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1.
J Med Syst ; 47(1): 104, 2023 Oct 13.
Article in English | MEDLINE | ID: mdl-37828245

ABSTRACT

INTRODUCTION: Workplace disruptive behavior/ violence (WDBV) is underreported in health care. This study evaluated a 7-year implementation of the Disruptive Behavior Reporting System (DBRS), the most robust consolidated WDBV reporting system developed in the United States within the Veterans Health Administration (VHA). METHODS: After implementation of the system, implementation success was measured in real time by number of reports, types of staff entering reports, time to review the reports and time between when the incident occurred and report entry. RESULTS: Over the seven years since implementation, there has been a significant increase in reporting within DBRS with more than 50,000 reports in fiscal year (FY) 2021 up from 0 to 2014. Types of staff reporting increased to 67 from 54. The median number of days to review events in FY19 Q2 was 4.79 days and the report latency has almost completely disappeared. DISCUSSION: DBRS was designed to democratize reporting so staff can report WDBV anytime and anywhere playing a large role in the successful implementation. The increase in total number of reported events is an indication of the success of the system as it captures data historically lost due to underreporting. CONCLUSION: DBRS development and implementation showcases how information systems can empower front-line personnel to voice behavioral safety concerns.


Subject(s)
Problem Behavior , Humans , United States , Delivery of Health Care
2.
Nat Commun ; 14(1): 4221, 2023 07 14.
Article in English | MEDLINE | ID: mdl-37452026

ABSTRACT

Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients' tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.


Subject(s)
Breast Neoplasms , Animals , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Oxidative Phosphorylation , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Receptors, Estrogen/metabolism , Disease Models, Animal
3.
J Food Prot ; 86(8): 100117, 2023 08.
Article in English | MEDLINE | ID: mdl-37327999

ABSTRACT

In 2016, the U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and state partners investigated nine Listeria monocytogenes infections linked to frozen vegetables. The investigation began with two environmental L. monocytogenes isolates recovered from Manufacturer A, primarily a processor of frozen onions, that were a match by whole genome sequencing (WGS) to eight clinical isolates and historical onion isolates with limited collection details. Epidemiologic information, product distribution, and laboratory evidence linked suspect food items, including products sourced from Manufacturer B, also a manufacturer of frozen vegetable/fruit products, with an additional illness. The environmental isolates were obtained during investigations at Manufacturers A and B. State and federal partners interviewed ill people, analyzed shopper card data, and collected household and retail samples. Nine ill persons between 2013 and 2016 were reported in four states. Of four ill people with information available, frozen vegetable consumption was reported by three, with shopper cards confirming purchases of Manufacturer B brands. Two identified outbreak strains of L. monocytogenes (Outbreak Strain 1 and Outbreak Strain 2) were a match to environmental isolates from Manufacturer A and/or isolates from frozen vegetables recovered from open and unopened product samples sourced from Manufacturer B; the investigation resulted in extensive voluntary recalls. The close genetic relationship between isolates helped investigators determine the source of the outbreak and take steps to protect public health. This is the first known multistate outbreak of listeriosis in the United States linked to frozen vegetables and highlights the significance of sampling and WGS analyses when there is limited epidemiologic information. Additionally, this investigation emphasizes the need for further research regarding food safety risks associated with frozen foods.


Subject(s)
Foodborne Diseases , Listeria monocytogenes , Listeriosis , Humans , United States , Vegetables , Foodborne Diseases/epidemiology , Food Microbiology , Listeriosis/epidemiology , Disease Outbreaks , Onions
4.
J Nurs Adm ; 52(10): 560-565, 2022 Oct 01.
Article in English | MEDLINE | ID: mdl-36166634

