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Deep Brain Stimulation in Pediatric Status Dystonicus: A Case Series Investigation on Rapid Activation & ICU Stays
No full textResearch Appreciation Day Award Winner - Texas College of Osteopathic Medicine, 2024 Pediatric Research AwardPurpose: Status dystonicus (SD) is a life-threatening movement disorder characterized by a sudden and severe worsening of generalized dystonia, often complicated by rhabdomyolysis with associated metabolic and respiratory consequences, including death. Deep brain stimulation (DBS) is a potential treatment modality for pharmaco-resistant SD (PRSD) which, despite growing interest in its use, requires further research into ideal patient selection and optimum timing for device activation. Timely deployment of this therapy can lead to shorter ICU stays and better outcomes for patients by reducing the need for additional invasive procedures and escalating pharmaceutical therapy.
Methods: This is a retrospective case series of 6 consecutive pediatric SD patients who were admitted to the PICU at Cook Children’s Medical Center between October 2010 and March 2022. Following their admission, these patients were treated with DBS and were all subsequently discharged from the ICU. We examined ICU time between patients who underwent rapid activation of DBS systems and those who delayed the start of this intervention.
Results: Patients with acquired forms of dystonia demonstrated a mean ICU stay of 58 following DBS activation, and patients with genetic dystonias had a mean stay of 18 days after the procedure. Rapid deployment of DBS systems and two stage procedures were associated with more positive patient outcomes,
Conclusions: SD is a condition with a wide range of clinical presentations and responsiveness to treatment. This unpredictability and variation in disease outcomes emphasizes the need for further controlled studies to clarify optimal timing and patient selection for DBS. Ethical and parental concerns regarding the recruitment of children into clinical trials remains a major limiting factor to this goal, making meaningful clinical reports and data sharing between care centers essential in advancing the collective understanding of this condition and in optimizing patient care
Atypical Leiomyosarcomas of the Great Saphenous Vein and Subcutaneous Superficial Vein
No full textTwo outpatient adult cases of primary leiomyosarcomas are reported in atypical locations. As a tumor of smooth muscle origin, leiomyosarcomas are most frequently found in the uterus, intestines, and other parts of the digestive tract (Rizwan et al., 2020). Here, we highlight and discuss two separate relatively nonaggressive appearing cases of leiomyosarcoma in the wrist and the thigh, encasing a superficial wrist vein and the greater saphenous vein respectively. The leiomyosarcoma of the right wrist was found in a 65-year-old male who presented with a non-painful ulnar sided nodule progressing in size for one year. Similarly, the leiomyosarcoma of the left thigh was discovered in a 52-year-old man who presented with a non-painful "knot" he had noticed enlarging over the course of just a few months. Review of the literature suggests less than 50 patients have been reported to have leiomyosarcoma of the great saphenous vein from 1868 to 2020 (Tresgallo-Parés et al., 2021). The number of vascular leiomyosarcomas arising in the superficial veins of the wrist are even lower with a 2006 case report from the Annals of Vascular Surgery suggesting only one previous case has arisen from the superficial vein over the dorsal wrist (Fu, T. Y et.al., 2007). The purpose of this report is to draw attention to a rare yet grave diagnosis to ensure that leiomyosarcoma is at least included in the differential diagnosis of rapidly enlarging nontender soft tissue masses of the extremities that encase veins
Temporal and region-specific tau hyperphosphorylation in the medulla and forebrain coincides with development of functional changes in male obese Zucker rats
Get PDFMetabolic syndrome (MetS) is associated with development of tauopathies that contribute to cognitive decline. Without functional leptin receptors, male obese Zucker rats (OZRs) develop MetS, and they have increased phosphorylated tau (ptau) with impaired cognitive function. In addition to regulating energy balance, leptin enhances activation of the hippocampus, which is essential for spatial learning and memory. Whether spatial learning and memory are always impaired in OZRs or develop with MetS is unknown. We hypothesized that male OZRs develop MetS traits that promote regional increases in ptau and functional deficits associated with those brain regions. In the medulla and cortex, tau-pSer(199,202) and tau-pSer(396) were comparable