Fetal behavior and gestational serotonin reuptake inhibitor exposure: relationships between behavior, drug dosage, plasma drug level, and a measure of drug bioeffect.

Determination of the relationships between drug dosage, maternal and infant (cord blood) plasma drug concentrations, and serotonin reuptake inhibitor (SRI) bioeffect on offspring neurobehavior is crucial to assessing the effects of gestational SRI exposure. Measurement of maternal and cord blood platelet serotonin (5-HT) provides an index of inhibitory bioeffect at the 5-HT transporter and complements other measures of drug exposure. Three groups of mother-infant pairs were evaluated: (1) mothers with depression untreated with SRIs (DEP, n = 17), (2) mothers treated for depression with SRIs (DEP + SRI, n = 17), and (3) mothers who were not depressed and untreated (ND, n = 29). Fetal movement was assessed using a standardized ultrasound imaging and rating protocol. Maternal and cord blood platelet 5-HT levels were obtained from all participants. For the SRI + DEP group, maternal and infant plasma drug concentrations and an estimate of third-trimester maternal SRI drug exposure were obtained. As expected, substantially lower median platelet 5-HT levels were observed in the DEP + SRI group than in the non-exposed, combined ND and DEP groups. In non-exposed mothers and infants, platelet 5-HT levels were not affected by the presence of maternal depression. Lower maternal and infant platelet 5-HT levels were associated with more immature fetal movement quality. Although these data are limited by small sample size, the bioeffect index of in vivo platelet 5-HT transporter inhibition appears to provide a valuable approach for elucidating and possibly predicting the effects of gestational SRI exposure on fetal and perinatal neurobehavior.

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.

Specification of human regional brain lineages using orthogonal gradients of WNT and SHH in organoids.

The repertory of neurons generated by progenitor cells depends on their location along antero-posterior and dorso-ventral axes of the neural tube. To understand if recreating those axes was sufficient to specify human brain neuronal diversity, we designed a mesofluidic device termed Duo-MAPS to expose induced pluripotent stem cells (iPSC) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison of single cell transcriptomes with fetal human brain revealed that Duo-MAPS-patterned organoids generated the major neuronal lineages of the forebrain, midbrain, and hindbrain. Morphogens crosstalk translated into early patterns of gene expression programs predicting the generation of specific brain lineages. Human iPSC lines from six different genetic backgrounds showed substantial differences in response to morphogens, suggesting that interindividual genomic and epigenomic variations could impact brain lineages formation. Morphogen gradients promise to be a key approach to model the brain in its entirety.

Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration.

We believe there are serious problems with a recently published and highly publicized paper entitled "Serotonin reduction in post-acute sequelae of viral infection." The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the "Discussion" section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, "Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment", it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs' effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.

Exposure to Plasticiser DEHP Affects Eggs Spawned by Blue Mussels: A Possible Risk to Fertilisation?

The endocrine disruptive chemical DEHP is a plasticiser often found in marine waters. Here, we assessed the effect of this additive on the number and size of eggs spawned by female mussels during a synchronised spawning event. After achieving the ripeness of the gonads, mussels of both sexes were exposed to two environmentally relevant concentrations of DEHP (nominal concentrations 0.5 and 50 µg/L) for one week. A spawning event was then induced and eggs were collected, counted, and their size measured (area and diameter). A slight but not significant effect was observed in lowering the number of eggs spawned when increasing the DEHP concentration. This effect was greater when adding spent gonads (possibly fully spawned females) to the total number of females. A significant effect of the lower dose on the average egg sizes was noticed, with a smaller area and diameter measured with respect to the control and the higher concentrated treatments. These results once again underline the importance for ecotoxicological studies to address the nonlinear dose-response effects of endocrine disruptive chemicals environmentally present at concentrations in the order of just a few µg/L that could not elicit a strong defence mechanism at low levels and be absorbed by filter feeder animals such as mussels.

Anterior cervical discectomy and fusion versus cervical disc arthroplasty: an epidemiological review of 433,660 surgical patients from 2011 to 2021.

