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Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition
Trace amine-associated receptor 1 (TAAR1) agonists have been shown to have procognitive, antipsychotic-like, anxiolytic, weight-reducing, glucose-lowering, and wake-promoting activities. We used Taar1 knockout (KO) and overexpressing (OE) mice and TAAR1 agonists to elucidate the role of TAAR1 in sleep/wake. EEG, EMG, body temperature (T
), and locomotor activity (LMA) were recorded in Taar1 KO, OE, and WT mice. Following a 24 h recording to characterize basal sleep/wake parameters, mice were sleep deprived (SD) for 6 h. In another experiment, mice were given three doses of the TAAR1 partial agonist RO5263397, caffeine, or vehicle p.o. Baseline wakefulness was modestly increased in OE compared with WT mice. Baseline theta (4.5-9 Hz) and low gamma (30-60 Hz) activity was elevated in KO compared with OE mice in NREM and REM sleep. Following SD, both KO and OE mice exhibited a homeostatic sleep rebound. In WT mice, RO5263397 increased waking and reduced NREM and REM sleep, decreased gamma power during wake and NREM, and decreased T
without affecting LMA; these effects were absent in KO mice and potentiated in OE mice. In contrast, caffeine increased wake time, NREM gamma power, and LMA in all strains compared with vehicle; this effect was attenuated in KO and potentiated in OE mice. TAAR1 overexpression modestly increases wakefulness, whereas TAAR1 partial agonism increases wakefulness and also reduces NREM and also REM sleep. These results indicate a modulatory role for TAAR1 in sleep/wake and cortical activity and suggest TAAR1 as a novel target for wake-promoting therapeutics.
Journal Article
Black enough : stories of being young & black in America
A collection of short stories explore what it is like to be young and black, centering on the experiences of black teenagers and emphasizing that one person's experiences, reality, and personal identity are different than someone else.
Book
Macphatics and PoEMs in Postpartum Mammary Development and Tumor Progression
Postpartum mammary gland involution is a mammalian tissue remodeling event that occurs after pregnancy and lactation to return the gland to the pre-pregnant state. This event is characterized by apoptosis and lysosomal-mediated cell death of the majority of the lactational mammary epithelium, followed by remodeling of the extracellular matrix, influx of immune cell populations (in particular, T helper cells, monocytes, and macrophages), and neo-lymphangiogenesis. This postpartum environment has been shown to be promotional for tumor growth and metastases and may partially account for why women diagnosed with breast cancer during the postpartum period or within 5 years of last childbirth have an increased risk of developing metastases when compared to their nulliparous counterparts. The lymphatics and macrophages present during mammary gland involution have been implicated in promoting the observed growth and metastasis. Of importance are the macrophages, which are of the “M2” phenotype and are known to create a pro-tumor microenvironment. In this report, we describe a subset of postpartum macrophages that express lymphatic proteins (PoEMs) and directly interact with lymphatic vessels to form chimeric vessels or “macphatics”. Additionally, these PoEMs are very similar to tumor-associated macrophages that also express lymphatic proteins and are present at the sites of lymphatic vessels where tumors escape the tissue and enter the lymphatic vasculature. Further characterizing these PoEMs may offer insight in preventing lymphatic metastasis of breast cancer, as well as provide information for how developmental programming of lymphatic endothelial cells and macrophages can contribute to different disease progression.
Journal Article
Developmental pathways from preschool irritability to multifinality in early adolescence: the role of diurnal cortisol
Early irritability predicts a broad spectrum of psychopathology spanning both internalizing and externalizing disorders, rather than any particular disorder or group of disorders (i.e. multifinality). Very few studies, however, have examined the developmental mechanisms by which it leads to such phenotypically diverse outcomes. We examined whether variation in the diurnal pattern of cortisol moderates developmental pathways between preschool irritability and the subsequent emergence of internalizing and externalizing symptoms 9 years later.
When children were 3 years old, mothers were interviewed about children's irritability and completed questionnaires about their children's psychopathology. Six years later, children collected saliva samples at wake-up and bedtime on three consecutive days. Diurnal cortisol patterns were modeled as latent difference scores between evening and morning samples. When children were approximately 12 years old, mothers again completed questionnaires about their children's psychopathology.
Among children with higher levels of irritability at age 3, a steeper diurnal cortisol slope at age 9 predicted greater internalizing symptoms and irritability at age 12, whereas a blunted slope at age 9 predicted greater externalizing symptoms at age 12, adjusting for baseline and concurrent symptoms.
