Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:
This US 2018 review lead author was a gynecologic oncologist in private practice:
“Sexual orientation is biologically conferred in the first trimester of pregnancy. Gender identity is biologically conferred during the middle trimester of pregnancy.
Since the genitals differentiate in the first trimester, and the brain becomes imprinted in the latter half of gestation, it is possible for the fetal brain to be imprinted differently than the genitals. As children mature, this innate imprinting expresses as genital anatomy, gender identity, sexual orientation and other physiologic capabilities and natural preferences along a continuum, between masculine and feminine.
The evidence shows that both orientation and identity are biologic features that co-vary with a very large number of other biologic sexually dimorphic traits.”
A fetus’ development is influenced by survival reactions to their environment. Although fetal and placental responses to environmental stressors are relevant to sexual orientation and gender identity, the subject wasn’t explored.
Epigenetic adaptations to the prenatal environment involving microRNA were mentioned in a small subsection. But the review didn’t cite relevant studies involving DNA methylation, chromatin and histone modifications for epigenetic causes of and effects on sexual orientation and gender identity.
The authors included a half-dozen anecdotal quotations from personal correspondence that promoted their narrative. These came across as appeals to authority rather than evidence for scientific understanding of the subject.
It was insufficient for the review to note “a continuum between masculine and feminine” without also exploring evidence for an individual’s placement on the continuum, including possible epigenetic causes for sexual orientation and gender identity.
https://www.sciencedirect.com/science/article/pii/S009082581731510X “Biological origins of sexual orientation and gender identity: Impact on health” (not freely available)
This 2018 Italy/UK meta-analysis subject was the use of dietary supplement acetyl-L-carnitine to treat depression symptoms:
“Deficiency of acetyl-L-carnitine (ALC) appears to play a role in the risk of developing depression, indicating dysregulation of fatty acids transport across the inner membrane of mitochondria. However, the data regarding ALC supplementation in humans are limited. We thus conducted a systematic review and meta-analysis investigating the effect of ALC on depressive symptoms across randomized controlled trials (RCTs).
Pooled data across nine RCTs (231 treated with ALC versus 216 treated with placebo and 20 no intervention) showed that ALC significantly reduced depressive symptoms.
In three RCTs comparing ALC versus antidepressants (162 for each group), ALC demonstrated similar effectiveness compared with established antidepressants [fluoxetine (Prozac), duloxetine (Cymbalta), amisulpride (Solian) respectively below] in reducing depressive symptoms. In these latter RCTs, the incidence of adverse effects was significantly lower in the ALC group [79%] than in the antidepressant group.
From the Study selection subsection:
“Studies were excluded if:
- did not include humans;
- did not include a control group;
- did not use validated scales for assessing depression;
- did not report data at follow-up evaluation regarding tests assessing depression;
- included the use of ALC with another agent vs. placebo/no intervention.”
The Discussion section was informative regarding possible mechanisms of ALC affecting depression, pain, and linked symptoms. Several citations were of a review rather than of the original studies, however.
Research needs to proceed on to investigate therapies that address ultimate causes for depression and pain. Researchers and sponsors shouldn’t stop at just symptoms and symptom relief, notwithstanding the requirement from a statistical point of view for “future large scale trials.”
Here are other acetyl-L-carnitine topics I’ve curated:
- A common dietary supplement that has rapid and lasting antidepressant effects
- Familiar stress opens up an epigenetic window of neural plasticity
- A gaping hole in a review of nutritional psychiatry
https://journals.lww.com/psychosomaticmedicine/Citation/2018/02000/Acetyl_L_Carnitine_Supplementation_and_the.4.aspx “Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis” (not freely available)
This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.
This 2018 Canadian paper reviewed evidence for potential sex-specific differences in the lasting impacts of childhood trauma:
“This paper will provide a contextualized summary of neuroendocrine, neuroimaging, and behavioral epigenetic studies on biological sex differences contributing to internalizing psychopathology, specifically posttraumatic stress disorder and depression, among adults with a history of childhood abuse.
Given the breadth of this review, we limit our definition [of] trauma to intentional and interpersonal experiences (i.e., childhood abuse and neglect) in childhood. Psychopathological outcomes within this review will be limited to commonly explored internalizing disorders, specifically PTSD and depression.
Despite the inconsistent and limited findings in this review, a critical future consideration will be whether the biological effects of early life stress can be reversed in the face of evidence-based behavioral interventions, and furthermore, whether these changes may relate to potentially concurrent reductions in susceptibility to negative mental health outcomes.”
