Trained immunity responses to bacterial infections

This 2019 Swiss rodent study investigated immune responses to five types of bacterial infections:

“The innate immune system recalls a challenge to adapt to a secondary challenge, a phenomenon called trained immunity. Trained immunity protected mice from a large panel of clinically relevant bacterial pathogens inoculated systematically and locally to induce peritonitis, enteritis and pneumonia.

Induction of trained immunity remodeled bone marrow and blood cellular compartments, providing efficient barriers against bacterial infections. Protection was remarkably broad when considering the pathogens and sites of infection tested.

We are running experiments to delineate the length of protection conferred by trained immunity. Trained immunity is most typically induced with β-glucan.

Mice were injected with methicillin-resistant Staphylococcus aureus (MRSA). Trained mice survived better than control mice (31% vs. 0% survival) and had 10-fold less bacteria in blood 2 days post-infection.

Mice were challenged with a lethal dose of Listeria monocytogenes. Most strikingly, all trained mice survived infection while all control mice died within 5 days. Bacteria were not detected in blood collected from trained mice 2 and 3 days post-infection.”

One of the coauthors also published: “Trained immunity confers broad-spectrum protection against bacterial infections”

A review of fetal adverse events

This 2019 Australian review subject was fetal adversities:

“Adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature.

These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalizing behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalizing behaviours such as anxiety. The term ‘perinatal compromise’ serves as an umbrella term for intrauterine growth restriction, maternal immune activation, prenatal stress, early life stress, premature birth, placental dysfunction, and perinatal hypoxia.

The above conditions are associated with imbalanced excitatory-inhibitory pathways resulting from reduced GABAergic signalling. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA synthesizing enzyme Glutamate Decarboxylase 1, resulting in increased levels of glutamate is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD.

The posterior cerebellum’s role in higher executive functioning is becoming well established due to its connections with the prefrontal cortex, association cortices, and limbic system. It is now suggested that disruptions to cerebellar development, which can occur due to late gestation compromises such as preterm birth, can have a major impact on the region of the brain to which it projects.

Activation of the maternal hypothalamic-pituitary adrenal (HPA) axis and placental protection. Psychological stress is perceived by the maternal HPA axis, which stimulates cortisol release from the maternal adrenal gland.

High levels of maternal cortisol are normally prevented from reaching the fetus by the 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) enzyme, which converts cortisol to the much less active cortisone. Under conditions of high maternal stress, this protective mechanism can be overwhelmed, with the gene encoding the enzyme becoming methylated, which reduces its expression allowing cortisol to cross the placenta and reach the fetus.”

The reviewers extrapolated many animal study findings to humans, although most of their own work was with guinea pigs. The “suggest” and “may” qualifiers were used often – 22 and 37 times, respectively. More frequent use of the “appears,” “hypothesize,” “propose,” and “possible” terms was justified.

As a result, many reviewed items such as the above graphic and caption should be viewed as hypothetical for humans rather than reflecting solid evidence from quality human studies.

The reviewers focused on the prenatal (before birth) period more than the perinatal (last trimester of pregnancy to one month after birth) period. There were fewer mentions of birth and early infancy adversities. “Perinatal compromise contributes to programming of GABAergic and Glutamatergic systems leading to long-term effects on offspring behaviour” (not freely available)

Too cheap for clinical trials

Let’s compare and contrast a 2019 meta-analysis and a 2017 review of using acetyl-L-carnitine to treat diabetic neuropathy.

A 2019 Brazilian meta-analysis Acetyl‐L‐carnitine for the treatment of diabetic peripheral neuropathy of four previous trials stated:

  • “The risk of bias was high in both trials of different ALC doses and low in the other two trials.
  • No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief.
  • At doses greater than 1500 mg/day, ALC reduced pain more than placebo. This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.
  • The placebo-controlled studies did not measure functional impairment and disability scores.
  • No study used validated symptom scales.
  • Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer.

Authors’ conclusions:

  • We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty.
  • Data on functional and sensory impairment and symptoms are lacking, or of very low certainty.
  • The evidence on adverse events is too uncertain to make any judgements on safety.”

A 2017 Italian review Effects of acetyl-L-carnitine in diabetic neuropathy and other geriatric disorders stated:

“A long history of diabetes mellitus and increasing age are associated with the onset of diabetic neuropathy, a painful and highly disabling complication with a prevalence peaking at 50% among elderly diabetic patients. The management of diabetic neuropathy is extremely difficult: in addition to the standard analgesics used for pain control, common treatments include opioids, anticonvulsants, antidepressants, and local anesthetics, alone or in combination. Such therapies still show a variable, often limited efficacy, however.

