Cytosolic dopamine determines hypersensitivity to blunt force trauma.

The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is conserved across species, from nematodes to humans. However, the molecular mechanisms underlying this hypersensitivity to blunt force trauma remain elusive. We find that extravesicular dopamine, a key driver of Parkinson's disease, extends its toxic role to the acute challenges associated with injury. Ectopic dopamine synthesis in serotonergic neurons sensitizes this resilient neuronal subtype to trauma-induced degeneration. While dopaminergic neurons normally maintain dopamine in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Cytosolic dopamine accumulation, through perturbations to its synthesis, metabolism, or packaging, is necessary and sufficient to drive neurodegeneration upon injury and during aging. Additionally, degeneration is further exacerbated by rapid upregulation of the rate-limiting enzyme in dopamine synthesis, cat-2, via the FOS-1 transcription factor. Fundamentally, our study in C. elegans unravels the molecular intricacies rendering dopaminergic neurons uniquely prone to physical perturbation across evolutionary lines.

Personalization above anonymization? A role for considering the humanity and spirituality of the dead in anatomical education.

Clinical anatomy education is meant to prepare students for caring for the living, often by working with the dead. By their nature many clinical anatomy education programs privilege topographical form  over the donor's humanity. This inbalance between the living and the dead generates tensions between the tangible and the spiritual insofar as semblances of the humanity of donors endure even in depictions and derivatives. This article argues that considering the relevance of spirituality, and what endures of a donor's humanity after death, would enhance contemporary anatomy education and the ethical treatment of human body donors (and derivatives). In developing this argument, we (the authors) address the historical connection between spirituality and anatomy, including the anatomical locations of the soul. This serves as a basis for examining the role of the mimetic-or imitative-potential of deceased human donors as representations of the living. We deliberate on the ways in which the depersonalization and anonymization of those donating challenge the mimetic purpose of human body donors and the extent to which such practices are misaligned with the health care shift  from a biomedical to a biopsychosocial model. Weighing up the risks and opportunities of anonymization versus personalization of human body donors, we propose curricula that could serve to enhance the personalization of human donors to support students learning topographical form. In doing so, we argue that the personalization of human donors and depictions could prevent the ill effects of digital representations going "viral," and enhance opportunities for donors to help the general public learn more about the human form.

Blood Markers in Relation to a History of Traumatic Brain Injury Across Stages of Cognitive Impairment in a Diverse Cohort.

BACKGROUND: Traumatic brain injury (TBI) has been linked to multiple pathophysiological processes that could increase risk for Alzheimer's disease and related dementias (ADRD). However, the impact of prior TBI on blood biomarkers for ADRD remains unknown. OBJECTIVE: Using cross-sectional data, we assessed whether a history of TBI influences serum biomarkers in a diverse cohort (approximately 50% Hispanic) with normal cognition, mild cognitive impairment, or dementia. METHODS: Levels of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (T-tau), and ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) were measured for participants across the cognitive spectrum. Participants were categorized based on presence and absence of a history of TBI with loss of consciousness, and study samples were derived through case-control matching. Multivariable general linear models compared concentrations of biomarkers in relation to a history of TBI and smoothing splines modelled biomarkers non-linearly in the cognitively impaired groups as a function of time since symptom onset. RESULTS: Each biomarker was higher across stages of cognitive impairment, characterized by clinical diagnosis and Mini-Mental State Examination performance, but these associations were not influenced by a history of TBI. However, modelling biomarkers in relation to duration of cognitive symptoms for ADRD showed differences by history of TBI, with only GFAP and UCHL1 being elevated. CONCLUSIONS: Serum GFAP, NFL, T-tau, and UCHL1 were higher across stages of cognitive impairment in this diverse clinical cohort, regardless of TBI history, though longitudinal investigation of the timing, order, and trajectory of the biomarkers in relation to prior TBI is warranted.

Use of bevacizumab in a patient with Whipple's disease: managing diagnostic uncertainty.