Our results suggest that variation in stress system functioning can predict and differentiate developmental trajectories of early irritability that are relatively more internalizing v. those in which externalizing symptoms dominate in pre-adolescence.
Journal Article
Factors influencing conveyance of older adults with minor head injury by paramedics to the emergency department: a multiple methods study
Background
Head injury (HI) in older adults due to low-energy falls result in a substantial number of emergency department (ED) attendances. However, mortality associated with minor HI is very low. Reducing conveyance to hospital is important for older adults and is a priority for the National Health Service (NHS). Therefore, paramedics are required to make accurate decisions regarding conveyance to the ED. This study used routine data and semi-structured interviews to explore the factors that influence paramedic decision-making when considering whether to convey an adult aged 65 years and over with a minor HI to the ED.
Methods
Semi-structured telephone interviews were completed with ten UK paramedics from a single EMS (ambulance) provider organisation. Interviews explored the factors influencing the paramedics’ conveyance decision-making in adults aged 65 years and over with a minor HI. Data were initially analysed inductively to develop a thematic framework. A retrospective analysis of ambulance service data was also completed to determine the scope and scale of the issue in Southwest England. An in-depth audit of 100 conveyed patient records was used to determine the proportion of patients conveyed to the ED who met National Institute for Health and Care Excellence (NICE) and Joint Royal Colleges Ambulance Liaison Committee (JRCALC) guidelines.
Results
In 2019 South Western Ambulance Service NHS Foundation Trust (SWASFT) attended 15,650 emergency calls to patients aged 65 and over with minor HI, with 70.5% conveyed to ED. 81% of conveyed patients met NICE and JRCALC guideline criteria for conveyance, with the remainder conveyed due to wound care or other medical concerns. The framework developed from the interviews comprised four themes: resources; patient factors; consequences; paramedic factors. Important factors included: the patient’s social situation; guidelines; clinical support availability; the history and presentation of the patient; risk.
Conclusion
This study examined paramedic conveyance decisions for older people with minor HI. It identified multiple influencing factors, highlighting the complex nature of these decisions, and may serve as a basis for developing an intervention to safely decrease ED conveyance in this patient group.
Journal Article
How senior paramedics decide to cease resuscitation in pulseless electrical activity out of hospital cardiac arrest: a mixed methods study
Background
Evidenced-based guidelines on when to cease resuscitation for pulseless electrical activity are limited and support for paramedics typically defaults to the senior clinician. Senior clinicians include paramedics employed to work beyond the scope of clinical guidelines as there may be a point at which it is reasonable to cease resuscitation. To support these decisions, one ambulance service has applied a locally derived cessation of resuscitation checklist. This study aimed to describe the patient, clinical and system factors and examine senior clinician experiences when ceasing resuscitation for pulseless electrical activity.
Design and methods
An explanatory sequential mixed method study was conducted in one ambulance service in the South West of England. A consecutive sample of checklist data for adult pulseless electrical activity were retrieved from 1st December 2015 to 31st December 2018. Unexpected results which required exploration were identified and developed into semi-structured interview questions. A purposive sample of senior clinicians who ceased resuscitation and applied the checklist were interviewed. Content framework analysis was applied to the qualitative findings.
Results
Senior clinicians ceased resuscitation for 50 patients in the presence of factors known to optimise survival: Witnessed cardiac arrest (n = 37, 74%), bystander resuscitation (n = 30, 60%), defibrillation (n = 22, 44%), return of spontaneous circulation (n = 8, 16%). Significant association was found between witnessed cardiac arrest and bystander resuscitation (
p
= .00). Six senior clinicians were interviewed, and analysis resulted in four themes: defining resuscitation futility, the impact of ceasing resuscitation, conflicting views and clinical decision tools. In the local context, senior clinicians applied their clinical judgement to balance survivability. Multiple factors were considered as the decision to cease resuscitation was not always clear. Senior clinicians deviated from the checklist when the patient was perceived as non-survivable.
Conclusion
Senior clinicians applied clinical judgement to assess patients as non-survivable or when continued resuscitation was considered harmful with no patient benefit. Senior clinicians perceived pre-existing factors with duration of resuscitation and clinical factors known to optimise patient survival. Future practice could look beyond a set criteria in which to cease resuscitation, however, it would be helpful to investigate the value or threshold of factors associated with patient outcome.
