Publications by authors named "Kevin Weber"

15 Publications

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Dissociation of endocrine responses to the Trier Social Stress Test in Virtual Reality (VR-TSST) by the benzodiazepine alprazolam and the translocator protein 18 kDa (TSPO) ligand etifoxine.

Psychoneuroendocrinology 2021 Feb 5;124:105100. Epub 2020 Dec 5.

Department of Medicine, Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany.

Background: Activity of the two major stress systems, the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) axis, has already been shown to be modulated by different compounds that bind to the central benzodiazepine receptor. Less is known about ligands that modulate the peripheral benzodiazepine receptor - meanwhile known as the translocator protein 18 kDa (TSPO) - which constitute promising candidates in the search of novel anxiolytics. To close this gap, the present study compared the effects of the benzodiazepine alprazolam and the TSPO ligand etifoxine on responses of the HPA and SAM axes to the Trier Social Stress Test, a standardized paradigm to induce acute psychosocial stress in humans, performed in Virtual Reality (VR-TSST).

Methods: Sixty healthy males, aged between 18 and 55 years, were randomly assigned to receive either a daily dose of 1.5 mg alprazolam, 150 mg etifoxine, or placebo over five days. On the last day of intake, they were exposed to the VR-TSST. We assessed changes of salivary cortisol, allopregnanolone, (nor-) epinephrine in serum, TSPO expression in platelets as well as heart rate (HR), skin conductance level (SCL) and self-reports in response to the stress task. Repeated measures ANOVAs were conducted to examine treatment effects on these stress response variables during the course of VR-TSST.

Results: The response of salivary cortisol to the VR-TSST was significantly blunted in participants pre-treated with alprazolam but was not affected by etifoxine. While levels of allopregnanolone, epinephrine and norepinephrine increased in response to stress, TSPO expression decreased. None of those endocrine stress markers was affected by the active treatments, whereas TSPO expression increased after etifoxine administration over all study days. There were no effects of the two anxiolytics on HR, SCL or any self-report measurement.

Conclusion: The current study confirmed the attenuating effects of benzodiazepines on stress-induced HPA axis activity but did not reveal a comparable effect of the TSPO ligand etifoxine. The long-term consequences of a pharmacologically blunted response of the HPA axis to an acute stressor should be further elucidated. Due to the missing effects of etifoxine on stress-related parameters in our sample of healthy subjects, it might be concluded that the therapeutic effects of this TSPO ligand are restricted to stronger or pathological stress responses, respectively.
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http://dx.doi.org/10.1016/j.psyneuen.2020.105100DOI Listing
February 2021

Neuromodulation and Devices in Trigeminal Neuralgia.

Authors:
Kevin Weber

Headache 2017 Nov 14;57(10):1648-1653. Epub 2017 Sep 14.

Department of Neurology, The Ohio State University, Columbus, Ohio (K.Weber).

Premise: Trigeminal neuralgia is a severe facial pain disorder that has been studied for decades. Classical trigeminal neuralgia (CTN) is either idiopathic or caused by neurovascular compression. The related painful trigeminal neuropathies are often secondary to other causes, such as multiple sclerosis or trauma.

Problem: Therapies for trigeminal neuralgia and neuropathy have often been pharmacologic or surgical. Pharmacologic therapies are not effective in some cases and often cause side effects, some substantial. Surgery can have comorbidity (such as anesthesia dolorosa, or painful differentiation of the affected nerve distribution) and also is not always effective. There is a desire, as in all chronic conditions, to find effective treatments with minimal morbidity and side effects.

Potential Solutions: We review several devices including neuromodulation, ranging in invasiveness, for treatment of trigeminal neuralgia and neuropathy. We review existing data on sphenopalatine ganglion blocks, transcranial magnetic stimulation, transcortical direct stimulation, deep brain stimulation, spinal cord stimulation, peripheral nerve stimulation, and transcutaneous electrical stimulation for CTN and pain trigeminal neuropathies. We also offer hope for further research in this area with the goal of discovering a device that can provide treatment for many with few side effects and minimal morbidity.
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http://dx.doi.org/10.1111/head.13166DOI Listing
November 2017

High-Throughput Method of Whole-Brain Sectioning, Using the Tape-Transfer Technique.

PLoS One 2015 16;10(7):e0102363. Epub 2015 Jul 16.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.