A man in his 30s with intellectual disability presented with 1 month of diarrhoea, weight loss and dyspnoea. Investigations were hampered due to significant anxiety. Laboratory tests detected microcytic anaemia and hypoalbuminaemia. CT demonstrated a fat-containing infiltrate in the mediastinum, mesentery and axillae, and pulmonary ground-glass infiltrates. Biopsy of the axilla showed cystic lymphatic malformations involving adipose tissue and lymph nodes, leading to a provisional diagnosis of generalised lymphatic anomaly. Over the subsequent 4 months, the patient's respiratory status deteriorated, leading to type 1 respiratory failure necessitating intubation. After multidisciplinary discussion, a decision was made to trial bevacizumab, an anti-VEGF agent, with subsequent improvement in respiratory status. While intubated, gastroscopy was performed; duodenal biopsies revealed pathognomonic changes of Whipple's disease, confirmed on PCR of duodenal and axillae biopsies. This was deemed the most likely unifying diagnosis; antibiotic treatment was commenced, bevacizumab was ceased, and the patient has remained well after 18 months.

Comparison of Pediatric Dentistry Under General Anesthesia in a Surgery Center vs a Hospital.

OBJECTIVE: Pediatric patients who undergo general anesthesia (GA) for dentistry may be treated in different venues. This retrospective study compared patients treated in an ambulatory surgery center (ASC) to those treated in a hospital operating room (H-OR). The 2-venue model was also compared with a historical hospital-only model. METHODS: Twelve months of data were collected via records review: patient demographics, American Society of Anesthesiology (ASA) classification, and medical comorbidities. Data from patients treated at the H-OR 10 years prior were referenced for comparison. RESULTS: Between July 2017 and June 2018, 1148 patients were treated: 635 at the ASC and 513 at the H-OR. The most common age range for both venues was 3 to 8 years. Of all the ASC patients, 78% were ASA I, while 48% of H-OR patients were ASA III (P < .001). The number of patients treated with the 2-venue model represented a 240% annual increase compared with those treated historically using the hospital-only model. CONCLUSION: Because of differences in patient medical comorbidities, both the ASC and H-OR are needed to adequately address the needs of pediatric dental patients who require GA. Treating healthy patients in an ASC also creates increased capacity in the H-OR to better accommodate those with higher medical acuity.

Loss of heat shock factor initiates intracellular lipid surveillance by actin destabilization.

Cells sense stress and initiate response pathways to maintain lipid and protein homeostasis. However, the interplay between these adaptive mechanisms is unclear. Herein, we demonstrate how imbalances in cytosolic protein homeostasis affect intracellular lipid surveillance. Independent of its ancient thermo-protective properties, the heat shock factor, HSF-1, modulates lipid metabolism and age regulation through the metazoan-specific nuclear hormone receptor, NHR-49. Reduced hsf-1 expression destabilizes the Caenorhabditis elegans enteric actin network, subsequently disrupting Rab GTPase-mediated trafficking and cell-surface residency of nutrient transporters. The ensuing malabsorption limits lipid availability, thereby activating the intracellular lipid surveillance response through vesicular release and nuclear translocation of NHR-49 to both increase nutrient absorption and restore lipid homeostasis. Overall, cooperation between these regulators of cytosolic protein homeostasis and lipid surveillance ensures metabolic health and age progression through actin integrity, endocytic recycling, and lipid sensing.

Reduced bone morphogenic protein signaling along the gut-neuron axis by heat shock factor promotes longevity.

Aging is a complex and highly regulated process of interwoven signaling mechanisms. As an ancient transcriptional regulator of thermal adaptation and protein homeostasis, the Heat Shock Factor, HSF-1, has evolved functions within the nervous system to control age progression; however, the molecular details and signaling dynamics by which HSF-1 modulates age across tissues remain unclear. Herein, we report a nonautonomous mode of age regulation by HSF-1 in the Caenorhabditis elegans nervous system that works through the bone morphogenic protein, BMP, signaling pathway to modulate membrane trafficking in peripheral tissues. In particular, HSF-1 represses the expression of the neuron-specific BMP ligand, DBL-1, and initiates a complementary negative feedback loop within the intestine. By reducing receipt of DBL-1 in the periphery, the SMAD transcriptional coactivator, SMA-3, represses the expression of critical membrane trafficking regulators including Rab GTPases involved in early (RAB-5), late (RAB-7), and recycling (RAB-11.1) endosomal dynamics and the BMP receptor binding protein, SMA-10. This reduces cell surface residency and steady-state levels of the type I BMP receptor, SMA-6, in the intestine and further dampens signal transmission to the periphery. Thus, the ability of HSF-1 to coordinate BMP signaling along the gut-brain axis is an important determinate in age progression.