in juvenile (7-8 wk old) lean Zucker rats (LZRs) and OZRs but increased in 18- to 19-wk-old OZRs. Elevated tau-pSer(396) was concentrated in the dorsal vagal complex of the medulla, and by this age OZRs had hypertension with increased arterial pressure variability. In the hippocampus, tau-pSer(199,202) and tau-pSer(396) were still comparable in 18- to 19-wk-old OZRs and LZRs but elevated in 28- to 29-wk-old OZRs, with emergence of deficits in Morris water maze performance. Comparable escape latencies observed during acquisition in 18- to 19-wk-old OZRs and LZRs were increased in 28- to 29-wk-old OZRs, with greater use of nonspatial search strategies. Increased ptau developed with changes in the insulin/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in the hippocampus and cortex but not medulla, suggesting different underlying mechanisms. These data demonstrate that leptin is not required for spatial learning and memory in male OZRs. Furthermore, early development of MetS-associated autonomic dysfunction by the medulla may be predictive of later hippocampal dysfunction and cognitive impairment.NEW & NOTEWORTHY Male obese Zucker rats (OZRs) lack functional leptin receptors and develop metabolic syndrome (MetS). At 16-19 wk, OZRs are insulin resistant, with increased ptau in dorsal medulla and impaired autonomic regulation of AP. At 28-29 wk OZRs develop increased ptau in hippocampus with deficits in spatial learning and memory. Juvenile OZRs lack elevated ptau and these deficits, demonstrating that leptin is not essential for normal function. Elevated ptau and deficits emerge before the onset of diabetes in insulin-resistant OZRs.This research was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health (Grant R01-HL-132568-S1) to A.M.S. and in part by the JES Edwards Foundation, the Summerfield G. Roberts Foundation, and a seed grant from the Department of Physiology and Anatomy at University of North Texas Health Science Center to A.M.S. and D.A.S
Increasing Bioavailability of Simvastatin Using New Drug Formulation
No full textSimvastatin (SMV) is a cholesterol lowering drug. It is currently given independently to patients with hypercholesterolemia or in combination with other drugs when hyperlipidemia is a comorbidity. The drug itself is considered a BCS Class II drug because of its high permeability but low solubility properties. Currently, it is created as a prodrug, which means it needs to be converted by liver enzymes to work. This results in a high hepatic extraction with low bioavailability. Because of its low solubility and low bioavailability after high hepatic extraction, the amount of simvastatin being processed into tablets is not enough to effectively treat hypercholesterolemia. Therefore, a Simvastatin granule (SMV combined with other substances) was created to increase the solubility of the drug, which would increase its bioavailability in the body without causing adverse effects that are dose related. To test bioavailability is increased in the granule formulation, a UV spectrophotometer and two-step dissolution method were used to compare the granule to the Simvastatin powder by itself. The two-step dissolution method allows one to compare the concentration of the granule to that of the powder after certain time intervals, and the UV spectrophotometer was used to determine these concentrations throughout this study. From the two-step dissolution study conducted, it was shown that the granule consistently had higher bioavailability compared to the powder counterpart at the same time interval. Therefore, this indicates that the granule formulation has potential to increase Simvastatin’s solubility and bioavailability, which can change the way the drug is packaged into tablets and given as a medication in the future
Assessing Metabolic Changes in the Retina & Optic Nerve During Glaucoma
No full textPurpose: Glaucoma is an optic neuropathy characterized by retinal ganglion cell (RGC) death and optic nerve degeneration. Glial cells such as astrocytes form a metabolic unit with neurons to exchange metabolic substrates and neurotransmitters. When exposed to ocular hypertension (OHT), this metabolic unit is disrupted as astrocytes undergo morphological changes in response to increased pressure. ONHAs also reduce their GLUT1 expression, further exacerbating their metabolic function. It is unknown how these changes impact RGC axon structure and function, so we aim to gain insight into the metabolic relationship between glia and neurons during glaucoma. We hypothesize that glaucoma induces metabolic strain in optic nerve head astrocytes (ONHAs), preventing the exchange of metabolites between neurons, ultimately causing a decline in RGC structure and function. Methods: We have taken a two-sided approach