It was refreshing to read a paper where the reviewers often interrupted the reader’s train of thought to interject contradictory evidence, and display the scientific method. For example, immediately after citing a trio of well-respected studies that found:
“Psychobiological research on relationships linking impaired HPA axis functioning and adult internalizing disorders are suggestive of lower basal and afternoon levels of plasma cortisol in PTSD phenotype.”
the reviewers stated:
“However, a recent meta-analysis suggests no association between basal cortisol with PTSD.”
and effectively ended the cortisol discussion with:
“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:
- early adversity,
- age of onset,
- basal cortisol levels, as well as
- trauma forms and subtypes, and
- presence and severity of psychopathology symptomology.”
The reviewers also provided good summaries of aspects of the reviewed subject. For example, the “Serotonergic system genetic research, childhood trauma and risk of psychopathology” subsection ended with:
“Going forward, studies must explore the longitudinal effects of early trauma on methylation as well as comparisons of multiple loci methylation patterns and interactions to determine the greatest factors contributing to health outcomes. Only then, can we start to consider the role of sex in moderating risk.”
I didn’t agree with the cause-ignoring approach of the behavior therapy mentioned in the review. Does it make sense to approach one category of symptoms:
“the biological effects of early life stress”
by treating another category of symptoms?
“can be reversed in the face of evidence-based behavioral interventions.”
But addressing symptoms instead of the sometimes-common causes that generate both biological and behavioral effects continues to be the direction.
After receiving short-term symptom relief, wouldn’t people prefer treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?
I was encouraged by the intergenerational and transgenerational focus of one of the reviewer’s research:
“Dr. Gonzalez’s current research focus is to understand the mechanisms by which early experiences are transmitted across generations and how preventive interventions may affect this transmission.”
This line of hypotheses requires detailed histories, and should uncover causes for many effects that researchers may otherwise shrug off as unexplainable individual differences. Its aims include the preconception through prenatal periods when both the largest and the largest number of epigenetic changes occur, and is when our susceptibility and sensitivity to our environment is greatest. There are fewer opportunities for effective “preventive interventions” in later life compared with these early periods.
Unlike lab rats, women and men can reach some degree of honesty about our early lives’ experiential causes of ongoing adverse effects. Experiential therapies that allow humans to potentially change their responses to these causes deserve more investigation than do therapies that apply external “interventions.”
https://www.sciencedirect.com/science/article/pii/S0272735817302647 “Biological alterations affecting risk of adult psychopathology following childhood trauma: A review of sex differences” (not freely available) Thanks to lead author Dr. Ashwini Tiwari for providing a copy.
This 2018 UK human study detailed epigenetic muscle memory:
“We aimed to investigate an epigenetic memory of earlier hypertrophy in adult human skeletal muscle using a within measures design, by undertaking:
- Resistance exercise induced muscle growth (loading) [3 days a week for 7 weeks], followed by;
- Cessation of resistance exercise, to return muscle back towards baseline levels (unloading) [7 weeks], and;
- A subsequent later period of resistance exercise induced muscle hypertrophy (reloading) [3 days a week for 7 weeks].”
The findings were:
“Frequency of genome-wide hypomethylation is the largest after reloading induced hypertrophy where lean muscle mass is enhanced.
Hypomethylation is maintained from earlier load induced hypertrophy even during unloading where muscle mass returns back towards baseline, and is inversely associated with gene expression.
A single bout of acute resistance exercise evokes hypomethylation of genes that have enhanced gene expression in later reload induced hypertrophy.”
The study provided another example of how our bodies remember. It began with only eight male 27.6 ± 2.4 year-old subjects, though, and one of them dropped out.
See the discussion of a 2017 Netherlands human study in Are Underpowered Studies Ever Justified? with comments on studies with few subjects, such as:
“The problem occurs when people do small quantitative studies, but draw conclusions nonetheless, simply adding a disclaimer to the discussion (which they don’t put in the abstract, or the press release).”
“Underpowered studies may only be useful to check if the experiment works out wrt understanding instructions, do the programs run, etc, but not as much for testing and estimating effects.”