ABSTRACT

OBJECTIVE: This study compared outcomes between units that used either 8-hour or 12-hour shifts in acute inpatient mental health units. BACKGROUND: Most hospitals continue to use 12-hour shifts despite research suggesting safety concerns with longer shifts. There is a gap in the literature on effects of shift lengths on nursing and patient outcomes in acute mental health units. METHODS: This study is a retrospective comparative analysis of cross-sectional data between 32 inpatient mental health units that used 8-hour versus 12-hour shifts. Independent samples t test was used to examine differences on several staffing, quality, and safety measures. RESULTS: A moderate effect size was found between the groups in quality and safety measures involving patient disruptive behaviors, with the 8-hour group having more desirable outcomes. CONCLUSIONS: Nurse leaders in acute mental health units should consider the impacts of shift length on quality and safety when determining staffing patterns. More research is needed to evaluate correlations or causality.


Subject(s)
Nursing Staff, Hospital , Personnel Staffing and Scheduling , Cross-Sectional Studies , Humans , Inpatients , Mental Health , Quality of Health Care , Retrospective Studies
5.
Emerg Infect Dis ; 28(9): 1785-1795, 2022 09.
Article in English | MEDLINE | ID: mdl-35997313

ABSTRACT

We investigated invasive group A Streptococcus epidemiology in Idaho, USA, during 2008-2019 using surveillance data, medical record review, and emm (M protein gene) typing results. Incidence increased from 1.04 to 4.76 cases/100,000 persons during 2008-2019. emm 1, 12, 28, 11, and 4 were the most common types, and 2 outbreaks were identified. We examined changes in distribution of clinical syndrome, patient demographics, and risk factors by comparing 2008-2013 baseline with 2014-2019 data. Incidence was higher among all age groups during 2014-2019. Streptococcal toxic shock syndrome increased from 0% to 6.4% of cases (p = 0.02). We identified no differences in distribution of demographic or risk factors between periods. Results indicated that invasive group A Streptococcus is increasing among the general population of Idaho. Ongoing surveillance of state-level invasive group A Streptococcus cases could help identify outbreaks, track regional trends in incidence, and monitor circulating emm types.


Subject(s)
Shock, Septic , Streptococcal Infections , Antigens, Bacterial/genetics , Bacterial Outer Membrane Proteins/genetics , Humans , Idaho/epidemiology , Incidence , Shock, Septic/epidemiology , Streptococcal Infections/epidemiology , Streptococcus pyogenes/genetics
6.
Workplace Health Saf ; 70(7): 325-331, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35466840

ABSTRACT

BACKGROUND: The threat of workplace violence (WPV) is a primary safety concern for home health care workers (HHCWs). WPV prevention training is a critical tool for HHCWs' safety. Yet, most existing WPV prevention training is limited or not specific to HHCWs' environment, the patient's home, and neighborhood. The purpose of this study was to describe WPV prevention training, resources used, and commitment to HHCWs' safety. METHODS: Using a cross-sectional design, HHCWs from two sites located in Southwestern Ohio completed the Violence Against Home Healthcare and Hospice Workers survey, a 37-item survey used to describe frequency and characteristics of WPV prevention training and resources. Descriptive statistics were used to analyze the data. FINDINGS: Half (n = 25) of the HHCWs received WPV prevention training. Training content focused on characteristics of aggressive/violent patients and family members (n = 19, 82.6%), but limited content about characteristics of hazardous neighborhoods (n = 15, 65.2%). Cellular phones (n = 43, 97.7%) were primarily used as a resource to promote safety, few cellular phones (n = 1, 2.3%) were provided by the agency. CONCLUSIONS/APPLICATION TO PRACTICE: HHCWs described WPV prevention training content and resources used to promote safety. WPV prevention training is deficient in procedures for seeking psychological care, screening patients for violent behavior, skills for self-protection, characteristics of hazardous neighborhoods, and physical maneuvers and verbal methods to diffuse or avoid aggressive behavior. Access to WPV prevention training and resources for HHCWs needs to be strengthened. Occupational Health Nurses can assist their employers with developing WPV prevention training for HHCWs.