Many patients do not spontaneously report their symptoms to physicians, but, if asked, they often describe having experienced a persistent and non-abating pain for many years. The prevalence of painful symptoms is just as high in patients with mild neuropathy as in those with more advanced DPN.

Through the donation of acetyl groups, ALC exerts a positive action on mitochondrial energy metabolism. ALC has cytoprotective, antioxidant, and antiapoptotic effects in the nervous system.

ALC has also been proposed for the treatment of other neurological and psychiatric diseases, such as mood disorders and depression, dementia, Alzheimer’s disease, and Parkinson’s disease, given that synaptic energy states and mitochondrial dysfunctions are core factors in their pathogenesis. Compared to other treatments, ALC is safe and extremely well tolerated.”

“In nerve injury, the mGlu2 receptor overexpressed by ALC binds the glutamate, reducing its concentration in the synapses with an analgesic effect. ALC may improve nerve regeneration and damage repair after primary nerve trauma.”

Where will the money come from to realize what the 2017 review promised, as well as provide what the 2019 meta-analysis required?

Do we prefer the current “limited efficacy” treatments of “opioids, anticonvulsants, antidepressants, and local anesthetics?”

Who will initiate clinical trials of a multiple of the normal dietary supplement dose (500 mg at $.25 a day, retail)? How profitable is a product whose hypothetical effective dosage for diabetic neuropathy (3000 mg) sells for only $1.50 a day?

Perinatal stress and sex differences in circadian activity

This 2019 French/Italian rodent study used the PRS model to investigate its effects on circadian activity:

“The aim of this study was to explore the influence of PRS on the circadian oscillations of gene expression in the SCN [suprachiasmatic nucleus of the hypothalamus] and on circadian locomotor behavior, in a sex-dependent manner.

Research on transcriptional rhythms has shown that more than half of all genes in the human and rodent genome follow a circadian pattern. We focused on genes belonging to four functional classes, namely the circadian clock, HPA axis stress response regulation, signaling and glucose metabolism in male and female adult PRS rats.

Our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models.”

“There was a clear-cut effect of sex on the effect of PRS on the levels of activity:

  • During the period of lower activity (light phase), both CONT and PRS females were more active than males. During the light phase, PRS increased activity in males, which reached levels of CONT females.
  • More interestingly, during the period of activity (dark phase), male PRS rats were more active than male CONT rats. In contrast, female PRS rats were less active than CONT females.
  • During the dark phase, CONT female rats were less active than CONT male rats.

The study presented evidence for sex differences in circadian activity of first generation offspring that was caused by stress experienced by the pregnant mother:

“Exposure to gestational stress and altered maternal behavior programs a life-long disruption in the reactive adaptation such as:

  •  A hyperactive response to stress and
  • A defective feedback of the hypothalamus-pituitary-adrenal (HPA) axis together with
  • Long-lasting modifications in stress/anti-stress gene expression balance in the hippocampus.”

It would advance science if these researchers carried out experiments to two more generations to investigate possible transgenerational epigenetic inheritance of effects caused by PRS. What intergenerational and transgenerational effects would they possibly find by taking a few more months and extending research efforts to F2 and F3 generations? Wouldn’t these findings likely help humans?

One aspect of the study was troubling. One of the marginally-involved coauthors was funded by the person described in How one person’s paradigms regarding stress and epigenetics impedes relevant research. Although no part of the current study was sponsored by that person, there were three gratuitous citations of their work.

All three citations were reviews. Unlike study researchers, reviewers aren’t bound to demonstrate evidence from tested hypotheses. Reviewers are free to:

  • Express their beliefs as facts;
  • Over/under emphasize study limitations; and
  • Disregard and misrepresent evidence as they see fit.

Fair or not, comparisons of reviews with Cochrane meta-analyses of the same subjects consistently show the extent of reviewers’ biases. Reviewers also aren’t obligated to make post-publication corrections for their errors and distortions.

As such, reviews can’t be cited for reliable evidence. Higher-quality studies that were more relevant and recent than a 1993 review could have elucidated points.

Sucking up to the boss and endorsing their paradigm was predictable. Since that coauthor couldn’t constrain themself to funder citations only in funder studies, it was the other coauthors’ responsibilities to edit out unnecessary citations. “Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle”

OCD and neural plasticity

This 2019 New York rodent study investigated multiple avenues to uncover mechanisms of obsessive-compulsive disorder:

“Psychophysical models of OCD propose that anxiety (amygdala) and habits (dorsolateral striatum) may be causally linked. Numerous genetic and environmental factors may reduce striatum sensitivity and lead to maladaptive overcompensation, potentially accounting for a significant proportion of cases of pathological OCD-like behaviors.

