    ) & generates an immune has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    response that stimulates plaques which kill neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    (Jun 2018)
  • Alzheimer's is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    (May 2014May 2016)
  • Obama brain initiative (Sep 2015)
  • Brain maps (Connectome based Jul 2016)
  • Syngenta's Paraquat is NN-dimethyl-44-bipyridinium dichloride, a systemic weed killer, used on oranges, coffee and suger cane, manufactured and sold by the Swiss pesticide company Syngenta.  It is banned in the EU, but still allowed to be sold and used in the US.  Drinking even a sip can be lethal.  Recent research by the NIH links paraquat to Parkinson's disease.  The 2011 research found Iowa and North Carolina farmers and family members that handled paraquat or rotenone were 2.5 times more likely to develop Parkinson's disease.  A 2012 study found paraquat increased the likelihood 11 fold for people with certain genetic variations.  The link is disputed by Syngenta. 
    linked by N.I.H. is the National Institute of Health, Bethesda Maryland.  It is the primary federal agency for the support and conduct of biomedical and behavioral research.  It is also one of the four US special containment units of the CDC.   to Parkinson's disease corresponds to the breakdown of certain interneurons in the brain.  It is not fully understood why this occurs.  Dopamine system neuron breakdown generates the classical symptoms of tremors and rigidity.  In some instances an uncommon LRRK2 gene mutation confers a high risk of Parkinson's disease.  In rare cases Italian and Greek families are impacted in their early forties and fifties resulting from a single letter mutation in alpha-synuclein which alters the alpha-synuclein protein causing degeneration in the substantia nigra.  But poisoning from MPTP has also been shown to destroy dopamine system neurons.  People who have an appendectomy in their 20s are at lower risk of developing Parkinson's disease.  The Alpha-synuclein protein is known to build up in the appendix in association with changes in the gut microbiome.  This buildup may support the 'flow' of alpha-synuclein from the gut along neurons that route to the brain.  Paraquat has also been linked to Parkinson's disease.  Parkinson's disease does not directly kill many sufferers.  But it impacts swallowing which encourages development of pneumonia through inhaling or aspirating food.  And it undermines balance which can increase the possibility of falls.  Dememtia can also develop. 
    E.P.A. is the Environmental Protection Agency of the Federal government. 
    considers restrictions in US is the United States of America.   (Dec 2016)
  • Temporal Interference is a technique for targeting electrical stimulation at neurons within a brain by superposing two very high frequency electronic fields which only interfere constructively at the target neuron and at a low enough frequency to have an effect on the neuron. 
    technique developed by MIT is Massachusetts Institute of Technology.   Picower Institute of Learning's Tsai shows promise in mice (Jun 2017)
  • Brigham & Women's finds mothers' sounds needed for babies' brains to grow (Feb 2015)
  • McGurk effect is an illusion, described by Harry McGurk and John MacDonald, where a video shows a person speaking, and saying 'da da da da'.  But on closing your eyes you hear what is being said as 'ba ba ba'.   The illusion is generated by setting up conflicting signals: The mouth is moving to say 'ga'; while the sound is 'ba'.  the brain resolves the conflict into a single intermediate percept 'da'.  The illusion demonstrates how late in the processing chain and reconstructed our conscious experience is.  Imaging indicates the illusion is constructud in the frontal lobes and or superior temporal sulcus and is then sent back to the early sensory regions. 
    (Feb 2017)
  • Memories in the brain includes functionally different types: Declarative (episodic and semantic), Implicit, Procedural, Spatial, Temporal, Verbal; Hebb noted that glutamate receptive neurons learn by (NMDA channel based) synaptic strengthening.  This strengthening is sustained by subsequent LTP.  The non-realtime learning and planning processes operate through consciousness using the working memory structures, and then via sleep, the salient ones are consolidated while the rest are destroyed and garbage collected.   actively destroyed in fruit flies using Rac is a class of small monomeric GTP-binding proteins including Rac1 and Rac2.  Rac GTPases are implicated in memory removal (Feb 2010) and control of cytoskeleton assembly. 
    (Feb 2010