BACKGROUND CONTEXT: Anterior cervical discectomy and fusion (ACDF) and cervical disc arthroplasty (CDA) are commonly performed operations to address cervical radiculopathy and myelopathy. Trends in utilization and revision surgery rates warrant investigation. PURPOSE: To explore the epidemiology, postoperative complications, and reoperation rates of ACDF and CDA. DESIGN: Retrospective cohort study. PATIENT SAMPLE: A total of 433,660 patients who underwent ACDF or CDA between 2011 and 2021 were included in this study. OUTCOME MEASURES: The following data were observed for all cases: patient demographics, complications, and revisions. METHODS: The PearlDiver database was queried to identify patients who underwent ACDF and CDA between 2011 and 2021. Epidemiological analyses were performed to examine trends in cervical procedure utilization by age group and year. After matching by age, sex, Charlson Comorbidity Index (CCI), levels of operation, and reason for surgery, the early postoperative (2-week), short-term (2-year), and long-term (5-year) complications of both cervical procedures were examined. RESULTS: In total, 404,195 ACDF and 29,465 CDA patients were included. ACDF utilization rose by 25.25% between 2011 and 2014 while CDA utilization rose by 654.24% between 2011-2019 followed by relative plateauing in both procedures. Mann-Kendall trend test confirmed a significant but small rise in ACDF and large rise in CDA procedures from 2011 to 2021 (p<.001). After matching, ACDF and CDA had an overall complication rate of 12.20% and 8.77%, respectively, with the most common complications being subsequent anterior revision (4.96% and 3.35%) and dysphagia (3.70% and 2.98%). The ACDF cohort, especially multilevel ACDF patients, generally had more complications and higher revision rates than the CDA cohort (p<.05). CONCLUSIONS: While ACDF utilization has plateaued since 2014, CDA rates have risen by a staggering 654.24% over the past decade. ACDF and CDA complication and revision rates were relatively low in comparison to previously published values, with significantly lower rates in CDA. Although a lack of radiographic data in this study limits its power to recommend either procedure for individual patients with cervical radiculopathy or myelopathy, CDA may be associated with minor improvement in the complication and revision profile.

Polycystic Ovary Syndrome Pathophysiology: Integrating Systemic, CNS and Circadian Processes.

The conceptualization of polycystic ovary syndrome (PCOS) has primarily focused on hormonal alterations driven by changes within the hypothalamus and ovarian granulosa cells, with treatment by the contraceptive pill and weight loss. However, a growing body of data implicates wider systemic and central nervous system (CNS) changes in the pathoetiology and pathophysiology of PCOS, with consequent implications for targeted treatments. It is proposed that there is a significant role for night-time interactions of factors acting to regulate whether the rising level of cortisol over the night and during the morning cortisol awakening response (CAR) is able to induce the nuclear translocation of the glucocorticoid receptor (GR), thereby influencing how the immune and glial systems regulate cellular function in preparation for the coming day. Factors affording protection in PCOS also inhibit GR nuclear translocation including gut microbiome-derived butyrate, and pineal/local melatonin as well as melatonin regulated bcl2-associated athanogene (BAG)-1. A significant pathophysiological role in PCOS is attributed to the aryl hydrocarbon receptor (AhR), which shows heightened levels and activity in PCOS. The AhR is activated by ligands of many systemic processes, including white adipocyte-derived kynurenine, implicating obesity in the pathophysiological changes occurring in the hypothalamus and ovaries. AhR activation has consequences for the physiological function in the hypothalamic paraventricular nucleus, granulosa cells and adipocytes, partly mediated by AhR upregulation of the mitochondrial N-acetylserotonin/melatonin ratio, thereby decreasing melatonin availability whilst increasing local stress plasticity in the paraventricular nucleus. This article reviews in detail the wider systemic and CNS changes in PCOS highlighting interactions of local and pineal melatonergic pathway, gut microbiome-derived butyrate, white adipocyte-derived kynurenine, the hypothalamic paraventricular nucleus tanycytes/astrocytes, and the hypothalamus-pituitary-adrenal (HPA) axis driven glucocorticoid receptor activation in PCOS pathophysiology. This integrates a wide array of previously disparate data on the biological underpinnings of PCOS, including how PCOS associates with many other currently classified medical conditions, such as depression, bipolar disorder, type 1 diabetes mellitus and the autism spectrum. Numerous future research and treatment implications are detailed.

Utilization of Antibiotic Bone Cement in Spine Surgery: Pearls, Techniques, and Case Review.