Our results indicate that both the development and reversal of OCD-like behaviors involve neuroplasticity resulting in circuitry changes in BLA-DLS and possibly elsewhere.”

The researchers explored two genetic models of OCD, showed why these insufficiently explained observed phenomena, then followed up with epigenetic investigations. They demonstrated how and the degree to which histone modifications and DNA methylation regulated both the development and reversal of OCD symptoms.

However, the researchers also carelessly cited thirteen papers outside the specific areas of the study to support one statement in the lead paragraph:

“Novel studies propose that modulations in gene expression influenced by environmental factors, are connected to mental health disorders.”

Only one of the thirteen citations was more recent than 2011, and none of them were high-quality studies. “Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism”

The transgenerational impact of Roundup exposure

This 2019 Washington rodent study from Dr. Michael Skinner’s lab found adverse effects in the grand-offspring and great-grand-offspring following their ancestor’s exposure during pregnancy to the world’s most commonly used herbicide:

“Using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed.

The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities:

  1. Prostate disease in approximately 30% of F3 generation glyphosate lineage males, a three-fold increase in disease rate over controls.
  2. A transgenerational (F3 generation) obese phenotype was observed in approximately 40% of the glyphosate lineage females and 42% of the glyphosate lineage males.
  3. An increased incidence of kidney disease observed in the F3 generation glyphosate lineage females affecting nearly 40% of females.
  4. A significant increase in ovarian disease observed in the F2 [48% vs. 21% for controls] and F3 [36% vs. 15% for controls] generation glyphosate lineage females.
  5. During the gestation of F2 generation mothers with the F3 generation fetuses, dramatic parturition abnormalities were observed in the glyphosate lineage. The frequency of unsuccessful parturition was 35%. To further investigate the parturition abnormalities an outcross of F3 generation glyphosate lineage males with a wildtype female was performed. There were parturition abnormalities observed with a frequency of 30%.

Classic and current toxicology studies only involve direct exposure of the individual, while impacts on future generations are not assessed. The ability of glyphosate and other environmental toxicants to impact our future generations needs to be considered, and is potentially as important as the direct exposure toxicology done today for risk assessment.”

Why isn’t coverage of this study the top story of the world’s news organizations? Is what’s reported more important than reliable evidence of generational consequences to environmental experiences?

Current toxicology practices are a scientific disgrace:

  • What are the hypotheses of practices that only test effects on somatic cells, that don’t look for generational effects of germ cell modifications?
  • Are they selected for their relative convenience instead of chosen for their efficacy?

Why don’t sponsors fund and researchers perform human studies of transgenerational epigenetic inheritance? For example, from Burying human transgenerational epigenetic evidence:

“From the late 1930s through the early 1970s, DES was given to nearly two million pregnant women in the US alone.

Fourth [F3] generation effects of prenatal exposures in humans have not been reported.

Zero studies of probably more than 10,000,000 F3 great-grandchildren of DES-exposed women just here in the US!

There will be abundant human evidence to discover if sponsors and researchers will take their fields seriously. “Assessment of Glyphosate Induced Epigenetic Transgenerational Inheritance of Pathologies and Sperm Epimutations: Generational Toxicology”

Non-emotional memories

This 2019 US review covered memory mechanisms:

“With memory encoding reliant on persistent changes in the properties of synapses, a key question is how can memories be maintained from days to months or a lifetime given molecular turnover? It is likely that positive feedback loops are necessary to persistently maintain the strength of synapses that participate in encoding.

These levels are not isolated, but linked by shared components of feedback loops.”

Despite the review’s exhaustive discussion, the reviewers never came to the point. The word cloud I made of the review’s most frequent thirty words had little to do with why memory occurs:

  • Why do some stimuli evoke a memory in response?
  • Why are almost all of the stimuli an organism receives not remembered?

Much of the discussion was baseless because it excluded emotion. Many of the citations’ memory findings relied on emotion, though.

For example, in the subsection Roles of persistent epigenetic modifications for maintaining LTF [long-term facilitation], LTP [long-term potentiation], and LTM [long-term memory]:

  • Histone acetylation is increased after fear conditioning in the hippocampus and amygdala.
  • Correspondingly, inhibition of histone deacetylase enhances fear conditioning and LTP.
  • Following fear conditioning, histone phosphorylation is also increased.
  • DNA methylation is also up-regulated in the hippocampus and amygdala after fear conditioning, and inhibition of DNA methylation blocks fear LTM.” “How can memories last for days, years, or a lifetime? Proposed mechanisms for maintaining synaptic potentiation and memory”