Subject(s)
Home Health Aides , Workplace Violence , Cross-Sectional Studies , Humans , Surveys and Questionnaires , Workplace/psychology
7.
Home Healthc Now ; 38(4): 193-201, 2020.
Article in English | MEDLINE | ID: mdl-32618777

ABSTRACT

The threat of workplace violence (WPV) is a significant occupational hazard for home healthcare workers (HHCWs). The purpose of this integrative review is to examine WPV interventions used by HHCWs to stay safe while working in the patient's home and community. The methodology used was the integrative review by , which allows for inclusion of experimental and non-experimental research, reflecting the state of the science on interventions used by HHCWs to mitigate and prevent WPV. A total of 17 articles pertained to interventions used by HHCWs. Interventions were further categorized by WPV Type. There are a number of interventions used for Type I and II WPV. However, interventions for Type III WPV are minimal and interventions for Type IV WPV are obsolete. Safety and health training were shown to be significant in increasing HHCWs' confidence and knowledge about WPV prevention. Researchers demonstrated safety and health training are effective in promoting a safe work environment and reducing incidents of WPV. This review begins to fill the gap in the literature on interventions used by HHCWs to mitigate and prevent WPV.


Subject(s)
Home Health Aides , Workplace Violence/prevention & control , Humans
8.
Int J Health Care Qual Assur ; 31(6): 464-473, 2018 Jul 09.
Article in English | MEDLINE | ID: mdl-29954277

ABSTRACT

Purpose The purpose of this paper is to describe the process used to standardize a Workplace Violence Prevention Program (WVPP) within a five-hospital healthcare system in Veterans Health Administration (VHA). Design/methodology/approach A description of the lean process improvement principles, used to bring the WVPP into compliance with Occupational Safety and Health Administration (OSHA) and other agencies through streamlining/standardizing processes. Findings There was significant standardization in both the threat assessment and education arms of the WVPP. Compliance with all major US Department of Labor OSHA requirements, as well as substantial time savings, were realized as part of this process improvement. Originality/value VHA is leading the way in inter/multidisciplinary assessment and mitigation of workplace violence, however, there are significant competing demands on staff time. This first ever use of lean principles to streamline processes around workplace violence prevention freed up clinician time for care while improving internal and external customer satisfaction, representing a major step forward in workplace violence risk mitigation.


Subject(s)
Total Quality Management/organization & administration , United States Department of Veterans Affairs/organization & administration , Workplace Violence/prevention & control , Humans , Inservice Training/organization & administration , Occupational Health , Total Quality Management/standards , United States , United States Department of Veterans Affairs/standards , United States Occupational Safety and Health Administration
9.
J Neurosci ; 37(34): 8102-8115, 2017 08 23.
Article in English | MEDLINE | ID: mdl-28733355

ABSTRACT

The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R-MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK-deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity-associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R-MSNs.SIGNIFICANCE STATEMENT Alterations in ERK/MAPK activity are associated with drug abuse, as well as neuropsychiatric and movement disorders. However, genetic evidence defining the functions of ERK/MAPK signaling in striatum-related neurophysiology and behavior is lacking. We show that loss of ERK/MAPK signaling leads to pathway-specific alterations in motor function, reduced neuronal excitability, and the inability of medium spiny neurons to regulate activity-induced gene expression. Our results underscore the potential importance of the ERK/MAPK pathway in human movement disorders.


Subject(s)
Corpus Striatum/physiology , Locomotion/physiology , MAP Kinase Signaling System/physiology , Movement/physiology , Animals , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Random Allocation
11.
Brain Behav Immun ; 57: 68-78, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27311830