Journal Article
Subcortical Intermittent Theta-Burst Stimulation (iTBS) Increases Theta-Power in Dorsolateral Prefrontal Cortex (DLPFC)
Cognitive symptoms from Parkinson's disease cause severe disability and significantly limit quality of life. Little is known about mechanisms of cognitive impairment in PD, although aberrant oscillatory activity in basal ganglia-thalamo-prefrontal cortical circuits likely plays an important role. While continuous high-frequency deep brain stimulation (DBS) improves motor symptoms, it is generally ineffective for cognitive symptoms. Although we lack robust treatment options for these symptoms, recent studies with transcranial magnetic stimulation (TMS), applying intermittent theta-burst stimulation (iTBS) to dorsolateral prefrontal cortex (DLPFC), suggest beneficial effects for certain aspects of cognition, such as memory or inhibitory control. While TMS is non-invasive, its results are transient and require repeated application. Subcortical DBS targets have strong reciprocal connections with prefrontal cortex, such that iTBS through the permanently implanted lead might represent a more durable solution. Here we demonstrate safety and feasibility for delivering iTBS from the DBS electrode and explore changes in DLPFC electrophysiology.
We enrolled seven participants with medically refractory Parkinson's disease who underwent DBS surgery targeting either the subthalamic nucleus (STN) or globus pallidus interna (GPi). We temporarily placed an electrocorticography strip over DLPFC through the DBS burr hole. After placement of the DBS electrode into either GPi (
= 3) or STN (
= 4), awake subjects rested quietly during iTBS (three 50-Hz pulses delivered at 5 Hz for 2 s, followed by 8 s of rest). We contrasted power spectra in DLPFC local field potentials during iTBS versus at rest, as well as between iTBS and conventional high-frequency stimulation (HFS).
Dominant frequencies in DLPFC at rest varied among subjects and along the subdural strip electrode, though they were generally localized in theta (3-8 Hz) and/or beta (10-30 Hz) ranges. Both iTBS and HFS were well-tolerated and imperceptible. iTBS increased theta-frequency activity more than HFS. Further, GPi stimulation resulted in significantly greater theta-power versus STN stimulation in our sample.
Acute subcortical iTBS from the DBS electrode was safe and well-tolerated. This novel stimulation pattern delivered from the GPi may increase theta-frequency power in ipsilateral DLPFC. Future studies will confirm these changes in DLPFC activity during iTBS and evaluate whether they are associated with improvements in cognitive or behavioral symptoms from PD.
Journal Article
Anatomic Landmarks for Minimally Invasive Exposure for Flexor Digitorum Longus (FDL) Tendon Transfers and Spring Ligament Reconstruction
Category:
Other; Basic Sciences/Biologics; Hindfoot; Midfoot/Forefoot
Introduction/Purpose:
The approach for identification of the FDL tendon is classically described through an incision proximal to the medial malleolus extending past the navicular following the inferior border of the first metatarsal.1This incision is lengthy, and we believe that the navicular tuberosity, medial malleolus, and/or sustentaculum tali can be used as reliable landmarks for identification of the FDL more precisely and reliably. The purpose of this study is to detail spatial anatomy of the medial arch to allow for a more reliable and less invasive exposure of the FDL.
Methods:
Ten cadaver specimens were used for a total of 20 extremities. Anatomic locations were identified and pinned with the foot positioned in neutral dorsiflexion. Anatomic locations pinned included tip of the anterior colliculus, navicular tuberosity, proximal portion of the sustentaculum tali, and the distal portion of the sustentaculum tali. Photographs were taken of each cadaveric specimen with pins in place. Image J calibrated software was then used to calculate the distance between anatomic points. Averages were calculated for all measurements.
Results:
On average the superior margin of the sustentaculum tali was located 8 mm from the FDL with a range of 5-15 mm. Average distance from inferior sustentaculum tali to the FDL was 9 mm with a range of 5-12 mm. Average distance from medial malleolus to superior FDL was 18 mm with a range of 11-27 mm. Average distance from medial malleolus to inferior FDL was 27 mm with a range of 20-36mm. Average distance from navicular tuberosity to anterior FDL was 22 mm with a range of 11-27 mm. Average distance from navicular tuberosity to posterior FDL was 30 mm with a range of 19-42 mm.
Conclusion:
The 'lighthouse' for the harvest of the FDL tendon is the sustentaculum tali. Intraoperatively, the FDL tendon is found 22-31 mm directly posterior to the navicular and 18-27 mm inferior to the medial malleolus. This provides a reliable anatomic region where a 40 mm oblique approach can be made to access the FDL and spring ligament complex for a more minimally invasive approach in all of the studied specimen.
Journal Article