  • Purpose of sleep facilitates salient memory formation and removal of non-salient memories.  The five different stages of the nightly sleep cycles support different aspects of memory formation.  The sleep stages follow Pre-sleep and include: Stage one characterized by light sleep and lasting 10 minutes, Stage two where theta waves and sleep spindles occur, Stage three and Stage four together represent deep slow-wave sleep (SWS) with delta waves, Stage five is REM sleep; sleep cycles last between 90-110 minutes each and as the night progresses SWS times reduce and REM times increase.   Sleep includes the operation of synapse synthesis and maintenance through DNA based activity including membrane trafficking, synaptic vesicle recycling, myelin structural protein formation and cholesterol and protein synthesis. 
    is to forget.  The mechanism includes removing synapses, a neuron structure which provides a junction with other neurons.  It generates signal molecules, either excitatory or inhibitory, which are kept in vesicles until the synapse is stimulated when the signal molecules are released across the synaptic cleft from the neuron.  The provisioning of synapses is under genetic control and is part of long term memory formation as identified by Eric Kandel.  Modulation signals (from slow receptors) initiate the synaptic strengthening which occurs in memory. 
    Wisconsin-Madison's de Vivo supports synaptic homeostasis is Tonini & Cirelli's hypothesis that proposes sleep-wake cycles cause generalized synaptic weakening which leads to down-selection of weak synapses.  Pruning does not strike every synapse.  They argue that well established memories are left intact. 
    Johns Hopkins's Diering shows Homer1A is the product of the Homer1 gene short form splice.  The HomeriA has an EVH1 domain which competes with the long splice forms such as Homer1B and Homer1C, uncoupling mGluR signalling and shrinking dendritic spline structures.  Homer1a is expressed by neuronal activity.   is shipped to synapses where in sleep it pairs back synapses (Feb 2017). 
  • Northeastern & Mass. General hospital psychologist Feldman Barrett's fMRI is functional magnetic resonance imaging.  Seiji Ogawa leveraged the coupling of neuronal circuit activity and blood flow through the associated glial cells to build a 3 dimensional picture of brain cell activity.  As haemoglobin gives up its oxygen to support the neural activity it becomes magnetic and acts as a signal detected by the fMRI.  fMRI easily visualizes the state of activity in the living human brain at millimeter resolution, up to several times a second but it cannot track the time course of neural firing so it is augmented with EEG. 
    studies found superagers' is a older person who remains as mentally agile: in terms of memory and attention; as a twenty year old according to neurologist Marsel Mesulam.  In fMRI analyses superagers are found to retain well developed 'emotional' brain regions: midcingulate cortex, anterior insula; which are major hubs for general communication throughout the brain.  In comparison in other older people these regions have thined and their mental responses are relatively poor.  The superagers maintain the communication networks by regularly performing hard tiring and taxing mental or physical work (Jan 2016). 
    hard mental work sustains their major neural communication networks (Jan 2017)
  • Cohen & Andersen's review common reference frames is a coordinate system (set of axis) centered on a particular aspect of the situation that describes the location of an object.  The brain supports many frames of reference including for vision (2009), hearing & movement planning (Jul 2002).  Auditory stimuli are initially coded in a head-centered reference frame.  The motor system codes actions in reference frames that depend on motor effectors.  Eye movements are codes in a reference frame that depends on the difference between current and desired arm position.  It is often necessary to transform the location representation of the sensory stimulus into a representation appropriate for the motor act.  An eye-centered reference frame depends on the location of the eye in the head.  A retinotopic reference frame depends on the retinal location that is activated by a visual stimulus.  Double-saccade tasks show how the location of the second visual target is coded relative to current and desired eye position (eye-centered).  
    for movement plans in the posterior parietal cortex of the cerebral cortex is at the back of the brain divided into two.  It associates sensory signals of various modalities with:
    • Details about the location of the body and
    • Models interpreting touch, visual signals, language and mathematics. 
    (Jul 2002)