ABSTRACT

Herpes simplex virus (HSV)-1 is a ubiquitous human infection, with increased prevalence in obese populations. Obesity has been linked to increased inflammation, susceptibility to infection, and higher rates of anxiety disorder and cognitive impairment. To determine how obesity alters neuroinflammation and behavior following infection, we infected weanling C57BL/6 or CCR2(RFP/+)/CX3CR1(GFP/+) mice with a very low dose of HSV-1. Following viral latency (14days post infection (d p.i.)), mice were randomly assigned to remain on the low fat (LF) diet or switched to a 45% high fat (HF) diet. Eight weeks post diet shift, latently infected mice on the HF diet (HSV-HF) had greater microglial activation and infiltration of inflammatory CCR2(+) monocytes in the hypothalamus and dentate gyrus, in comparison to both HSV-LF mice and uninfected mice on LF and HF diets. VCAM staining was present in hypothalamus and hippocampus of the HSV-HF mice in the areas of monocyte infiltration. Infiltrating monocytes also produced proinflammatory cytokines demonstrating that, along with activated microglia, monocytes contribute to sustained neuroinflammation in latently infected obese mice. Utilizing a light-dark preference test, we found that HSV-HF mice had increased anxiety-like behavior. In the marble-burying test, HF diet and HSV infection resulted in increased numbers of buried marbles. Together, these mice provide a useful, testable model to study the biobehavioral effects of obesity and latent HSV-1 infection in regards to anxiety and may provide a tool for studying diet intervention programs in the future.


Subject(s)
Anxiety/immunology , Behavior, Animal/physiology , Herpes Simplex/immunology , Herpesvirus 1, Human , Inflammation/immunology , Monocytes/immunology , Obesity/immunology , Receptors, CCR2 , Animals , Diet, Fat-Restricted , Diet, High-Fat , Disease Models, Animal , Male , Mice , Mice, Inbred C57BL
12.
Dev Biol ; 352(1): 40-7, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-21256837

ABSTRACT

The HMG-Box transcription factor SOX2 is expressed in neural progenitor populations throughout the developing and adult central nervous system and is necessary to maintain their progenitor identity. However, it is unclear whether SOX2 levels are uniformly expressed across all neural progenitor populations. In the developing dorsal telencephalon, two distinct populations of neural progenitors, radial glia and intermediate progenitor cells, are responsible for generating a majority of excitatory neurons found in the adult neocortex. Here we demonstrate, using both cellular and molecular analyses, that SOX2 is differentially expressed between radial glial and intermediate progenitor populations. Moreover, utilizing a SOX2(EGFP) mouse line, we show that this differential expression can be used to prospectively isolate distinct, viable populations of radial glia and intermediate cells for in vitro analysis. Given the limited repertoire of cell-surface markers currently available for neural progenitor cells, this provides an invaluable tool for prospectively identifying and isolating distinct classes of neural progenitor cells from the central nervous system.


Subject(s)
Neural Stem Cells/cytology , Neural Stem Cells/metabolism , SOXB1 Transcription Factors/metabolism , Telencephalon/cytology , Telencephalon/embryology , Animals , Biomarkers/metabolism , Cell Aggregation , Cell Proliferation , Cell Separation , Cell Size , Female , Flow Cytometry , Gene Expression Regulation, Developmental , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Multipotent Stem Cells/cytology , Multipotent Stem Cells/metabolism , Neuroglia/cytology , Neuroglia/metabolism , Neurons/cytology , Neurons/metabolism , SOXB1 Transcription Factors/genetics , Telencephalon/metabolism
13.
AAOHN J ; 56(4): 168-75, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18444405

ABSTRACT

The purpose of this study was to examine incivility experienced by direct health care staff in their workplaces. The sample (N = 184) was 91% female and 77% White, with 71% of the participants having earned an associate degree or above and 81% being registered nurses. The Work Limitations Questionnaire and the Incivility in Healthcare Survey were distributed to all direct care staff at a major metropolitan hospital (22% response rate). Correlations were found between workplace incivility from direct supervisors and productivity (r = 0.284, p = .000) and workplace incivility from patients and productivity (r = 0.204, p = .006). Incivility from physicians, incivility from other direct care staff, and general environmental incivility were not shown to be significantly related to productivity. Demographics were not related to levels of workplace incivility. Workplace incivility from patients and management appears to have a greater impact on employees' productivity than workplace incivility from other sources.