Cryostat sectioning is a popular but labor-intensive method for preparing histological brain sections. We have developed a modification of the commercially available CryoJane tape collection method that significantly improves the ease of collection and the final quality of the tissue sections. The key modification involves an array of UVLEDs to achieve uniform polymerization of the glass slide and robust adhesion between the section and slide. This report presents system components and detailed procedural steps, and provides examples of end results; that is, 20 μm mouse brain sections that have been successfully processed for routine Nissl, myelin staining, DAB histochemistry, and fluorescence. The method is also suitable for larger brains, such as rat and monkey.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102363PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504703PMC
April 2016

The Diagnosis and Management of Concussion in Children and Adolescents.

Pediatr Neurol 2015 Aug 11;53(2):108-18. Epub 2015 Apr 11.

Departments of Pediatrics and Neurology, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio. Electronic address:

Background: Concussion is a complex brain injury that results in more than 100,000 emergency department visits for school-aged children each year in the United States. All 50 US states have passed concussion legislation designed to promote safety in youth sports. Most of these laws require medical clearance by a licensed health care provider before returning to sport, which may have contributed to an increase in pediatric subspecialty referrals, particularly referrals to the child neurologist.

Methods: We reviewed the literature on pediatric concussion.

Results: This review summarizes the current knowledge and recommendations for concussion diagnosis and management in children and adolescents, athletes and nonathletes. It highlights concussion epidemiology, pathophysiology, advances in neuroimaging, and potential health risks including second impact syndrome and chronic traumatic encephalopathy. It also underscores clinical areas where evidence is lacking.

Conclusions: The diagnosis and management of concussion requires specific considerations in children. Further concussion research must be done to minimize injury risk and to optimize medical care for this common problem.
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http://dx.doi.org/10.1016/j.pediatrneurol.2015.04.003DOI Listing
August 2015

High school principals' resources, knowledge, and practices regarding the returning student with concussion.

J Pediatr 2015 Mar 25;166(3):594-9.e7. Epub 2014 Oct 25.

Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH.

Objective: To determine high school principals' self-reported resources, knowledge, and practices regarding the management of students returning to school following concussion.

Study Design: A cross-sectional survey of public high school principals in the state of Ohio assessed respondent and school demographics, respondent concussion training, school resources, and monitoring and accommodation practices for students with concussion.

Results: Of the 695 eligible high school principals, 465 (66.9%) completed the survey. Over one-third of principals (37.2%) had some form of concussion training in the past year. Those with training were more likely to promote training of other school faculty (57.4% vs 30.6%, P < .001). Principals were asked to identify school personnel who are designated as case managers for students with concussion. Schools without a designated case manager were less likely to have an athletic trainer (P < .001) and had fewer students (median 424.5 vs 599) than schools with a case manager. Principals could list at least 1 faculty designee who communicates with health professionals more often for student-athletes than for nonathletes (P < .001). Most principals were willing to provide students with short-term academic accommodations, but 30.1% required a health professional's note prior to making any academic changes. Only 32% of principals reported providing families with a written academic plan following concussion.

Conclusions: Schools differ in their resources and management strategies for students returning to school after concussion. Understanding these differences can help health professionals to overcome potential barriers in managing their school-aged patients with concussion.
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http://dx.doi.org/10.1016/j.jpeds.2014.09.038DOI Listing
March 2015

Theoretical study of the hydrogen abstraction of substituted phenols by nitrogen dioxide as a source of HONO.

J Phys Chem A 2014 Nov 5;118(46):11002-14. Epub 2014 Nov 5.

Department of Chemistry and Biochemistry, California State University , Fullerton, California 92834, United States.

The mild yet promiscuous reactions of nitrogen dioxide (NO2) and phenolic derivatives to produce nitrous acid (HONO) have been explored with density functional theory calculations. The reaction is found to occur via four distinct pathways with both proton coupled electron transfer (PCET) and hydrogen atom transfer (HAT) mechanisms available. While the parent reaction with phenol may not be significant in the gas phase, electron donating groups in the ortho and para positions facilitate the reduction of nitrogen dioxide by electronically stabilizing the product phenoxy radical. Hydrogen bonding groups in the ortho position may additionally stabilize the nascent resonantly stabilized radical product, thus enhancing the reaction. Catechol (ortho-hydroxy phenol) has a predicted overall free energy change ΔG(0) = -0.8 kcal mol(-1) and electronic activation energy Ea = 7.0 kcal mol(-1). Free amines at the ortho and para positions have ΔG(0) = -3.8 and -1.5 kcal mol(-1); Ea = 2.3 and 2.1 kcal mol(-1), respectively. The results indicate that the hydrogen abstraction reactions of these substituted phenols by NO2 are fast and spontaneous. Hammett constants produce a linear correlation with bond dissociation energy (BDE) demonstrating that the BDE is the main parameter controlling the dark abstraction reaction. The implications for atmospheric chemistry and ground-level nitrous acid production are discussed.
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http://dx.doi.org/10.1021/jp508516cDOI Listing
November 2014