  • Jul 2016 NYT A new Harbinger of Alzheimers

    Pam Belluck reports personality differs in at least five key ways:
    • Extroversion-introversion - whether the person gains energy from socializing or retiring
    • Neuroticism-stability - does a person worry or are they calm and self-satisfied
    • Agreeableness-antagonism - is a person courteous & trusting or rude and suspicious
    • Conscientiousness-un-directedness - is a person careful or careless
    • Openness-non-openness - are they daring or conforming
    changes could indicate the earliest stage of dementia is a classification of memory impairment, constrained feelings and enfeebled or extinct intellect.  The most common form for people under 60 is FTD.  Dementia has multiple causes including: vascular disease (inducing VCI) including strokes, head trauma, syphilis and mercury poisoning for treating syphilis, alcoholism, B12 deficiency (Sep 2016), privation, Androgen deprivation therapy (Oct 2016), stress, Parkinson's disease and prion infections such as Alzheimer's disease, CJD and kuru.  The condition is typically chronic and treatment long term (Laguna Honda ward) and is predicted by Stanley Prusiner to become a major burden on the health system.  It appears to develop faster in women than men.  

    Alzheimer is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    's experts want to recognize and measure sharp changes in mood and behavior that can precede the memory and thinking problems of dementia.  They are proposing a new diagnosis: MBI is mild behavioral impairment, a proposed early diagnosis for dementia.  It recognizes and measures something that some experts say is often overlooked: Sharp changes in mood and behavior can precede the memory and thinking problems of dementia.  But there is a risk of over diagnosis which could leave many people unnecessarily fearful about their futures and seeking more tests.  And the diagnosis could affect insurance premiums.  To imply MBI the symptoms must last for more than six months and be a fundamental change in behavior.  
    which would precede MCI is mild cognitive impairment, a sense of memory loss despite normal performance on memory tests.  It is often associated with Alzheimer's disease. 


    University of Calgary neuropsychiatrist Dr. Zahinoor Ismail notes that studies and anecdotes suggest emotional are low level agents distributed across the brain and body which associate, via the amygdala and rich club hubs, important environmental signals with encoded high speed sensors, and distributed programs of action to model: predict, prioritize guidance signals, select and respond effectively, coherently and rapidly to the initial signal.  The majority of emotion centered brain regions interface to the midbrain through the hypothalamus.  The most accessible signs of emotions are the hard to control and universal facial expressions.  Emotions provide prioritization for conscious access given that an animal has only one body, but possibly many cells, with which to achieve its highest level goals.  Because of this emotions clash with group goals and are disparaged by the powerful.  Evolutionary psychology argues evolution shaped human emotions during the long period of hunter-gatherer existence in the African savanna.  Human emotions are universal and include: Anger, Appreciation of natural beauty, Disgust, Fear, Gratitude, Grief, Guilt, Happiness, Honor, Jealousy, Liking, Love, Rage, Romantic love, Lust for revenge, Passion, Sadness, Self-control, Shame, Sympathy, Surprise; and the sham emotions and distrust induced by reciprocal altruism.   and behavioral changes are symptomatic of dementia, not seperate from it.  People with MCI that also have mood and behavior changes develop full-blown dementia faster and do much worse over time.  Autopsies show they had more brain damage. 