Subject(s)
Agonistic Behavior , Attitude of Health Personnel , Interprofessional Relations , Nursing Staff, Hospital/psychology , Workplace/psychology , Adult , Cross-Sectional Studies , Efficiency, Organizational , Female , Humans , Male , Midwestern United States , Nurse Administrators/organization & administration , Nurse Administrators/psychology , Nursing Assistants/education , Nursing Assistants/organization & administration , Nursing Assistants/psychology , Nursing Methodology Research , Nursing Staff, Hospital/education , Nursing Staff, Hospital/organization & administration , Occupational Health Nursing/organization & administration , Social Behavior , Surveys and Questionnaires , Workplace/organization & administration
14.
CSH Protoc ; 2008: pdb.prot5077, 2008 Nov 01.
Article in English | MEDLINE | ID: mdl-21356718

ABSTRACT

INTRODUCTIONThe ability to prospectively identify and characterize neural progenitor cells in vivo has been difficult due to a lack of cell-surface markers specific for these cell types. A widely used in vitro culture method, known as the Neurosphere Assay (NSA), has provided a means to retrospectively identify neural progenitor cells as well as to determine both their self-renewal capacity and their ability to generate the three primary cell types of the nervous system: neurons, astrocytes, and oligodendrocytes. Today, combined with the establishment of multiple transgenic mouse strains expressing fluorescent markers and advances in cell isolation techniques such as fluorescence-activated cell sorting (FACS), the NSA provides a powerful system to prospectively elucidate neural progenitor characteristics and functions. Here we describe methods for the isolation, culture, and differentiation of neural progenitors from the developing mouse and adult cortex.

15.
AAOHN J ; 54(12): 515-20, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17190094

ABSTRACT

It is estimated that employers spend more than 75 billion dollars annually on obesity-attributable health care. Interventions to reduce or prevent the risk of obesity are increasingly common at worksites and include health fairs, weight loss and nutrition classes, and fitness programs. However, many companies lack the resources to plan and implement these types of programs. Environmental approaches offer companies a low-cost option. A community-based participatory research model was used to bring academic researchers, human resources personnel, and health department educators together to plan and implement an environmental program aimed at increasing healthy eating and physical activity at four small manufacturing companies. The Diffusion of Innovations Theory guided the development of focus group questions. A focus group study was then conducted to gather information from employees and managers at these four companies. The questions identified workplace strategies that would aid in reducing barriers and developing appropriate communication channels to enhance employee participation in the program. The researchers identified themes from manager and employee focus groups regarding the following five environmental components: signs, walking paths, food changes, educational strategies, and advisory groups.


Subject(s)
Focus Groups , Health Promotion , Obesity/prevention & control , Organizational Culture , Workplace , Adolescent , Adult , Diffusion of Innovation , Female , Humans , Male , Middle Aged , Program Development , United States
16.
Genes Dev ; 20(9): 1187-202, 2006 May 01.
Article in English | MEDLINE | ID: mdl-16651659

ABSTRACT

Approximately 10% of humans with anophthalmia (absent eye) or severe microphthalmia (small eye) show haploid insufficiency due to mutations in SOX2, a SOXB1-HMG box transcription factor. However, at present, the molecular or cellular mechanisms responsible for these conditions are poorly understood. Here, we directly assessed the requirement for SOX2 during eye development by generating a gene-dosage allelic series of Sox2 mutations in the mouse. The Sox2 mutant mice display a range of eye phenotypes consistent with human syndromes and the severity of these phenotypes directly relates to the levels of SOX2 expression found in progenitor cells of the neural retina. Retinal progenitor cells with conditionally ablated Sox2 lose competence to both proliferate and terminally differentiate. In contrast, in Sox2 hypomorphic/null mice, a reduction of SOX2 expression to <40% of normal causes variable microphthalmia as a result of aberrant neural progenitor differentiation. Furthermore, we provide genetic and molecular evidence that SOX2 activity, in a concentration-dependent manner, plays a key role in the regulation of the NOTCH1 signaling pathway in retinal progenitor cells. Collectively, these results show that precise regulation of SOX2 dosage is critical for temporal and spatial regulation of retinal progenitor cell differentiation and provide a cellular and molecular model for understanding how hypomorphic levels of SOX2 cause retinal defects in humans.


