A Review of Glymphatics and the Impact of Osteopathic Manipulative Treatment in Alzheimer's Disease, Concussions, and Beyond.

Glymph is a fluid that circulates in the brain interstitium and, under pathological conditions, unusually accumulates and enhances the buildup of other noxious molecules. The study of this process of circulation, accumulation, and clearance is called glymphatics. We review the physiology of glymphatics and then dive into recent innovative research surrounding this neurological field of study and how it has applied to mainstream pathological processes, including Alzheimer's disease and spectrums of traumatic brain injury that range from a concussion to chronic traumatic encephalopathy (CTE). Furthermore, we explore the implications of glymphatics and a new and developing frontier of healthcare in space travel; with the advent of a Space Force and the introduction of space travel to consumer markets, this is an exciting time to develop novel techniques in enhancing its safety and optimizing human physiology for best outcomes. Therefore, we also propose that osteopathic manipulative treatment (OMT) plays an intuitive role in the treatment of abnormal glymphatics, as adjunctive therapy in Alzheimer's and CTE, and as a future staple before, during, and after space travel for the benefit of both enhancing healthcare in chronic conditions and advancing the capabilities of the human race in its shining new endeavor.

Using the Decrease in Trauma Admissions During the COVID-19 Pandemic to Evaluate Compliance With Stay-at-Home and Social Distancing Guidelines.

Introduction The coronavirus disease 2019 (COVID-19) virus was declared a pandemic on March 10, 2020 by the World Health Organization (WHO) and has massively burdened healthcare systems with cases exponentially rising throughout the United States and the rest of the world. Since implementing precautions to reduce the spread of this disease, emergency departments have seen a decrease in the number of traumas. By evaluating the differences in the number of trauma admissions in different subgroups of patients, we can assess where to target messaging to increase compliance with these precautions. In this study, we aim to analyze the effect of the COVID-19 pandemic on trauma admissions. Methodology This was a retrospective review of the trauma database at our institution, a level 2 trauma center in Southern California, to assess the impact of COVID-19 on the number of traumas. The inclusion criteria were patients activated as traumas, regardless of age. Patients were excluded from the study if they did not have complete information in the trauma database. Data were stratified by date into two groups: (a) COVID period (January to April 2020) and (b) pre-COVID period (January to April 2019). The primary endpoint of this study was to determine whether there was a significant change in the number of patients presenting as trauma during the COVID-19 pandemic. This difference was analyzed and divided into subgroups based on age and trauma type. Results In our review, an average of 279 patients per month presented as trauma from January to April in 2019, and an average of 222 patients per month presented as trauma from January to April 2020 (p = 0.049). We found a significant decrease in the number of patients presenting with the chief complaint of fall and vehicular accident, but a nonsignificant difference in patients presenting as assaults or pedestrian accidents. There was also a significant decrease in the number of traumas in the 18-39 and 65+ age groups and a nonsignificant decrease in the 40-64 age group. It was also noted that the number of trauma admissions in May 2020 increased to 253 compared to 269 in 2019. This increase was most notable in the 18-39 and 40-64 age groups. Discussion As seen in the data, the most notable year-over-year difference was seen in March and April. In California specifically, a stay-at-home order was set in place in March, which was in conjunction with the WHO's declaration of a pandemic. An interesting finding was the significant decrease in patients with traumas in the age groups of 18-39 and 65+ from 2019 to 2020. There was a smaller, nonsignificant decrease in patients aged 40-64. This would be a good group to target with future messaging to increase compliance with health advisories. There was also a notable increase in the number of traumas in May 2020, signaling an end to the cooperation of the majority of people, also indicating that further measures needed to be enacted in all groups. Conclusions COVID-19 has disrupted social structures worldwide. As the pandemic continued, even the observers of stay-at-home and social distancing measures, the 18-39 age group, became fatigued with the guidelines and ventured out into the warming weather and summer activities. This difference in trauma admission due to COVID-19 between subsequent years can highlight the behavioral changes in our patient population and can be further extrapolated to target additional messaging to help reduce the spread of COVID-19.

Use of constitutive and inducible oncogene-containing iPSCs as surrogates for transgenic mice to study breast oncogenesis.