    Jun 2018 NYT A Common Virus May Play Role in Alzheimer's Disease, Study Finds

    Pam Belluck reports it has been a controversial theory about Alzheimer's disease is a dementia which correlates with deposition of amyloid plaques in the neurons.  As of 2015 there are 5 million Alzheimer's patients in the USA.  It was originally defined as starting in middle age which is rare, so it was a rare dementia.  But in 1980s it was redefined as any dementia without another known cause. Early indications include mood and behavioral changes (MBI) and memory and thinking problems (MCI).  Variants include: late-onset sporadic; with risk factors - ApoE4, presenilin, androgen deprivation therapy (Dec 2015).  There are multiple theories of the mechanism of Alzheimer's during aging: Allen Roses argues that it is due to gene alleles that limit the capacity of mitochondria to support neuron operation; It may be initiated by: stress induced HHV-6a, HHV7 herpes activation (Jun 2018) and or an increasingly leaky blood-brain barrier; and a subsequent innate immune response to the infections (May 2016).  The Alzheimer's pathway follows:
    • Plaques form and set off the formation of tangled thread-like tau protein.
      • Solanezumab aimed to inhibit plaque formation but clinical trials failed (Nov 2016).  
      • BACE inhibitors block an enzyme needed to form amyloid. 
    • The Tau tangles kill nerve cells.  LMTX is a drug treatment targeted at these tangles. 
    • The brain becomes inflamed resulting in the killing of many more nerve cells. 
    , often dismissed by experts as a sketchy cul-de-sac off the beaten path from mainstream research. 

    A new study, published in Neuron, associates Roseoloviruses is a subset: HHV6 (HHV-6A, HHV-6B), HHV7; of Herpes viruses.  HHV6 typically infects human infants before age two, with symptoms of fever, diarrhea, and a rash known as roseola.  : HHV-6A is a double stranded DNA Roseolovirus.  It infects all tested humans and is neuroinflammatory, being seen in diseases such as MS. 
    , HHV7 is a double stranded DNA Roseolovirus. 
    ; with Alzheimer's disease, judged by changes in the entorinal cortex is a main limbic association area between the hippocampus and the neocortex, in the medial temporal lobe.  It is a hub for memory and navigation. 
    , hippocampus is a part of the brain involved in the temporary storage or coding of long-term episodic memory.  Memory formation in the cells of the hippocampus uses the MAP kinase signalling network which is impacted by sleep deprivation.  The hippocampus dependent memory system is directly affected by cholinergic changes throughout the wake-sleep cycle.  Increased acetylcholine during REM sleep promotes information attained during wakefulness to be stored in the hippocampus by suppressing previous excitatory connections while facilitating encoding without interference from previously stored information.  During slow-wave sleep low levels of acetylcholine cause the release of the suppression and allow for spontaneous recovery of hippocampal neurons resulting in memory consolidation.  It was initially associated with memory formation by McGill University's Dr. Brenda Milner, via studies of 'HM' Henry Molaison, whose medial temporal lobes had been surgically destroyed leaving him unable to create new memories.  The size of neurons' dendritic trees expands and contracts over a female rat's ovulatory cycle, with the peak in size and cognitive skills at the estrogen high point.  Adult neurogenesis occurs in the hippocampus (3% of neurons are replaced each month) where the new neurons integrate into preexisting circuits.  It is enhanced by learning, exercise, estrogen, antidepressants, environmental enrichment, and brain injury and inhibited by various stressors explains Sapolsky.  Prolonged stress makes the hippocampus atrophy.  He notes the new neurons are essential for integrating new information into preexisting schemas -- learning that two things you thought were the same are actually different. 
    , and signalling, is an emergent capability which is used by cooperating agents to support coordination & rival agents to support control and dominance.  In eukaryotic cells signalling is used extensively.  A signal interacts with the exposed region of a receptor molecule inducing it to change shape to an activated form.  Chains of enzymes interact with the activated receptor relaying, amplifying and responding to the signal to change the state of the cell.  Many of the signalling pathways pass through the nuclear membrane and interact with the DNA to change its state.  Enzymes sensitive to the changes induced in the DNA then start to operate generating actions including sending further signals.  Cell signalling is reviewed by Helmreich.  Signalling is a fundamental aspect of CAS theory and is discussed from the abstract CAS perspective in signals and sensors.  In AWF the eukaryotic signalling architecture has been abstracted in a codelet based implementation.  To be credible signals must be hard to fake.  To be effective they must be easily detected by the target recipient.  To be efficient they are low cost to produce and destroy. 
    links with ApoE4 is a gene variant which produces the E4 variant of APOE.  It is a risk-factor for late-onset sporadic Alzheimer's disease.  Being homozygote for E4 does not imply getting Alzheimer's but does increase the risk 20 fold.  ApoE2 may reduce the risk of Alzheimer's.  It appears that ApoE4 differentially affects women.  Apoe4 is known to be broken down into fragments which impare mitochondrial operation.  It also promotes amyloid plaque buildup.  Therapies are being developed based on small molecules which reshape ApoE4 to be more like ApoE3 reducing the breakdown.   