Subject(s)
DNA-Binding Proteins/physiology , Gene Dosage , Retina/abnormalities , Stem Cells/physiology , Trans-Activators/physiology , Alleles , Animals , Anophthalmos/genetics , Cell Differentiation , Cell Proliferation , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Mice , Mice, Knockout , Microphthalmos/genetics , Mutation , Neurons/metabolism , Neurons/physiology , Receptor, Notch1/metabolism , Retina/embryology , Retina/metabolism , SOXB1 Transcription Factors , Signal Transduction , Stem Cells/metabolism , Trans-Activators/biosynthesis , Trans-Activators/genetics
17.
J Nurs Adm ; 36(1): 22-7; discussion 27-8, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16404196

ABSTRACT

The financial cost of workplace violence is 4.2 billion dollars a year. Workplace incivility may initiate a spiral that for 1,000 people a year ends in death at work. If an initial minor incident such as incivility could be mitigated, then the financial and human capital that could be realized by the healthcare organization is immense. This article is an in-depth look at the literature and theoretical frameworks related to workplace incivility.


Subject(s)
Occupational Exposure/prevention & control , Social Behavior , Violence/prevention & control , Violence/psychology , Workplace , Aggression/psychology , Coercion , Health Personnel , Humans , Models, Psychological , Risk Factors , Violence/legislation & jurisprudence
18.
Behav Neurosci ; 119(1): 26-37, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15727510

ABSTRACT

Available evidence indicates that common genes influence alcohol and tobacco abuse in humans. The studies reported here used mouse models to evaluate the hypothesis that genetically determined variability in the alpha4beta2* nicotinic receptor modulates genetically determined variability in the intake of both nicotine and alcohol. Data obtained with inbred mouse strains suggested an association between a polymorphism in the mouse alpha4 nAChR subunit gene, Chrna4, and variability in nicotine and ethanol preference. These associations were assessed in F2 animals derived by crossing C57BL/6-super(beta2-/-) mice and A/J mice. The results obtained by the authors indicate that the polymorphism in Chrna4 plays an important role in modulating variability in oral nicotine intake but is linked to a gene that regulates alcohol intake.


Subject(s)
Central Nervous System Depressants/administration & dosage , Central Nervous System Depressants/pharmacology , Ethanol/administration & dosage , Ethanol/pharmacology , Ganglionic Stimulants/administration & dosage , Ganglionic Stimulants/pharmacology , Nicotine/administration & dosage , Nicotine/pharmacology , Polymorphism, Genetic , Receptors, Nicotinic/genetics , Substance-Related Disorders/genetics , Animals , Disease Models, Animal , Drinking Behavior , Feeding Behavior , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains
19.
Nicotine Tob Res ; 6(1): 145-58, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14982698