“The problem with underpowered studies is that all estimates can vary erratically between samples. Combined with the desire of many researchers (and universities’ press offices) to find sensational patterns, this means that evidence from underpowered studies is ‘asymmetrically’ likely to be considered more conclusive. As in, something that seems really cool will probably be considered more conclusive than something that’s disappointing. Highly powered studies don’t afford this flexibility.”
https://www.nature.com/articles/s41598-018-20287-3 “Human Skeletal Muscle Possesses an Epigenetic Memory of Hypertrophy”
The first paper of Transgenerational epigenetic inheritance week was a 2017 Canadian/Netherlands review that’s organized as follows:
“First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming.”
A transgenerational phenotype was defined as an epigenetic modification that was maintained at least either to the F2 grandchildren in the paternal lineage or to the F3 great-grandchildren in the maternal lineage.
The reviewers noted that the mechanisms of transgenerational programming are complex and multivariate. The severity, timing, and type of exposure, lineage of transmission, germ cell exposure, and gender of an organism were the main factors that may determine the consequences. The mechanisms reviewed were:
- Parental exposure to an adverse environment;
- Altered maternal behavior and care of the offspring; and
- Experience-dependent modifications of the epigenome.
There was a long list of diseases and impaired functionalities that were consequences of ancestral experiences and exposures. Most of the studies were animal, but a few were human, such as those done on effects of extended power outages during the Quebec ice storm of January 1998.
One intervention that was effective in reversing a transgenerational phenotype induced by deficient rodent maternal care was to place pups with a caring foster female soon after birth. It’s probably unacceptable in human societies to preemptively recognize all poor-care human mothers and remove the infant to caring foster mothers, but researchers could probably find enough instances to develop studies of the effectiveness of the placements in reversing a transgenerational phenotype.
The review didn’t have suggestions for reversing human transgenerational phenotypes, just “potential interventions to reverse negative effects of transgenerational programming.” The interventions suggested for humans – exercise, enriched lifestyle, cognitive training, dietary regimens, and expressive art and writing therapies – only reduced the impact of transgenerational epigenetic effects.
The tricky wording of “reverse negative effects of transgenerational programming” showed that research paradigms weren’t aimed at resolving causes. The review is insufficient for the same reasons mentioned in How one person’s paradigms regarding stress and epigenetics impedes relevant research, prompting my same comment:
“Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?”
When reversals of human transgenerational phenotypes aren’t researched, the problems compound if they’re transmitted to the next generations.
http://www.sciencedirect.com/science/article/pii/S014976341630714X “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)
This 2017 review laid out the tired, old, restrictive guidelines by which current US research on the epigenetic effects of stress is funded. The reviewer rehashed paradigms circumscribed by his authoritative position in guiding funding, and called for more government funding to support and extend his reach.
The reviewer won’t change his beliefs regarding individual differences and allostatic load since he helped to start those memes. US researchers with study ideas to develop evidence beyond such memes may have difficulties finding funding.
Here’s one example of the reviewer’s restrictive views taken from the Conclusion section:
“Adverse experiences and environments cause problems over the life course in which there is no such thing as “reversibility” (i.e., “rolling the clock back”) but rather a change in trajectory  in keeping with the original definition of epigenetics  as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage. By the same token, we mean “redirection” instead of “reversibility”—in that changes in the social and physical environment on both a societal and a personal level can alter a negative trajectory in a more positive direction.”
What would happen if US researchers proposed tests of his “there is no such thing as reversibility” axiom? To secure funding, his sphere of influence would probably steer the prospective studies’ experiments toward altering “a negative trajectory in a more positive direction” instead.
An example of his influence may be found in the press release of Familiar stress opens up an epigenetic window of neural plasticity where the lead researcher stated a goal of:
“Not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”
I found nothing in citation  (of which the reviewer is a coauthor) where the rodent study researchers even attempted to directly reverse the epigenetic changes! The researchers under his guidance simply asserted:
without making any therapeutic efforts to test the permanence assumption!
Never mind that researchers outside the reviewer’s sphere of influence have done exactly that, reverse both gene expression patterns and behavioral responses!!
In any event, citation  didn’t support an “there is no such thing as reversibility” axiom.
The reviewer also implied that humans respond just like lab rats and can be treated as such. Notice that the above graphic conflated rodent and human behaviors. Further examples of this inappropriate merger of behaviors are in the Conclusion section.
What may be a more promising research approach to human treatments of the epigenetic effects of stress? I pointed out in The current paradigm of child abuse limits pre-childhood causal research:
“If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of the damage would also reverse damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.
Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?”
http://journals.sagepub.com/doi/full/10.1177/2470547017692328 “Neurobiological and Systemic Effects of Chronic Stress”