    The findings imply new treatment strategies:
    • Vaccines & drugs to preempt infections
    • Screen people for the genes that increase vulnerability to these infections. 

    Lead Author Dr. Joel Dudley, is a Big Data encompasses the IT systems and processes necessary to do population based data collection, management and analysis.  The very low cost, robust, data storage organized by infrastructure: HADOOP; allows digital data to be stored en mass.  Data scientists then apply assumptions about the world to the data, analogous to evolved mechanisms in vision, in the form of algorithms.  Rather than depending on averages, analysis at Verisk drills down to specifics and then highlights modeling problems by identifying the underlying CAS.  For the analysis to be useful it requires a hierarchy of supporting BI infrastructure:
    • Analytics utilization and integration delivered via SaaS and the Cloud to cope with the silos and data intensive nature. 
    • Analytics tools (BI) for PHM will be hard to develop.  
      • Complex data models must include clinical aspects of the patient specific data, including disease state population wide.  
      • A key aspect is providing clear signals about the nature of the data using data visualization. 
    • Data communication with the ability to exchange and transact.  HIEs and EMPI alliance approaches are all struggling to provide effective exchange. 
    • Data labeling and secure access and retreival.  While HIPAA was initially drafted as a secure MPI the index was removed from the legislation leaving the US without such a tool.  Silos imply that the security architecture will need to be robust. 
    • Raw data scrubbing, restructuring and standardization.  Even financial data is having to be restandarized shifting from ICD-9 to -10.  The intent is to transform the unstructured data via OCR and NLP to structured records to support the analytics process. 
    • Raw data warehousing is distributed across silos including PCP, Hospital system and network, cloud and SaaS for process, clinical and financial data. 
    • Data collection from the patient's proximate environment as well as provider CPOE, EHRs, workflow and process infrastructure.  The integration of the EHR into a big data collection tool is key. 
    researcher, who was looking for drug associations within Alzheimer's disease studies.  But instead he kept finding associations with Roseoloviruses.  It is proposed that these viruses is a relatively small capsule containing genetic material which utilizes the cellular infrastructure of its target host to replicate its genetic material and operational proteins.  The relationship with the host is short term, relative to parasites, with the virus entering the host cell, leveraging the host infrastructure to replicate its self massively and then exiting the host cell by rupturing it. 
    , reactivated from a dormant state within neurons, specialized eukaryotic cells include channels which control flows of sodium and potassium ions across the massively extended cell membrane supporting an electro-chemical wave which is then converted into an outgoing chemical signal transmission from synapses which target nearby neuron or muscle cell receptors.  Neurons are supported by glial cells.  Neurons include a:
    • Receptive element - dendrites
    • Transmitting element - axon and synaptic terminals
    • Highly variable DNA schema using transposons. 
    by stress is a multi-faceted condition reflecting high cortisol levels.  Dr. Robert Sapolsky's studies of baboons indicate that stress helps build readiness for fight or flight.  As these actions occur the levels of cortisol return to the baseline rate.  A stressor is anything that disrupts the regular homeostatic balance.  The stress response is the array of neural and endocrine changes that occur to respond effectively to the crisis and reestablish homeostasis. 
    • The short term response to the stressor