Vertebral osteomyelitis (VO) encompasses a spectrum of spinal infections ranging from isolated mild vertebral osteomyelitis to severe diffuse infection with associated epidural abscess and fracture. Although patients can often be treated with an initial course of intravenous antibiotics, surgery is sometimes required in patients with sepsis, spinal instability, neurological compromise, or failed medical treatment. Antibiotic bone cement (ABC) has been widely used in orthopedic extremity surgery for more than 150 years, both for prophylaxis and treatment of bacterial infection. However, relatively little literature exists regarding its utilization in spine surgery. This article describes ABC utilization in orthopedic surgery and explains the technique of ABC utilization in spine surgery. Surgeons can choose from multiple premixed ABCs with variable viscosities, setting times, and antibiotics or can mix in antibiotics to bone cements themselves. ABC can be used to fill large defects in the vertebral body or disc space or in some cases to coat instrumentation. Surgeons should be wary of complications such as ABC extravasation as well as an increased difficulty with revision. With a thorough understanding of the properties of the cement and the methods of delivery, ABC is a powerful adjunct in the treatment of spinal infections.

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses.

A dysregulated circadian rhythm is significantly associated with cancer risk, as is aging. Both aging and circadian dysregulation show suppressed pineal melatonin, which is indicated in many studies to be linked to cancer risk and progression. Another independently investigated aspect of the circadian rhythm is the cortisol awakening response (CAR), which is linked to stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR and HPA axis activity are primarily mediated via activation of the glucocorticoid receptor (GR), which drives patterned gene expression via binding to the promotors of glucocorticoid response element (GRE)-expressing genes. Recent data shows that the GR can be prevented from nuclear translocation by the B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), which translocates the GR to mitochondria, where it can have diverse effects. Melatonin also suppresses GR nuclear translocation by maintaining the GR in a complex with heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, can upregulate BAG-1, suggesting that the dramatic 10-fold decrease in pineal melatonin from adolescence to the ninth decade of life will attenuate the capacity of night-time melatonin to modulate the effects of the early morning CAR. The interactions of pineal melatonin/BAG-1/Hsp90 with the CAR are proposed to underpin how aging and circadian dysregulation are associated with cancer risk. This may be mediated via differential effects of melatonin/BAG-1/Hsp90/GR in different cells of microenvironments across the body, from which tumors emerge. This provides a model of cancer pathogenesis that better integrates previously disparate bodies of data, including how immune cells are regulated by cancer cells in the tumor microenvironment, at least partly via the cancer cell regulation of the tryptophan-melatonin pathway. This has a number of future research and treatment implications.

Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Cancer.

Platelets have traditionally been investigated for their role in clot formation in the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect of wider systemic processes, with relevance to the pathophysiology of a host of diverse medical conditions, including neurodegenerative disorders and cancer. This article reviews platelet function and interactions with the gut microbiome and circadian systems, highlighting the role of the platelet mitochondrial melatonergic pathway in determining platelet activation, fluxes and plasticity. This provides a number of novel conceptualizations of platelet function and mode of interaction with other cell types, including in the pathoetiology and pathophysiology of diverse medical conditions, such as cancer, Alzheimer's disease, and amyotrophic lateral sclerosis. It is proposed that a platelet-gut axis allows platelets to contribute to many of the pathophysiological processes linked to gut dysbiosis and gut permeability. This is at least partly via platelet sphingosine- 1-phosphate release, which regulates enteric glial cells and lymphocyte chemotaxis, indicating an etiological role for platelets in a wide array of medical conditions linked to alterations in the gut microbiome. Platelets are also an important regulator of the various microenvironments that underpin most human medical conditions, including the tumor microenvironment, neurodegenerative diseases, and autoimmune disorders. Platelet serotonin release regulates the availability of the mitochondrial melatonergic pathway systemically, thereby being an important determinant of the dynamic metabolic interactions occurring across cell types that underpin the pathoetiology of many medical conditions. In addition, a number of novel and diverse future research directions and treatment implications are proposed.

Development of an Endoscopic Spine Surgery Program: Overview and Basic Considerations for Implementation.

Endoscopic spine surgery (ESS) is an innovative technique allowing for minimally invasive, direct visualization of spinal abnormalities. The growth of ESS in the United States has been stunted by high start-up costs, low reimbursement rates, and the steep learning curve associated with mastering endoscopic techniques. Hergrae, we describe the current state and future direction of ESS and provide key action items for ESS program implementation.

History and Metamorphosis of Hand Surgery India.