Artificial intelligence and clinical anatomical education: Promises and perils.

Anatomy educators are often at the forefront of adopting innovative and advanced technologies for teaching, such as artificial intelligence (AI). While AI offers potential new opportunities for anatomical education, hard lessons learned from the deployment of AI tools in other domains (e.g., criminal justice, healthcare, and finance) suggest that these opportunities are likely to be tempered by disadvantages for at least some learners and within certain educational contexts. From the perspectives of an anatomy educator, public health researcher, medical ethicist, and an educational technology expert, this article examines five tensions between the promises and the perils of integrating AI into anatomy education. These tensions highlight the ways in which AI is currently ill-suited for incorporating the uncertainties intrinsic to anatomy education in the areas of (1) human variations, (2) healthcare practice, (3) diversity and social justice, (4) student support, and (5) student learning. Practical recommendations for a considered approach to working alongside AI in the contemporary (and future) anatomy education learning environment are provided, including enhanced transparency about how AI is integrated, AI developer diversity, inclusion of uncertainty and anatomical variations within deployed AI, provisions made for educator awareness of AI benefits and limitations, building in curricular "AI-free" time, and engaging AI to extend human capacities. These recommendations serve as a guiding framework for how the clinical anatomy discipline, and anatomy educators, can work alongside AI, and develop a more nuanced and considered approach to the role of AI in healthcare education.

Intracellular lipid surveillance by small G protein geranylgeranylation.

Imbalances in lipid homeostasis can have deleterious effects on health1,2. Yet how cells sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption remains unclear. Here we describe a mechanism for intracellular lipid surveillance in Caenorhabditis elegans that involves transcriptional inactivation of the nuclear hormone receptor NHR-49 through its cytosolic sequestration to endocytic vesicles via geranylgeranyl conjugation to the small G protein RAB-11.1. Defective de novo isoprenoid synthesis caused by lipid depletion limits RAB-11.1 geranylgeranylation, which promotes nuclear translocation of NHR-49 and activation of rab-11.2 transcription to enhance transporter residency at the plasma membrane. Thus, we identify a critical lipid sensed by the cell, its conjugated G protein, and the nuclear receptor whose dynamic interactions enable cells to sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption and lipid metabolism.

MR Angiography Series: MR Angiography of the Extremities.

MR angiography (MRA) is a powerful tool for imaging of the extremities, allowing a thorough assessment of the arteries and veins in both the upper and lower limbs. Both contrast-enhanced and noncontrast MRA techniques are described in the online presentation, including practical tips and tricks to obtain all necessary information at every examination. This module is the sixth and final segment in a series created on behalf of the Society for Magnetic Resonance Angiography (SMRA), a group of researchers and clinicians who are passionate about the benefits of MRA but understand its challenges. The full digital presentation is available online. ©RSNA, 2022.

Mild Traumatic Brain Injury Is Related to Elevated Cerebrospinal Fluid Tau in Alzheimer's Disease Dementia.

Few studies have examined an association between mild traumatic brain injury (mTBI) and Alzheimer's disease (AD). For this reason, we compared an AD dementia group with an mTBI history (n = 10) to a matched AD control group (n = 20) on measures of cognitive function, cerebral glucose metabolism, and markers of amyloid and tau deposition. Only a trend and medium-to-large effect size for higher phosphorylated and total tau was identified for the mTBI group. A history of mTBI may be associated with greater tau in AD, indicating a potential pathway for increasing risk for AD, though further evaluation with larger samples is needed.

The impact of spatially varying wetland source signatures on the atmospheric variability of δD-CH4.