to studying these neural-glial interactions. First, we have induced OHT as well as glucose transport inhibition in ONHAs in vivo to examine the effect of pressure-induced stress on metabolism and the visual system. Currently, we are working in vitro to study the metabolic exchange between RGCs and ONHAs co-cultured in microfluidic chambers when the ONHAs are exposed to biaxial strain as well as GLUT1 KO. Results: Preliminary results in vivo have shown that OHT and glucose transport inhibition in ONHAs disrupt anterograde transport. However, RGCs can compensate for glucose transport inhibition in astrocytes by upregulating GLUT3 and MCT2.In vitro we expect to see RGCs respond to alterations in ONHA metabolism, similarly, upregulating their lactate transporters and relying on mitochondrial metabolism to maintain their energetic needs. Conclusion: Using this model will allow us to directly observe the metabolic changes in the neural-glial unit induced by glaucoma, ultimately providing us insight into targets for future glaucoma therapies.NIH/NEI: EY02666
Association between everyday perceived discrimination and cognitive function as mediated by depression in diverse populations: A HABS-HD Study
No full textPurpose: Previous research suggests that perceived discrimination is associated with cognitive function impairment, and such association is mediated by depression. With minority populations continuously growing, it is crucial to investigate such relationships in diverse populations. This study aims to examine and compare the above relationships among non-Hispanic white (NHW), Mexican American (MA), and African American (AA) participants. Method: A sample size of 1,129 participants (640 AAs, 248 NHWs, 241 MAs) aged 50+ came from the Health and Aging Brain Study – Health Disparities (HABS-HD). Structural equation modelling (SEM) was conducted to explore the effect between perceived discrimination, measured by the Everyday Discrimination Scale mean score, and cognitive function, measured by the Mini Mental State Examination (MMSE) Score. The mediation effect of depression, measured by the Geriatric Depression Scale total score, was evaluated by the indirect effect estimate using SEM. Result: Everyday perceived discrimination negatively influenced cognitive function, and the effect was mediated by depression across the three populations (β= -0.15, 95% CI = [-0.22, -0.08]). When stratified, the mediation effect of depression on the association between discrimination and cognitive function remained significant for NHW (β= -0.37, 95% CI = [-0.60, -0.15]) and MA (β = -0.27, 95% CI = [-0.50, -0.05]). However, such mediation effect was not observed for the AA population. Conclusion: Depression mediates the link between everyday discrimination and cognitive decline, but differences between racial/ethnic groups underscore the need for further research into underlying mechanisms among minority groups, including Mexican American and African American populations. Depression interventions may mitigate negative cognitive effects from discrimination. Tailoring such interventions by race/ethnicity and targeting at-risk groups could optimally promote cognitive health
The Interaction Between Arterial Stiffness, Amplitude of Cerebral Blood Flow Oscillations, and Cerebral Tissue Oxygenation
Get PDFInducing 0.1 Hz (10-s cycle) oscillations in cerebral blood flow attenuates the reduction in cerebral tissue oxygenation during simulated hemorrhage in humans. Our laboratory has developed a potential therapeutic technique called pulsatile perfusion therapy (PPT) which induces 0.1 Hz oscillations in cerebral blood flow. It is unknown, however, how stiffness of the arteries influences the magnitude of cerebral blood flow oscillations, and/or the protection of cerebral tissue oxygenation. When 0.1 Hz oscillations are induced during simulated hemorrhage, we hypothesized that: 1) arterial stiffness of the internal carotid artery (ICA) and common carotid artery (CCA) would increase from rest; 2) the amplitude of 0.1 Hz oscillations in cerebral blood flow would be higher in individuals with stiffer arteries, and; 3) the reduction in cerebral tissue oxygenation would be smaller with higher amplitude of cerebral blood flow oscillations. Two studies using two different techniques of PPT were performed to investigate these hypotheses. Study 1: In a retrospective analysis, 8 healthy human participants (age: 30.1±7.6 y) underwent a 10-min hypovolemic oscillatory lower body negative pressure (OLBNP) protocol, where chamber pressure oscillated every 5-s between -30 mmHg and -90 mmHg (i.e., 0.1 Hz). ICA β-stiffness index was calculated from measurements of ICA diameter (via ultrasound imaging), and arterial pressure (via finger photoplethysmography). Middle cerebral