The advent of hand surgery in India reads like a fortuitous saga, a continuum of the hand deformity correction on leprosy patients pioneered by Dr. Paul Wilson Brand at the Christian Medical College (CMC) Vellore, Madras State (Tamil Nadu [TN]), in 1948. The "Hand Research Unit," established in 1951, became the largest repository for hand reconstructive surgeries and with its head-start drew in most hand dysfunctions in the country. Early industrialization and disorderly road traffic generated hand injuries that threatened workforce in India. Propitiously, a hand injury service was opened in 1971 at the Government Stanley Medical College Hospital, Chennai. The inexorable growth of hand surgery continued and incorporated the gamut of conditions that required hand care and rehabilitation, including brachial plexus injuries. Continuing Medical Education programs, Hand Surgery workshops, Indian Society for Surgery of the Hand meetings, Hand Fellowships, etc., increased the number of "hand surgery" practitioners, which drew the attention of the Medical Council of India to commence a postgraduate Hand Surgery program that it eventually gazetted. The sagacity of the members of the Board of Studies of TN Medical University honored the historical role of CMC Vellore in hand surgery and allowed it to commence the first Master of Chirurgiae Hand Surgery course in India in 2015. An intuitive understanding of 70 years of hand surgery accomplishments that redesigned and restored deformed and injured hands and protected livelihoods have made young surgeons increasingly take hand surgery as a career.

How much are patients willing to pay for spine surgery? An evaluation of attitudes toward out-of-pocket expenses and cost-reducing measures.

BACKGROUND CONTEXT: With rising healthcare expenditures in the United States, patients and providers are searching to maintain quality while reducing costs. PURPOSE: The aim of this study was to investigate patient willingness to pay for anterior cervical discectomy and fusion (ACDF), degenerative lumbar spinal fusions (LF), and adult spine deformity (ASD) surgery. STUDY DESIGN/SETTING: A survey was developed and distributed to anonymous respondents through Amazon Mechanical Turk (MTurk). METHODS: The survey introduced 3 procedures: ACDF, LF, and ASD surgery. Respondents were asked sequentially if they would pay at each increasing price option. Respondents were then presented with various cost-saving methods and asked to select the options that made them most uncomfortable, even if those would save them out-of-pocket costs. RESULTS: In total, 979 of 1,172 total responses (84%) were retained for analysis. The average age was 36.2 years and 44% of participants reported a household income of $50,000 to 100,000. A total of 63% used Medicare and 13% used Medicaid. A total of 40% stated they had high levels of financial stress. A total of 30.1% of participants were willing to undergo an ACDF, 30.3% were willing to undergo a LF, and 29.6% were willing to undergo ASD surgery for the cost of $3,000 (p=.98). Regression demonstrated that for ACDF surgery, a $100 increase in price resulted in a 2.1% decrease in willingness to pay. This is comparable to degenerative LF surgery (1.8% decrease), and ASD surgery (2%). When asked which cost-saving measures participants were least comfortable with for ACDF surgery, 60% stated "Use of the older generation implants/devices" (LF: 51%, ASD: 60%,), 61% stated "Having the surgery performed at a community hospital instead of at a major academic center" (LF: 49%, ASD: 56%), and 55% stated "Administration of anesthesia by a nurse anesthetist" (LF: 48.01%, ASD: 55%). Conversely, 36% of ACDF patients were uncomfortable with a "Video/telephone postoperative visit" to cut costs (LF: 51%, ASD: 39%). CONCLUSIONS: Patients are unwilling to contribute larger copays for adult spinal deformity correction than for ACDF and degenerative lumbar spine surgery, despite significantly higher procedural costs and case complexity/invasiveness. Patients were most uncomfortable forfeiting newer generation implants, receiving the operation at a community rather than an academic center, and receiving care by physician extenders. Conversely, patients were more willing to convert postoperative visits to telehealth and forgo neuromonitoring, indicating a potentially poor understanding of which cost-saving measures may be implemented without increasing the risk of complications.

Melatonin modulates tumor metabolism and mitigates metastasis.