We present the first spatially resolved distribution of the [Formula: see text] signature of wetland methane emissions and assess its impact on atmospheric [Formula: see text]. The [Formula: see text] signature map is derived by relating [Formula: see text] of precipitation to measured [Formula: see text] of methane wetland emissions at a variety of wetland types and locations. This results in strong latitudinal variation in the wetland [Formula: see text] source signature. When [Formula: see text] is simulated in a global atmospheric model, little difference is found in global mean, inter-hemispheric difference and seasonal cycle if the spatially varying [Formula: see text] source signature distribution is used instead of a globally uniform value. This is because atmospheric [Formula: see text] is largely controlled by OH fractionation. However, we show that despite these small differences, using atmospheric records of [Formula: see text] to infer changes in the wetland emissions distribution requires the use of the more accurate spatially varying [Formula: see text] source signature. We find that models will only be sensitive to changes in emissions distribution if spatial information can be exploited through the spatially resolved source signatures. In addition, we also find that on a regional scale, at sites measuring excursions of [Formula: see text] from background levels, substantial differences are simulated in atmospheric [Formula: see text] if using spatially varying or uniform source signatures. This article is part of a discussion meeting issue 'Rising methane: is warming feeding warming? (part 1)'.

Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.

Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

Concussion is a type of traumatic brain injury that results from a sudden blow or jolt to the head. Symptoms can include a passing headache, dizziness, confusion or sensitivity to light, but experiencing multiple concussions can have drastic repercussions in later life. Studies of professional athletes have shown that those who experience one or more concussions are prone to developing Alzheimer's and Parkinson's disease, two well-known neurodegenerative diseases. Both conditions involve the progressive loss or breakdown of nerve cells, called neurons. But exactly how this so-called neurodegeneration of brain cells stems from the original, physical injury remains unclear. Head trauma may cause damage to the structural support of a cell or disrupt the flow of electrical impulses through neurons. Energy use and production in damaged cells could shift into overdrive to repair the damage. The chemical properties of different types of brain cells could also make some more vulnerable to trauma than others. Besides neurons, star-shaped support cells in the brain called astrocytes, which may have some protective ability, could also be affected. To investigate which cells may be more susceptible to traumatic injuries, Solano Fonseca et al. modelled the impacts of concussion-like head trauma in roundworms (C. elegans) and mice. In both animals, one type of neuron was extremely vulnerable to cell death after trauma. Neurons that release dopamine, a chemical involved in cell-to-cell communication and the brain's reward system, showed signs of cell damage and deteriorated after injury. Dopaminergic cells, as these cells are called, are involved in motor coordination, and the loss of dopaminergic cells has been linked to both Alzheimer's and Parkinson's disease. Astrocytes, however, had a role in reducing the death of dopaminergic neurons after trauma. In experiments, astrocytes appeared to restore the balance of energy production to meet the increased energy demands of impacted neurons. Single-cell analyses showed that genes involved in metabolism were switched on in astrocytes to produce energy via an alternative pathway. This energetic shift facilitated via astrocytes may help mitigate against some damage to dopamine-producing neurons after trauma, reducing cell death. This work furthers our understanding of cellular changes in the concussed brain. More research will be required to better characterise how this immediate trauma to cells, and the subsequent loss of dopaminergic neurons, impacts brain health long-term. Efforts to design effective therapies to slow or reverse these changes could then follow.

Quantitative pupillometry in patients with traumatic brain injury and loss of consciousness: A prospective pilot study.

OBJECTIVE: Loss of consciousness (LOC) is a hallmark feature in Traumatic Brain Injury (TBI), and a strong predictor of outcomes after TBI. The aim of this study was to describe associations between quantitative infrared pupillometry values and LOC, intracranial hypertension, and functional outcomes in patients with TBI. METHODS: We conducted a prospective study of patients evaluated at a Level 1 trauma center between November 2019 and February 2020. Pupillometry values including the Neurological Pupil Index (NPi), constriction velocity (CV), and dilation velocity (DV) were obtained. RESULTS: Thirty-six consecutive TBI patients were enrolled. The median (range) age was 48 (range 21-86) years. The mean Glasgow Coma Scale score on arrival was 11.8 (SD = 4.0). DV trichotomized as low (<0.5 mm/s), moderate (0.5-1.0 mm/s), or high (>1.0 mm/s) was significantly associated with LOC (P = .02), and the need for emergent intervention (P < .01). No significant association was observed between LOC and NPi (P = .16); nor between LOC and CV (P = .07). CONCLUSIONS: Our data suggests that DV, as a discrete variable, is associated with LOC in TBI. Further investigation of the relationship between discrete pupillometric variables and NPi may be valuable to understand the clinical significance of the pupillary light reflex findings in acute TBI.