ABSTRACT

The nicotinic acetylcholine receptor (nAChR) subtypes alpha4beta2 and alpha7 comprise the majority of brain nicotine-binding sites. Classical genetic strategies using inbred mice and their hybrids suggest that nicotine's effects on locomotor activity and body temperature are influenced by alpha4beta2 but not alpha7 receptors. To evaluate directly the role of these nicotinic subtypes on responses to nicotine, beta2 and alpha7 null mutant (-/-) mice, as well as wild-type (+/+) and heterozygous (+/-) mice, were tested for baseline body temperature and locomotion and nicotine (0-1.5 mg/kg)-induced changes in these responses. Basal responses for these measures were similar for all beta2 genotypes, but baseline Y-maze activity was higher in alpha7-/- mice compared with alpha7+/+ mice. Following nicotine injection, dose-dependent decreases in body temperature and locomotor activity were observed for all three genotypes of both beta2 and alpha7 mice. Although responses in alpha7 mice did not differ among genotypes, beta2 gene deletion was found to have a gene-dependent effect on nicotine's effects. beta2-/- mice were less sensitive to nicotine-induced locomotor depression and hypothermia at low nicotine doses (.25-.5 mg/kg) but were no different from beta2+/+ mice at the highest doses tested (1.0-1.5 mg/kg). Residual responses at high nicotine doses in beta2-/- mice as well as responses in all alpha7 and beta2 mouse genotypes were mediated by nicotinic receptors, since mecamylamine (1.0 mg/kg) blocked all responses following 1.0 mg/kg nicotine. This finding suggests receptors that include the beta2 nAChR subunit partially mediate nicotine's effects on locomotor activity and body temperature.


Subject(s)
Gene Deletion , Locomotion/genetics , Nicotine/blood , Point Mutation/genetics , Protein Subunits/physiology , Psychomotor Disorders/chemically induced , Receptors, Nicotinic/genetics , Animals , Body Temperature/physiology , DNA Mutational Analysis , DNA Primers/genetics , Mice , Mice, Inbred C57BL , Sensitivity and Specificity
20.
Dev Neurosci ; 26(2-4): 148-65, 2004.
Article in English | MEDLINE | ID: mdl-15711057

ABSTRACT

Multipotent neural stem cells are present throughout the development of the central nervous system (CNS), persist into adulthood in defined locations and can be derived from more primitive embryonic stem cells. We show that SOX2, an HMG box transcription factor, is expressed in multipotent neural stem cells at all stages of mouse ontogeny. We have generated transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the endogenous locus-regulatory regions of the Sox2 gene to prospectively identify neural stem/progenitor cells in vivo and in vitro. Fluorescent cells coexpress SOX2 protein, and EGFP fluorescence is detected in proliferating neural progenitor cells of the entire anterior-posterior axis of the CNS from neural plate stages to adulthood. SOX2-EGFP cells can form neurospheres that can be passaged repeatedly and can differentiate into neurons, astrocytes and oligodendrocytes. Moreover, prospective clonal analysis of SOX2-EGFP-positive cells shows that all neurospheres, whether isolated from the embryonic CNS or the adult CNS, express SOX2-EGFP. In contrast, the pattern of SOX2-EGFP expression using randomly integrated Sox2 promoter/reporter construct differs, and neurospheres are heterogeneous for EGFP expression. These studies demonstrate that SOX2 may meet the requirements of a universal neural stem cell marker and provides a means to identify cells which fulfill the basic criteria of a stem cell: self-renewal and multipotent differentiation.


Subject(s)
Cell Lineage/genetics , Central Nervous System/embryology , DNA-Binding Proteins/genetics , Neurons/metabolism , Nuclear Proteins/genetics , Pluripotent Stem Cells/metabolism , Stem Cells/metabolism , Animals , Antigens, Differentiation/analysis , Antigens, Differentiation/metabolism , Cell Differentiation/genetics , Cell Proliferation , Cells, Cultured , Central Nervous System/cytology , Central Nervous System/metabolism , Chimera , Clone Cells/cytology , Clone Cells/metabolism , Gene Expression Regulation, Developmental/genetics , Genes, Reporter/genetics , Green Fluorescent Proteins/genetics , HMGB Proteins , Immunohistochemistry , Mice , Mice, Transgenic , Neuroglia/cytology , Neuroglia/metabolism , Neurons/cytology , Pluripotent Stem Cells/cytology , Promoter Regions, Genetic/genetics , SOXB1 Transcription Factors , Spheroids, Cellular/cytology , Spheroids, Cellular/metabolism , Stem Cells/cytology , Transcription Factors
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