BACKGROUND: Powerful constitutive and inducible transgenic / bitransgenic / tritransgenic murine models of breast cancer have been used over the past two decades to shed light on the molecular mechanisms by which the given transgenic oncogenes have interacted with other cellular genes and set in motion breast cancer initiation and progression. However, these transgenic models, as in vivo models only, are expensive and restrictive in the opportunities they provide to manipulate the experimental variables that would enable a better understanding of the molecular events related to initial transformation and the target cell being transformed. METHODS: To overcome some of these limitations, we derived oncogene-containing induced pluripotent stem cell (iPSC) clones from tail vein fibroblasts of these transgenic mice and manipulated them both in vitro and in vivo in non-transgenic background mice. We created the iPSC clones with a relatively low M.O.I, producing retroviral integrations which averaged only 1 to 2 sites per retroviral plasmid construct used. RESULTS: Most iPSC clones derived from each group displayed an essentially normal murine karyotype, strong expression of the exogenous reprogrammable genes and significant expression of characteristic endogenous murine surface stem cell markers including SSEA-1 (CD15), PECAM-1 (CD31), Ep-Cam (CD326), and Nectin (CD112), but no expression of their transgene. A majority (75%) of iPSC clones displayed a normal murine karyotype but 25% exhibited a genomically unstable karyotype. However, even these later clones exhibited stable and characteristic iPSC properties. When injected orthotopically, select iPSC clones, either constitutive or inducible, no longer expressed their exogenous pluripotency reprogramming factors but expressed their oncogenic transgene (PyVT or ErbB2) and participated in both breast ontogenesis and subsequent oncogenesis. When injected non-orthotopically or when differentiated in vitro along several different non-mammary lineages of differentiation, the iPSC clones failed to do so. Although many clones developed anticipated teratomas, select iPSC clones under the appropriate constitutive or inducible conditions exhibited both breast ontogenesis and oncogenesis through the same stages as exhibited by their transgenic murine parents and, as such, represent transgenic surrogates. CONCLUSIONS: The iPSC clones offer a number of advantages over transgenic mice including cost, the ability to manipulate and tag in vitro, and create an in vitro model of breast ontogeny and oncogenesis that can be used to gain additional insights into the differentiated status of the target cell which is susceptible to transformation. In addition, the use of these oncogene-containing iPSC clones can be used in chemopreventive studies of breast cancer.

Why is cancer so common a disease in people yet so rare at a cellular level?

Cancers are common diseases in people and yet, on a cellular level, are quite rare. The vast majority of both sporadic, spontaneous cancers and inherited germline cancers arise in single foci from singly transformed cells despite the fact that, in the former, carcinogenic factors bathe fields of millions of potential target cells and, in the latter, the predisposing germline mutations are present in every cell of a given organ and, in fact, every cell of the body. Although the multi-hit theory of carcinogenesis has been invoked to explain such things as cancer latency, which is the period between cancer initiation and emergence and the cancer-aging relationship where an accumulation of "hits" over a period of time are necessary for cancer emergence, the multi-hit theory falls short in explaining the rareness of transformation at a cellular level. This is so because many cancers are not due to multiple hits, and even for those that are, it would be expected that many cells would be exposed to those factors inducing the hits. Although the tumor stem/progenitor cell compartmental theory of tumorigenesis characterizes a tumor compartment that is capable of self-renewal and multipotency, accounting for cancer relapses and recurrences, this compartmental theory alone cannot account for the rareness of initial transformation at a cellular level as the cancer stem/progenitor cell compartment is already transformed and considerable in size. This study advances a different and novel hypothesis that oncogenesis is regulated and ultimately determined by a cell of origin's critical state of differentiation. Before and after this critical state of differentiation has been reached, target cells cannot transform and give rise to cancer even when they receive the necessary carcinogenic insults or have the requisite transforming tumor suppressor genes or oncogenes. As support for this hypothesis, the study cites preliminary evidence using oncogene-containing transgenic mice that develop mammary carcinomas, to derive tail vein fibroblasts converted to iPSCs which, when left undifferentiated, and injected into the cleared fat pads of non-transgenic background mice give rise to mammary gland ontogeny and mammary gland carcinogenesis. However, when first differentiated in vitro into multiply different non-mammary lineages prior to injection, they fail to do so. The hypothesis has widespread implications for chemopreventive strategies.

Regulation of breast cancer oncogenesis by the cell of origin's differentiation state.

Human breast cancer which affects 1/8 women is rare at a cellular level. Even in the setting of germline BRCA1/BRCA2, which is present in all breast cells, solitary cancers or cancers arising at only several foci occur. The overwhelming majority of breast cells (109-1012 cells) resist transformation. Our hypothesis to explain this rareness of transformation is that mammary oncogenesis is regulated by the cell of origin's critical window of differentiation so that target cells outside of this window cannot transform. Our novel hypothesis differs from both the multi-hit theory of carcinogenesis and the stem/progenitor cell compartmental theory of tumorigenesis and utilizes two well established murine transgenic models of breast oncogenesis, the FVB/N-Tg (MMTV-PyVT)634Mul/J and the FVB-Tg (MMTV-ErbB2) NK1Mul/J. Tail vein fibroblasts from each of these transgenics were used to generate iPSCs. When select clones were injected into cleared mammary fat pads, but not into non-orthotopic sites of background mice, they exhibited mammary ontogenesis and oncogenesis with the expression of their respective transgenes. iPSC clones, when differentiated along different non-mammary lineages in vitro, were also not able to exhibit either mammary ontogenesis or oncogenesis in vivo. Therefore, in vitro and in vivo regulation of differentiation is an important determinant of breast cancer oncogenesis.