Theoretical study on stable small clusters of oxalic acid with ammonia and water.

J Phys Chem A 2014 Feb 14;118(8):1451-68. Epub 2014 Feb 14.

Department of Chemistry and Biochemistry, California State University , Fullerton, California 92834, United States.

Thermodynamically stable small clusters of oxalic acid (CO2H)2, ammonia (NH3), and water (H2O) are studied through quantum chemical calculations. The (CO2H)2-NH3 core system with up to three waters of hydration was examined by B3LYP density functional theory and MP2 molecular orbital theory with the aug-cc-pVDZ basis set. The (CO2H)2-NH3 core complexes are observed to hydrogen bond strongly and should be found in appreciably significant concentrations in the atmosphere. Subsequent hydration of the (CO2H)2-NH3 core, however, is found to be somewhat prohibitive under ambient conditions. Relative populations of the examined clusters are predicted and the binding patterns detailed. Atmospheric implications related to new particle formations are discussed.
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http://dx.doi.org/10.1021/jp4128226DOI Listing
February 2014

A low-cost technique to cryo-protect and freeze rodent brains, precisely aligned to stereotaxic coordinates for whole-brain cryosectioning.

J Neurosci Methods 2013 Sep 29;218(2):206-13. Epub 2013 Mar 29.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.

A major challenge in the histological sectioning of brain tissue is achieving accurate alignment in the standard coronal, horizontal, or sagittal planes. Correct alignment is desirable for ease of subsequent analysis and is a prerequisite for computational registration and algorithm-based quantification of experimental data. We have developed a simple and low-cost technique for whole-brain cryosectioning of rodent brains that reliably results in a precise alignment of stereotactic coordinates. The system utilises a 3-D printed model of a mouse brain to create a tailored cavity that is used to align and support the brain during freezing. The alignment of the frozen block is achieved in relation to the fixed edge of the mold. The system also allows for two brains to be frozen and sectioned simultaneously. System components, procedural steps, and examples of the end results are presented.
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http://dx.doi.org/10.1016/j.jneumeth.2013.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265468PMC
September 2013

Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors.

J Med Chem 2013 Mar 27;56(5):1922-39. Epub 2013 Feb 27.

BIO5 Institute (Oro Valley), The University of Arizona, 1580 East Hanley Boulevard, Oro Valley, Arizona 85737, United States.

Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials. Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials. This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors. We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein.
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http://dx.doi.org/10.1021/jm301522mDOI Listing
March 2013

Theoretical study on the structure and stabilities of molecular clusters of oxalic acid with water.

J Phys Chem A 2012 Nov 9;116(47):11601-17. Epub 2012 Nov 9.

Department of Chemistry and Biochemistry, California State University, Fullerton, 800 N. State College Boulevard, Fullerton, California 92834, United States.

The importance of aerosols to humankind is well-known, playing an integral role in determining Earth's climate and influencing human health. Despite this fact, much remains unknown about the initial events of nucleation. In this work, the molecular properties of common organic atmospheric pollutant oxalic acid and its gas phase interactions with water have been thoroughly examined. Local minima single-point energies for the monomer conformations were calculated at the B3LYP and MP2 level of theory with both 6-311++G(d,p) and aug-cc-pVDZ basis sets and are compared with previous works. Optimized geometries, relative energies, and free energy changes for the stable clusters of oxalic acid conformers with up to six waters were then obtained from B3LYP calculations with 6-31+G(d) and 6-311++G(d,p) basis sets. Initially, cooperative binding is predicted to be the most important factor in nucleation, but as the clusters grow, dipole cancellations are found to play a pivotal role. The clusters of oxalic acid hydrated purely with water tend to produce extremely stable and neutral core systems. Free energies of formation and atmospheric implications are discussed.
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http://dx.doi.org/10.1021/jp308499fDOI Listing
November 2012

Semimembranosus tendinopathy: one cause of chronic posteromedial knee pain.