MR Angiography Series: Fundamentals of Contrast-enhanced MR Angiography.

The Society for Magnetic Resonance Angiography (SMRA) is a group of researchers and clinicians who are passionate about the benefits of MR angiography (MRA) but understand its challenges. Their mission is to study MRA, continually improve and innovate for the benefit of patients, and most important, educate the medical community so they can take full advantage of the benefits of MRA and overcome its challenges. In support of that mission, the authors have created a series of self-learning modules on behalf of the SMRA to demystify MRA protocols and help the reader perform patient-friendly high-quality MRA on a routine basis in clinical practice. The full digital presentation is available online. ©RSNA, 2021.

Singlet and Triplet State Properties and Singlet Oxygen Yield of an Amino-Acyl-Quinoxalinone Yellow Dye.

Amino-acyl-quinoxalinone yellow dyes are cyclised analogues of the yellow azomethine dyes developed for, and still used in, silver halide colour photography. Unlike image azomethine dyes, which are rapidly deactivated in their excited states by torsion about the azomethine bond, amino-acyl-quinoxalinone dyes have an interesting photophysics because torsion is not possible due to their cyclised structure. We report results from studies on singlet and triplet state properties, and singlet oxygen yields, of the yellow dye, 7-diethylamino-3-(2,2-dimethyl-propionyl)-5-methyl-1-phenyl-1H-quinoxalin-2-one, in polar and nonpolar solvents. The dye photophysics is characterised by a weak fluorescence, with a solvent dependent emission yield (ΦF ≈ 0.002-0.004), and short singlet state lifetime (τexpt ≈ 20-50 ps), both increasing by a factor of ≈2 in going from polar acetonitrile to non-polar dioxane as solvent. DFT ZINDO calculations show a transition involving significant electron transfer from the diethyl-amino group into the carbonyl region of the molecule. In solution, in the presence of oxygen, the triplet state decays almost exclusively by oxygen quenching, and singlet oxygen is produced in high yield (Φ∆ ≈ 0.5-0.55). The triplet state absorbs across the 450-750 nm region with maxima around 480 and 650 nm, and moderate molar absorption coefficients (ca. 6000-8000 M-1 cm-1). In a glass at 77 K, triplet decay gives a red phosphorescence, with λmax ≈ 640-650 nm, and a ≈ 0.25 s lifetime. If singlet oxygen yields are a good indication of triplet yields, then internal conversion and intersystem crossing occur with roughly equal efficiency.

Corona mortis injury causing delayed presentation of pelvic pseudoaneurysm.

Pseudoaneurysms are rare complications in urological surgery. Typically, they would present with pain, haematuria or anaemia. We report a 60-year-old patient who was found to have a chronic pseudoaneurysm via a corona mortis vascular variant, 3 months after a robotic-assisted prostatectomy. Unlike other rare reports of delayed vascular complications after minimally invasive urological surgery, the patient was entirely asymptomatic.Apart from careful intraoperative dissection, a high index of suspicion and low threshold for imaging are also required in the follow up period. Percutaneous trans-arterial embolization is safe and effective in dealing with post-surgical pseudoaneurysms.

Trauma-induced regulation of VHP-1 modulates the cellular response to mechanical stress.

Mechanical stimuli initiate adaptive signal transduction pathways, yet exceeding the cellular capacity to withstand physical stress results in death. The molecular mechanisms underlying trauma-induced degeneration remain unclear. In the nematode C. elegans, we have developed a method to study cellular degeneration in response to mechanical stress caused by blunt force trauma. Herein, we report that physical injury activates the c-Jun kinase, KGB-1, which modulates response elements through the AP-1 transcriptional complex. Among these, we have identified a dual-specificity MAPK phosphatase, VHP-1, as a stress-inducible modulator of neurodegeneration. VHP-1 regulates the transcriptional response to mechanical stress and is itself attenuated by KGB-1-mediated inactivation of a deubiquitinase, MATH-33, and proteasomal degradation. Together, we describe an uncharacterized stress response pathway in C. elegans and identify transcriptional and post-translational components comprising a feedback loop on Jun kinase and phosphatase activity.