artery velocity (MCAv) was measured using transcranial doppler ultrasound, and cerebral tissue oxygenation (ScO2) was measured with near infrared spectroscopy. Fast Fourier transformation was used to quantify oscillations in mean MCAv at ~0.1 Hz. While mean MCAv 0.1 Hz oscillations increased from baseline to OLBNP (N=8, 34.0±33.9 (cm/s)2 vs. 104.7±58.1 (cm/s)2, p=0.01), ICA β stiffness did not increase (N=5, 6.1±0.7 au vs. 8.2±2.7 au, p=0.21). There was no relationship between baseline ICA β-stiffness and the percent change in mean MCAv 0.1 Hz oscillations (N=5; r=0.44, p=0.46). ScO2 decreased from baseline to OLBNP (N=8, 66.5±2.9 % vs. 64.8±2.9 %, p=0.03), but there was also no relationship between the percent change in mean MCAv 0.1 Hz oscillations and the decrease in ScO2 (r=0.28, p=0.50). Study 2: In a prospective pilot study, 3 participants underwent a 10-min LBNP protocol to a chamber pressure of -60 mmHg, and hemodynamic oscillations were simultaneously induced with bilateral thigh cuffs inflating for 5-s to 230 mmHg then deflating for 5-s in a 10-s cycle (i.e., 0.1 Hz). β-stiffness index of the CCA was measured. In this pilot study, insufficient data were collected to perform statistics for each of the three aims, so descriptive results are presented. Adequate ultrasound measurements were made for assessment of CCA β- stiffness in two participants; in the control condition, CCA β-stiffness was 6.7 ± 2.4 au during baseline and increased to 7.4 ± 1.1 au during LBNP (N=2). With PPT, CCA β-stiffness was 6.6 ± 1.6 au during baseline and increased to 7.8 ± 2.2 au during LBNP (N=2). The amplitude of MCAv 0.1 Hz oscillations increased from 7.9 (cm/s)2 at baseline of the control condition to 179.8 (cm/s)2 (i.e., a ~23-fold increase) during LBNP. The amplitude of MCAv 0.1 Hz oscillations increased from 25.8 (cm/s)2 during baseline of PPT to 210.2 (cm/s)2 (~8-fold increase) during LBNP (N=1). ScO2 decreased from 75.0% to 71.3% during LBNP in the control condition, and from 73.4% to 71.6% in the PPT condition (N=1). Based on the results of Study 1, 0.1 Hz OLBNP does not increase ICA stiffness, and there is no relationship between ICA stiffness, amplitude of induced 0.1 Hz cerebral blood flow oscillations, and the reduction in cerebral tissue oxygenation during simulated hemorrhage. However, as this analysis was performed retrospectively, and arterial stiffness was not initially an outcome measure, there were limited data available for analysis. For Study 2, we were successfully able to induce 0.1 Hz oscillations in cerebral blood flow by combining LBNP with bilateral thigh cuff inflations. However, insufficient data were available to make definitive conclusions about the role of PPT on CCA β-stiffness, 0.1 Hz oscillations in cerebral blood flow, or the relationship in 0.1 Hz oscillations in cerebral blood flow and protection of cerebral tissue oxygenation. This study is currently ongoing, and additional data will provide further insight into these relationships
Reconstituted HDL ameliorated renal injury of diabetic kidney disease in mice
Get PDFDiabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high-density lipoprotein (rHDL) ameliorated renal injury in eNOS(-/-) dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non-diabetes), eNOS(-/-) dbdb (diabetes), and eNOS(-/-) dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS(-/-) dbdb mice at Week 16 at 5 mug/g body weight in ~100 muL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS(-/-) dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD.The author declares no conflicts of interest
Exploring Freely Available Data Tools to Support Open Data and Open Science
No full textThis is an original manuscript of an article published by Taylor & Francis in Journal of Hospital Librarianship on January 2024 available at: https://doi.org/10.1080/15323269.2024.2326787Librarians support researchers by promoting open science and open data practices. This article explores five freely available tools that support and facilitate open science practices. Open Science Framework provides a platform for project management, data sharing, and data storage. OpenRefine cleans and formats data. DMPTool has templates for data management and sharing plans that comply with funder mandates. The NIH Common Data Elements is a repository for standardized data elements, and finally, the NLM Scrubber is a tool for de-identifying clinical text data. Information professionals can add these tools to their repertoire and share them with researchers at their institution.This work was supported by the National Library of Medicine (NLM), National Institutes of Health (NIH), under Cooperative Agreement UG4L013724, UG4L013736, and UG4LM012345. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health