Sports Health 2010 Sep;2(5):380-4

Uniformed Services University, Great Falls, Virginia.

Context: Semimembranosus tendinopathy (SMT) is an uncommon cause of chronic knee pain that is rarely described in the medical literature and may be underdiagnosed or inadequately treated owing to a lack of understanding of the condition.

Evidence Acquisition: A search of the entire PubMed (MEDLINE) database using the terms knee pain semimembranosus and knee tendinitis semimembranosus, returned only 5 references about SMT-4 case series and 1 case report-and several relevant anatomical or imaging references.

Results: The incidence of SMT is unknown in the athletic population and is probably more common in older patients. The usual presentation for SMT is aching posteromedial knee pain. Physical examination can usually localize the area of tenderness to the distal semimembranosus tendon or its insertion on the medial proximal tibia. In unclear cases, bone scan, magnetic resonance imaging, or ultrasound may distinguish SMT from other causes of posteromedial knee pain. Treatment should begin with relative rest, ice, nonsteroidal anti-inflammatory drugs, and rehabilitative exercise. In the minority of cases that persist greater than 3 months, a corticosteroid injection at the tendon insertion site may be effective. Surgery to reroute and reattach the tendon is rarely needed but may be effective.

Conclusion: SMT is an uncommon cause of knee pain, but timely diagnosis can lead to effective treatments.
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http://dx.doi.org/10.1177/1941738109357302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3445062PMC
September 2010

Antitumor efficacy and molecular mechanism of TLK58747, a novel DNA-alkylating prodrug.

Anticancer Res 2009 Oct;29(10):3845-55

Telik, Inc., Palo Alto, CA 94304, USA.

Background: DNA-damaging agents are widely used for the treatment of human malignancies. Agents containing the multifunctional alkylating moiety tetrakis(2-chloroethyl)phosphorodiamidic acid are currently under development as cancer therapeutics.

Materials And Methods: TLK58747, a phophorodiamidate-based prodrug, was tested in vivo for antitumor efficacy and safety. The in vitro responses of tumor cells to TLK58747 were examined by cytotoxicity assays, cell cycle analysis, immunoblots and microscopy.

Results: TLK58747 was efficacious in xenograft models of human breast, pancreas, and prostate cancer, as well as in leukemia and glioma. It caused less bone marrow suppression in rats than did cyclophosphamide. In vitro, TLK58747 inhibited the growth of a wide variety of cancer cells and activated the DNA damage-response pathway, leading to G(2)/M cell cycle arrest and subsequent premature senescence or apoptosis.

Conclusion: TLK58747 is a promising new alkylating agent with broad antitumor activity and superior safety that warrants further development.
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October 2009

Flash pyrolysis of ethyl, n-propyl, and isopropyl iodides as monitored by supersonic expansion vacuum ultraviolet photoionization time-of-flight mass spectrometry.

J Phys Chem A 2009 Jan;113(3):583-91

Department of Chemistry, University of California, Riverside, California 92521, USA.

The thermal decomposition of ethyl and propyl iodides, along with select isotopomers, up to 1300 K was performed by flash pyrolysis with a 20-100 mus time scale. The pyrolysis was followed by supersonic expansion to isolate the reactive intermediates and initial products, and detection was accomplished by vacuum ultraviolet single photon ionization time-of-flight mass spectrometry (VUV-SPI-TOFMS). The products monitored, such as CH(3), CH(3)I, C(2)H(5), C(2)H(4), HI, I, C(3)H(7), C(3)H(6), and I(2), provide for the simultaneous and direct observation of molecular elimination and bond fission pathways in ethyl and propyl iodides. In the pyrolysis of ethyl iodide, both C-I bond fission and HI molecular elimination pathways are competitive at the elevated temperatures, with C-I bond fission being preferred; at temperatures >or=1000 K, the ethyl radical products further dissociate to ethene + H atoms. In the pyrolysis of isopropyl iodide, both HI molecular elimination and C-I bond fission are observed and the molecular elimination channel is more important at all the elevated temperatures; the isopropyl radicals produced in the C-I fission channel undergo further decomposition to propene + H at temperatures >or=850 K. In contrast, bond fission is found to dominate the n-propyl iodide pyrolysis; at temperatures >or=950 K the n-propyl radicals produced decompose into methyl radical + ethene and propene + H atom. Isotopomer experiments characterize the extent of surface reactions and verify that the HI molecular eliminations in ethyl and propyl iodides proceed by a C1, C2 elimination mechanism (the 1,2 intramolecular elimination).
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http://dx.doi.org/10.1021/jp808155aDOI Listing
January 2009

Mechanistic study of thermal decomposition of isoprene (2-methyl-1,3-butadiene) using flash pyrolysis supersonic jet VUV photoionization mass spectrometry.