      • activates the amygdala which: Stimulates the brain stem resulting in inhibition of the parasympathetic nervous system and activation of the sympathetic nervous system with the hormones epinephrine and norepinephrine deployed around the body, Activates the PVN which generates a cascade resulting in glucocorticoid secretion to: get energy to the muscles with increased blood pressure for a powerful response.  The brain's acuity and cognition are stimulated.  The immune system is stimulated with beta-endorphin and repair activities curtail.  But when the stressor is
    • long term: loneliness, debt; and no action is necessary, or possible, long term damage ensues.  Damage from such stress may only occur in specific situations: Nuclear families coping with parents moving in.  Sustained stress provides an evolved amplifier of a position of dominance and status.  It is a strategy in female aggression used to limit reproductive competition.  Sustained stress:
      • Stops the frontal cortex from ensuring we do the harder thing, instead substituting amplification of the individual's propensity for risk-taking and impairing risk assessment! 
      • Activates the integration between the thalamus and amygdala. 
        • Acts differently on the amygdala in comparison to the frontal cortex and hippocampus: Stress strengthens the integration between the Amygdala and the hippocampus, making the hippocampus fearful. 
        • BLA & BNST respond with increased BDNF levels and expanded dendrites persistently increasing anxiety and fear conditioning. 
      • Makes it easier to learn a fear association and to consolidate it into long-term memory.  Sustained stress makes it harder to unlearn fear by making the prefrontal cortex inhibit the BLA from learning to break the fear association and weakening the prefrontal cortex's hold over the amygdala.  And glucocorticoids decrease activation of the medial prefrontal cortex during processing of emotional faces.  Accuracy of assessing emotions from faces suffers.  A terrified rat generating lots of glucocorticoids will cause dendrites in the hippocampus to atrophy but when it generates the same amount from excitement of running on a wheel the dendrites expand.  The activation of the amygdala seems to determine how the hippocampus responds. 
      • Depletes the nucleus accumbens of dopamine biasing rats toward social subordination and biasing humans toward depression. 
      • Disrupts working memory by amplifying norepinephrine signalling in the prefrontal cortex and amygdala to prefrontal cortex signalling until they become destructive.  It also desynchronizes activation in different frontal lobe regions impacting shifting of attention.  
      • Increases the risk of autoimmune disease (Jan 2017) 
    • During depression, stress inhibits dopamine signalling.  
    • Strategies for stress reduction include: Mindfulness. 
    or illness, amplify a pathological immune system has to support and protect an inventory of host cell types, detect and respond to invaders and maintain the symbiont equilibrium within the microbiome.  It detects microbes which have breached the secreted mucus barrier, driving them back and fortifying the barrier.  It culls species within the microbiome that are expanding beyond requirements.  It destroys invaders who make it into the internal transport networks.  As part of its initialization it has immune cells which suppress the main system to allow the microbiome to bootstrap.  The initial microbiome is tailored by the antibodies supplied from the mother's milk while breastfeeding.  The immune system consists of two main parts the older non-adaptive part and the newer adaptive part.  The adaptive part achieves this property by being schematically specified by DNA which is highly variable.  By rapid reproduction the system recombines the DNA variable regions in vast numbers of offspring cells which once they have been shown not to attack the host cell lines are used as templates for interacting with any foreign body (antigen).  When the immune cell's DNA hyper-variable regions are expressed as y-shaped antibody proteins they typically include some receptor like structures which match the surfaces of the typical antigen.  Once the antibody becomes bound to the antigen the immune system cells can destroy the invader. 
    response, which leads to an accumulation of amyloid plaques.  It is likely that other pathogens may generate a similar response. 