INTRODUCTION: Melatonin, originally isolated from the mammalian pineal gland, was subsequently identified in many animal cell types and in plants. While melatonin was discovered to inhibit cancer more than 5 decades ago, its anti-cancer potential has not been fully exploited despite its lack of serious toxicity over a very wide dose range, high safety margin, and its efficacy. AREAS COVERED: This review elucidates the potential mechanisms by which melatonin interferes with tumor growth and metastasis, including its ability to alter tumor cell metabolism, inhibit epithelial-mesenchymal transition, reverse cancer chemoresistance, function synergistically with conventional cancer-inhibiting drugs while limiting many of their side effects. In contrast to its function as a potent antioxidant in normal cells, it may induce oxidative stress in cancer cells, contributing to its oncostatic actions. EXPERT OPINION: Considering the large amount of experimental data supporting melatonin's multiple and varied inhibitory effects on numerous cancer types, coupled with the virtual lack of toxicity of this molecule, it has not been thoroughly tested as an anti-cancer agent in clinical trials. There seems to be significant resistance to such investigations, possibly because melatonin is inexpensive and non-patentable, and as a result there would be limited financial gain for its use.

Spinal Cord Stimulators and Intrathecal Pain Pump Removal Versus Retention During Posterior Lumbar Fusion: A Matched Cohort Analysis.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine risks associated with posterior lumbar arthrodesis after spinal cord stimulator (SCS) and intrathecal pain pump (IPP) insertion. SUMMARY OF BACKGROUND DATA: SCS and IPPs aid in the management of chronic back and radicular pain. Little is known regarding the risks of subsequent fusion with these devices in place. METHODS: The PearlDiver Mariner database was queried for spinal fusion between 2010 and 2020. Study groups were created for indwelling SCS or IPP and matched to a separate cohort without SCS or IPP. Subgroups were created for those who had their device removed and those who retained their device at the time of surgery. Complications up to 2 years postoperatively were reviewed and confounding variables were controlled using multivariable logistic regression. RESULTS: Four thousand five hundred three patients had an indwelling SCS/IPP and underwent posterior lumbar fusion. Compared with patients without history of an SCS/IPP, patients undergoing a lumbar fusion with an SCS/IPP which was removed or retained had higher rates of revision surgery at 1 year [7.3% vs. 5.0%, odds ratio (OR) =1.48, P <0.001] and 2 year (10.8% vs. 7.0%, OR =1.59, P <0.001). For all time intervals, there were higher odds of instrumentation failure (2 y: OR =1.65, P <0.001), and pulmonary complications (2 y: OR =1.18, P <0.001). At 2 years, there were higher odds of surgical site complications (OR 1.15, P =0.02) and urinary complications (OR=1.07, P =0.04). There were no differences in complications up to 2 years postoperatively in patients with an SCS/IPP who had their devices retained or removed ( P >0.05). CONCLUSIONS: Patients with a history of spinal cord stimulators and intrathecal pain pumps are at increased risk of mechanical complications and revision fusion compared with patients without these devices. Patients with an SCS or IPP have similar rates of complications during lumbar fusion whether the device is removed or retained.

Determination of Indolepropionic Acid and Related Indoles in Plasma, Plasma Ultrafiltrate, and Saliva.

The microbial metabolite indolepropionic acid (IPA) and related indolic metabolites, including indolecarboxylic acid (ICA), indolelactic acid (ILA), indoleacetic acid (IAA), indolebutyric acid (IBA), indoxylsulfate (ISO4), and indole, were determined in human plasma, plasma ultrafiltrate (UF), and saliva. The compounds were separated on a 150 × 3 mm column of 3 µm Hypersil C18 eluted with a mobile phase of 80% pH 5 0.01 M sodium acetate containing 1.0 g/L of tert-butylammonium chloride/20% acetonitrile and then detected fluorometrically. Levels of IPA in human plasma UF and of ILA in saliva are reported for the first time. The determination of IPA in plasma UF enables the first report of free plasma IPA, the presumed physiologically active pool of this important microbial metabolite of tryptophan. Plasma and salivary ICA and IBA were not detected, consistent with the absence of any prior reported values. Observed levels or limits of detection for other indolic metabolites usefully supplement limited prior reports.

Redefining Autoimmune Disorders' Pathoetiology: Implications for Mood and Psychotic Disorders' Association with Neurodegenerative and Classical Autoimmune Disorders.

Although previously restricted to a limited number of medical conditions, there is a growing appreciation that 'autoimmune' (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8+ T cell and B-cell 'autoimmune'-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8+ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many 'autoimmune'/'immune-mediated' disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies.