1 Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan; 2 Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; and 3 Faculty of Dentistry, Jaw Function and ...Orofacial Pain Research Unit, Westmead Hospital, University of Sydney, New South Wales, Sydney, Australia
Submitted 26 May 2008;
accepted in final form 24 June 2008
The mechanisms whereby orofacial pain affects motor function are poorly understood. The aims were to determine whether 1 ) lingual algesic chemical stimulation affected face primary motor cerebral cortex (face MI) excitability defined by intracortical microstimulation (ICMS); and 2 ) any such effects were limited to the motor efferent MI zones driving muscles in the vicinity of the noxious stimulus. Ketamine-anesthetized Sprague–Dawley male rats were implanted with electromyographic (EMG) electrodes into anterior digastric, masseter, and genioglossus muscles. In 38 rats, three microelectrodes were located in left face MI at ICMS-defined sites for evoking digastric and/or genioglossus responses. ICMS thresholds for evoking EMG activity from each site were determined every 15 min for 1 h, then the right anterior tongue was infused (20 µl, 120 µl/h) with glutamate (1.0 M, n = 18) or isotonic saline ( n = 7). Subsequently, ICMS thresholds were determined every 15 min for 4 h. In intact control rats ( n = 13), ICMS thresholds were recorded over 5 h. Only left and right genioglossus ICMS thresholds were significantly increased ( 350%) in the glutamate infusion group compared with intact and isotonic saline groups ( P < 0.05). These dramatic effects of glutamate on ICMS-evoked genioglossus activity contrast with its weak effects only on right genioglossus activity evoked from the internal capsule or hypoglossal nucleus. This is the first documentation that intraoral noxious stimulation results in prolonged neuroplastic changes manifested as a decrease in face MI excitability. These changes appear to occur predominantly in those parts of face MI that provide motor output to the orofacial region receiving the noxious stimulation.
Address for reprint requests and other correspondence: B. J. Sessle, Faculty of Dentistry, University of Toronto, 124 Edward Street, Toronto, Ontario, Canada M5G 1G6 (E-mail: barry.sessle{at}dentistry.utoronto.ca )
Background
Neuronal dysfunction is central to the clinical manifestation of Alzheimer’s disease (AD). However, genome‐wide studies also suggest important roles for non‐neuronal brain cell‐types such ...as microglia and astrocytes. Our objective was to study whether brain cell type‐specific polygenic risk scores (PGRS) for AD, including single nucleotide polymorphisms (SNPs) of genes expressed in one brain cell type, showed relationships with levels of cerebrospinal fluid (CSF) AD markers in individuals across the clinical spectrum of AD.
Method
We selected 1,535 subjects (552 controls/709 mild cognitive impairment/274 AD‐dementia, age 71±8 years, 48%female) from the ADNI (N=617) and EMIF‐AD MBD (N=918) study, who had genetic data available. We labelled AD risk genes as specific for neurons, astrocytes, microglia, oligodendrocytes or endothelial cells when more than 50% of the gene expression was produced by one cell type (otherwise as ‘non‐specific’) according to the BRAIN RNASeq database (Zhang et al., 2014). We calculated cell type‐specific‐PGRS with cell type‐corresponding SNPs (P<5e‐8) using weights from De Rojas et al., (2020) AD case‐control summary statistics. Associations between cell type‐specific‐PGRS and CSF biomarkers (amyloid‐beta, total tau (t‐tau), phosphorylated tau (p‐tau), neurofilament light, neurogranin and YKL‐40) were examined using linear regressions, adjusted for population structure, study, age and sex.
Result
Of 40 AD risk genes, 26 had detectable RNA levels in at least one brain cell type. Of these, sixteen were cell type‐specific: 11 were microglia‐specific, 4 astrocyte‐specific (including APOE) and 1 neuron‐specific (Figure 1). Astrocyte‐PGRS (P=1.4e‐6, Pwithout_APOE=.1) and microglia‐PGRS (P=6.3e‐3) were increased in AD‐type dementia compared to controls, whereas other PGRS were not (Figure 2). Astrocyte‐PGRS (including APOE) were most strongly associated with CSF amyloid‐beta (P=1.4e‐31), t‐tau (P=6.3e‐10), p‐tau (P=4.9e‐9), and neurogranin (P=0.01). Astrocyte‐specific (excluding APOE) and microglia‐specific PGRS‐AD also associated with CSF amyloid‐beta (P<0.05), and with p‐tau at trend‐level (Figure 2). Apart from the tentative association between neuron‐PGRS and CSF YKL‐40, no other associations were observed.
Conclusion
Findings indicate that AD risk variants have cell type‐specific associations with amyloid and tau pathology, which seems mostly expressed by astrocytes (also without APOE) and microglia, suggesting that these cell types play a role in amyloid pathogenesis.
The Kunitz trypsin inhibitor (KTi) in soybean has several polymorphic types that are controlled by multiple alleles, which behave in a co-dominant fashion. Of these, Tia and Tib, which differ by nine ...amino acids, are the predominant types. In order to develop a single nucleotide amplified polymorphism (SNAP) marker for the classification of the predominant KTi types, Tia and Tib, and evaluate KTi activities by differing KTi type total 451 soybean mutant lines (M₁₂-M₁₆ generation) were incorporated in this study. Among 451 soybean mutants, 144 and 13 mutant lines showed decreased and increased trypsin inhibitor activity when compared with the original cultivars, respectively. To identify the KTi type, we designed a SNAP marker. Among 451 mutant lines from 12 soybean cultivars and landraces, 8 mutant lines derived from cvs. Baekwoon, Paldal and Suwon115 showed a change in KTi type when compared with the original cultivars using the SNAP marker. Five mutant lines in Suwon115 changed from Tib to Tia, while two mutant lines derived from cv. Baekwoon and one mutant line derived from cv. Paldal were changed from Tia to Tib. These changes of KTi types were confirmed by sequencing of the KTi genes and non-denaturing polyacrylamide gel electrophoresis of the KTi proteins. To identify the effect of KTi activity based on the change in KTi type, we measured the KTi activity using the three cultivars and eight mutant lines that showed changes in KTi type. Two mutant lines (BW-1 and 7-2) derived from cv. Baekwoon and one mutant line (PD-5-10) from cv. Paldal that changed from Tia to Tib showed lower activity than the original cultivar. In cv. Suwon115, five mutant lines that changed from Tib to Tia showed higher activity than the original cultivar. These results indicate that the designed SNAP marker was capable of identifying the KTi type and that Tia activity was higher than Tib activity in soybean.
Prescription drug misuse in transgender individuals is estimated to be 3 times higher than that of the general population in the United States, suggesting that opioid reduction strategies deserve ...significant consideration in gender-affirming surgeries. In this work, we describe the implementation of an enhanced recovery after surgery (ERAS) protocol to reduce opioid use after facial feminization surgery.
79 patients who underwent single-stage facial feminization surgery before (n=38) or after (n=41) ERAS protocol implementation were included. Primary outcomes assessed were: perioperative opioid consumption (morphine equivalent dose/kilogram, MED/kg), average patient-reported pain scores, and length of hospital stay. Comparisons between groups and multivariable linear regression analyses were conducted to define the contribution of the ERAS protocol to each of the three primary outcomes.
Age, body mass index, mental health diagnoses, and length of surgery did not differ between pre-ERAS and ERAS groups. Compared to pre-ERAS patients, patients treated under the ERAS protocol consumed less opioids (medianinterquartile range, IQR, 0.80.5-1.1 versus 1.51.0-2.1 MED/kg, p<0.001), reported lower pain scores (2.5±1.8 versus 3.7±1.6, p=0.002), and required a shorter hospital stay (medianIQR, 27.326.3-49.8 versus 32.424.8-39.1 hours, p<0.001). When controlling for other contributing variables such as previous gender-affirming surgeries, mental health diagnoses, and length of surgery using multivariable linear regression analyses, ERAS protocol implementation independently predicted reduced opioid use, lower pain scores, and shorter hospital stay after facial feminization surgery.
The current work details an ERAS protocol for facial feminization surgery that reduces perioperative opioid consumption, patient-reported pain scores, and hospital stay.
Epithelial-mesenchymal transition (EMT) programs are essential in promoting breast cancer invasion, systemic dissemination and in arousing proliferative programs in breast cancer micrometastases, a ...reaction that is partially dependent on focal adhesion kinase (FAK). Many functions of FAK are shared by its homolog, protein tyrosine kinase 2 (Pyk2), raising the question as to whether Pyk2 also participates in driving the metastatic outgrowth of disseminated breast cancer cells. In addressing this question, we observed Pyk2 expression to be (i) significantly upregulated in recurrent human breast cancers; (ii) differentially expressed across clonal isolates of human MDA-MB-231 breast cancer cells in a manner predictive for metastatic outgrowth, but not for invasiveness; and (iii) dramatically elevated in ex vivo cultures of breast cancer cells isolated from metastatic lesions as compared with cells that produced the primary tumor. We further show that metastatic human and murine breast cancer cells robustly upregulate their expression of Pyk2 during EMT programs stimulated by transforming growth factor-β (TGF-β). Genetic and pharmacological inhibition of Pyk2 demonstrated that the activity of this protein tyrosine kinase was dispensable for the ability of breast cancer cells to undergo invasion in response to TGF-β, and to form orthotopic mammary tumors in mice. In stark contrast, Pyk2-deficiency prevented TGF-β from stimulating the growth of breast cancer cells in 3D-organotypic cultures that recapitulated pulmonary microenvironments, as well as inhibited the metastatic outgrowth of disseminated breast cancer cells in the lungs of mice. Mechanistically, Pyk2 expression was inversely related to that of E-cadherin, such that elevated Pyk2 levels stabilized β1 integrin expression necessary to initiate the metastatic outgrowth of breast cancer cells. Thus, we have delineated novel functions for Pyk2 in mediating distinct elements of the EMT program and metastatic cascade regulated by TGF-β, particularly the initiation of secondary tumor outgrowth by disseminated cells.
SETTING: Eleven referring hospitals in South Korea.OBJECTIVE: To compare therapeutic responses in chronic obstructive pulmonary disease (COPD) subgroups, classified by diffusing capacity of the lung ...for carbon monoxide (DLCO) and lung volume.DESIGN: A total of 130
stable male COPD patients were classified into four subgroups according to baseline DLCO and residual volume/total lung capacity (RV/TLC) ratio. We compared therapeutic responses to short acting β2-agonist (SABA) and 3-month combined inhalation of long-acting β2-agonist
(LABA) and corticosteroid among patients with these subgroups.RESULTS: Among the 130 COPD patients, 41 (31.5%) had normal DLCO and RV/TLC, 28 (21.5%) low DLCO and normal RV/TLC, 31 (23.8%) normal DLCO and high RV/TLC, and 30 (23.1%) low DLCO
and high RV/TLC. The normal DLCO/high RV/TLC subgroup showed a significantly larger flow response (changes in forced expiratory volume in 1 s) to salbutamol than the normal DLCO/RV/TLC subgroups, and a larger volume response (changes in forced vital capacity) than the
two normal RV/TLC subgroups. The normal DLCO/high RV/TLC subgroup also showed significantly larger flow and volume response to 3-month combined inhalation of LABA and corticosteroid than the two normal RV/TLC subgroups.CONCLUSION: COPD subgroups classified by DLCO
and RV/TLC may have different pulmonary function responses to pharmacological treatment.
The main field activities of the Coordinated Airborne Studies in the Tropics (CAST) campaign took place in the west Pacific during January–February 2014. The field campaign was based in Guam (13.5°N, ...144.8°E), using the U.K. Facility for Airborne Atmospheric Measurements (FAAM) BAe-146 atmospheric research aircraft, and was coordinated with the Airborne Tropical Tropopause Experiment (ATTREX) project with an unmanned Global Hawk and the Convective Transport of Active Species in the Tropics (CONTRAST) campaign with a Gulfstream V aircraft. Together, the three aircraft were able to make detailed measurements of atmospheric structure and composition from the ocean surface to 20 km. These measurements are providing new information about the processes influencing halogen and ozone levels in the tropical west Pacific, as well as the importance of trace-gas transport in convection for the upper troposphere and stratosphere. The FAAM aircraft made a total of 25 flights in the region between 1°S and 14°N and 130° and 155°E. It was used to sample at altitudes below 8 km, with much of the time spent in the marine boundary layer. It measured a range of chemical species and sampled extensively within the region of main inflow into the strong west Pacific convection. The CAST team also made ground-based measurements of a number of species (including daily ozonesondes) at the Atmospheric Radiation Measurement Program site on Manus Island, Papua New Guinea (2.1°S, 147.4°E). This article presents an overview of the CAST project, focusing on the design and operation of the west Pacific experiment. It additionally discusses some new developments in CAST, including flights of new instruments on board the Global Hawk in February–March 2015.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract There has been a dramatic rise in gene×environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer ...promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene–environment interactions across development in humans.
SETTING: Eleven referring hospitals in South Korea.OBJECTIVE: To classify the phenotypes in elderly subjects with obstructive lung disease (OLD).METHODS: We analysed 191 subjects aged ≥60 years with ...chronic respiratory symptoms and either obstructive spirometry or bronchial
hyperresponsiveness. Factor analysis was performed using commonly measured variables and revealed four significant variables: 1) the ratio of inspiratory capacity to total lung capacity, 2) the total score on the St George's Respiratory Questionnaire, 3) the volume fraction of the lung
less than 950 Hounsfield Unit at full inspiration on volumetric computed tomography and 4) post-bronchodilator forced expiratory volume in 1 second (FEV1) changes. We performed a cluster analysis on these four variables.RESULTS: The mean age was 68.5 (±5.2 SD) years and
the mean post-bronchodilator FEV1 was 52.4% (±16.5) predicted. Three clusters with the following phenotypes were identified: Cluster 1 included subjects with moderate to severe airflow obstruction and bronchodilator reversibility; Cluster 2 subjects had moderate airflow obstruction
without bronchodilator reversibility, and Cluster 3 subjects had severe airflow obstruction without bronchodilator reversibility.CONCLUSIONS: We identified three phenotypes in elderly subjects with OLD. Follow-up studies are needed to explore the clinical significance of each phenotype.
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