    Many Alzheimer's researchers see no causal link from viruses to Alzheimer's, noting that the disease may increase the opportunity for infection. 

    The new study:
    A further set of experiments, in mice & invitro brain cells, to be published soon, found HHV-6A and HHV7 generated a protective response in amyloid, resulting in the virus being held in plaque nets. 





    Sep 2015 NYT Putting Her Mind to How the Brain Works

    Claudia Dreifus reports that Dr. Cori Bargmann's mission to help lead a president's initiative starts with a search for the needed tools. 
    Dr. Bargmann was an M.I.T. graduate student when she discovered a gene HER2 is a gene encoding the protein 'human epidermal growth factor receptor 2', which is similar in structure to the native receptor HER1. 
    in rats that mutated to generate a cancer is the out-of-control growth of cells, which have stopped obeying their cooperative schematic planning and signalling infrastructure.  It results from compounded: oncogene, tumor suppressor, DNA caretaker; mutations in the DNA.  In 2010 one third of Americans are likely to die of cancer.  Cell division rates did not predict likelihood of cancer.  Viral infections are associated.  Radiation and carcinogen exposure are associated.  Lifestyle impacts the likelihood of cancer occurring: Drinking alcohol to excess, lack of exercise, Obesity, Smoking, More sun than your evolved melanin protection level; all significantly increase the risk of cancer occurring (Jul 2016).  .  Later other researchers noted that the same gene is altered in humans for a breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018).  Bargmann's work in the rat cancer showed the immune system could attack the product of the gene.  Genentech then developed Herceptin: breast tumors grow rapidly because they respond via the human EGF receptor (HER), coded for by the gene 'Her2', to cell growth signal epidermal growth factor (EGF).  Herceptin inhibits the growth of the Her-2+ tumors by inhibiting the EGFR.   to deploy the immune system against the cell surface receptor product of Bargmann's gene. 

    She then moved on to working on the nervous system using the simple system C. elegans because its genes had been completely sequenced and it was transparent.  It's brain has 7,000 connections and 300 neurons.  So Bargmann could observe and "know what any cell does.  I know what it's connected to.  I know what genes it expresses."  For a researcher she noted that's a lot. 

    Bargmann notes that her work provides details about human brains because the genes are not very different.  In 1993 Bargmann showed that C. Eligans could smell.  She then moved the gene that is the sensor for an attractant and moved it to a different neuron that senses things the worm finds dangerous. Now the worm ran away from the attractant.  Bargmann said "This said that the odor-sensing nerve cells form an innate map where each one knows whether something is good or bad about the environment.  There's a completely unlearned internal set of preferences, a set of instincts about what's good and bad. 

    Bargmann explained the problem facing the 'brain innitiative'.  We have $100 million for the first year.  They had to prioritize some aspects of brain research that the $100 million would really make a difference.  The team agreed on a basic outline: Use the money for mapping brain activity in circuits and networks. 

    Bargmann says to do this they will do two steps:
    1. Create new and improved technologies to study the brain.  With better tools, all the neuroscience will move forward. 
    2. Apply these technologies to make discoveries about how the brain functions. 
    The theme is understanding brain activity, the flows of information through millions of interconnected nerve cells. 

    The long term goal is to use that knowledge to help prevent and treat brain disorders.  That may be a decade or two away. 


    May 2018 NYT For Women With Early Breast Cancer, Herceptin Treatment Can Be Much Shorter

    Denise Grady reports over the past 20 years, hundreds of thousands of women with breast cancer is a variety of different cancerous conditions of the breast tissue.  World wide it is the leading type of cancer in women and is 100 times more common in women than men.  260,000 new cases of breast cancer will occur in the US in 2018 causing 41,000 deaths.  The varieties include: Hormone sensitive tumors that test negative for her2 (the most common type affecting three quarters of breast cancers in the US, BRCA1/2 positive, ductal carcinomas including DCIS, lobular carcinomas including LCIS.  Receptor presence on the cancer cells is used as a classification: Her2+/-, estrogen (ER)+/-, progesterone (PR)+/-.  Metastasis classes the cancer as stage 4.  Genetic risk factors include: BRCA, p53, PTEN, STK11, CHEK2, ATM, GATA3, BRIP1 and PALB2.  Treatments include: Tamoxifen, Raloxifene; where worrying racial disparities have been found (Dec 2013).  International studies indicate early stage breast cancer typed by a genomic test: Oncotype DX, MammaPrint; can be treated without chemotherapy (Aug 2016, Jun 2018)  have taken the drug Herceptin: breast tumors grow rapidly because they respond via the human EGF receptor (HER), coded for by the gene 'Her2', to cell growth signal epidermal growth factor (EGF).  Herceptin inhibits the growth of the Her-2+ tumors by inhibiting the EGFR.  , typically for a year or more.  The medicine, used to treat an aggressive fo