J Phys Chem A 2007 Nov 23;111(45):11487-92. Epub 2007 Oct 23.

Department of Chemistry, University of California, Riverside, California 92521, USA.

The thermal decomposition of isoprene up to 1400 K was performed by flash pyrolysis with an approximately 100 mus time scale. This pyrolysis was followed by supersonic expansion to isolate the reactive intermediates and initial products, and detection was accomplished by vacuum ultraviolet single photon ionization time-of-flight mass spectrometry (VUV-SPI-TOFMS) at lambda = 118.2 nm. Products CH(3), C(2)H(4), C(3)H(3), C(3)H(4), C(4)H(4), C(4)H(5), C(5)H(6), C(5)H(7), and C(6)H(6) were directly observed and provide mechanistic insights to the isoprene pyrolysis. At temperatures >or= approximately 1200 K, the molecular elimination of ethene to form C(3)H(4) and sigma bond homolysis producing C(4)H(5) and CH(3) radicals are competitive reaction pathways. The molecular elimination of acetylene to form C(3)H(6) was minimal and direct C(2)-C(3) sigma bond homolysis was not observed. The C(3)H(3) radicals are also observed, as a result of hydrogen loss of C(3)H(4) by pyrolysis or hydrogen abstraction by the CH(3) radical from C(3)H(4). Above approximately 1250 K, production of C(6)H(6) was observed and identified as the combination product of the C(3)H(3) radicals.
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http://dx.doi.org/10.1021/jp075689+DOI Listing
November 2007

How common is attention-deficit/hyperactivity disorder? Incidence in a population-based birth cohort in Rochester, Minn.

Arch Pediatr Adolesc Med 2002 Mar;156(3):217-24

Division of Developmental and Behavioral Pediatrics, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

Context: The frequency of occurrence of attention-deficit/hyperactivity disorder (AD/HD) is in dispute. This uncertainty has contributed to the concern that too many children in the United States are being treated with stimulant medication.

Objectives: To determine the cumulative incidence of AD/HD in a population-based birth cohort and to estimate the prevalence of pharmacologic treatment for children who fulfill research criteria for AD/HD.

Design: Population-based birth cohort study.

Setting And Subjects: All children born between 1976 and 1982 in Rochester, Minn, who remained in the community after age 5 years (N = 5718).

Main Outcome Measures: Medical and school records were reviewed for clinical diagnoses of AD/HD and supporting documentation (symptoms consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and positive results for AD/HD-related questionnaires). Research-identified cases were defined as: (1) "definite" AD/HD (clinical diagnosis and at least one type of supporting documentation); (2) "probable" AD/HD (clinical diagnosis but no supporting documentation or no clinical diagnosis but both types of supporting documentation); (3) "questionable" AD/HD (no clinical diagnosis, but at least one type of supporting documentation); and (4) "not AD/HD" (all other subjects). Information about pharmacologic treatment for AD/HD was abstracted for all subjects.

Results: The highest estimate of the cumulative incidence at age 19 years (with 95% confidence interval) of AD/HD (definite plus probable plus questionable AD/HD) was 16.0% (14.7-17.3). The lowest estimate (definite AD/HD only) was 7.4% (6.5-8.4). Prevalence of treatment with stimulant medication was 86.5% for definite AD/HD, 40.0% for probable AD/HD, 6.6% for questionable AD/HD, and 0.2% for not AD/HD.

Conclusions: These results provide insight into the apparent discrepancies in estimates of the occurrence of AD/HD, with less stringent criteria resulting in higher cumulative incidence. Children who met the most stringent criteria for AD/HD were most likely to receive pharmacologic treatment.
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http://dx.doi.org/10.1001/archpedi.156.3.217DOI Listing
March 2002