Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline

Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood-brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.65

Neuregulin-1 Regulates Cell Adhesion via an ErbB2/Phosphoinositide-3 Kinase/Akt-Dependent Pathway: Potential Implications for Schizophrenia and Cancer

Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer.Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/Akt1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063).Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion

Rapid Effects of Hearing Song on Catecholaminergic Activity in the Songbird Auditory Pathway

Catecholaminergic (CA) neurons innervate sensory areas and affect the processing of sensory signals. For example, in birds, CA fibers innervate the auditory pathway at each level, including the midbrain, thalamus, and forebrain. We have shown previously that in female European starlings, CA activity in the auditory forebrain can be enhanced by exposure to attractive male song for one week. It is not known, however, whether hearing song can initiate that activity more rapidly. Here, we exposed estrogen-primed, female white-throated sparrows to conspecific male song and looked for evidence of rapid synthesis of catecholamines in auditory areas. In one hemisphere of the brain, we used immunohistochemistry to detect the phosphorylation of tyrosine hydroxylase (TH), a rate-limiting enzyme in the CA synthetic pathway. We found that immunoreactivity for TH phosphorylated at serine 40 increased dramatically in the auditory forebrain, but not the auditory thalamus and midbrain, after 15 min of song exposure. In the other hemisphere, we used high pressure liquid chromatography to measure catecholamines and their metabolites. We found that two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, increased in the auditory forebrain but not the auditory midbrain after 30 min of exposure to conspecific song. Our results are consistent with the hypothesis that exposure to a behaviorally relevant auditory stimulus rapidly induces CA activity, which may play a role in auditory responses

Endoscopic Management of Lacrimal System Dysgenesis and Dacryocystoceles in Fraser Syndrome: A Case Report and Literature Review

Background Fraser syndrome is an autosomal recessive disorder characterized primarily by syndactyly, cryptophthalmos, urinary tract anomalies, ambiguous genitalia, and laryngeal anomalies. A 28-year-old man with Fraser syndrome presented with cryptophthalmos, microphthalmia, lacrimal system dysgenesis, and chronic sinusitis. Objective The patients’ clinical condition and surgical treatment are described. A literature review was conducted, and articles relevant to the case are presented. Methods Case report. Results To our knowledge, this is the first published case report of endonasal management of dacryocystoceles in a Fraser syndrome patient. The patient was treated via endoscopic endonasal marsupialization and drainage. Conclusion Fraser syndrome patients may initially present to many different specialties as the spectrum of clinical manifestations is broad. Physicians treating these patients should take a collaborative approach to surgical and medical management

Growth response of different species of <em>Ziziphus</em> to inoculation with arbuscular mycorrhizal fungi

International audienceIntroduction - Many of species of Ziziphus are underutilized crops despite their potential interests in agroforestry systems. Except for Ziziphus mauritiana, the effectiveness of arbuscular mycorrhizal fungi (AMF) on growth and mineral nutrition of Ziziphus spp. is not known. The aim of our study was to evaluate the mycorrhizal dependency (MD) of Ziziphus spp. in greenhouse conditions. Materials and methods - Three isolates of AMF were used: Rhizophagus irregularis isolate IR27, Funneliformis mosseae isolate DAOM227131 and Rhizoglomus intraradices isolate DAOM197198, on seven species of Ziziphus: Z. mauritiana, Z. lotus, Z. spina-christi, Z. mucronata, Z. amphibia, Z, abyssinica and Z. sphaerocarpa. Plants were grown in nursery receiving 20 g portions of a crude inoculum of AMF. The experiment was set up as a 4 x 7 factorial design consisting of three AMF, one control (disinfected soil without inoculum) and seven Ziziphus spp. Results and discussion - Inoculation by AMF significantly improved growth and mineral nutrition of Ziziphus spp., particularly the P nutrition. Mycorrhizal dependency values of Ziziphus spp. declined with AMF in the following order: R, irregularis (69.51%), R. intraradices (63.58%) and R mosseae (52.45%). Total length of AMF hyphae in soil samples from inoculated treatments was significantly higher in all Ziziphus spp. with II, intraradices combinations. The differences of MD among the tested Ziziphus spp. seem to be due to differences in the development of hyphal length in the soil and in P uptake by the external hyphae. Conclusion - Rhizophagus irregularis constitutes a promising tool for the production of higher quality nursery stock with expected improved performance of Ziziphus spp. in agroforestry systems

Comprehensive value implications of surgeon volume for lung cancer surgery: Use of an analytic framework within a regional health systemCentral MessagePerspective

Objective: We used a framework to assess the value implications of thoracic surgeon operative volume within an 8-hospital health system. Methods: Surgical cases for non–small cell lung cancer were assessed from March 2015 to March 2021. High-volume (HV) surgeons performed >25 pulmonary resections annually. Metrics include length of stay, infection rates, 30-day readmission, in-hospital mortality, median 30-day charges and direct costs, and 3-year recurrence-free and overall survival. Multivariate regression-based propensity scores matched patients between groups. Metrics were graphed on radar charts to conceptualize total value. Results: All 638 lung resections were performed by 12 surgeons across 6 hospitals. Two HV surgeons performed 51% (n = 324) of operations, and 10 low-volume surgeons performed 49% (n = 314). Median follow-up was 28.8 months (14.0-42.3 months). Lobectomy was performed in 71% (n = 450) of cases. HV surgeons performed more segmentectomies (33% [n = 107] vs 3% [n = 8]; P < .001). Patients of HV surgeons had a lower length of stay (3 [2-4] vs 5 [3-7]; P < .001) and infection rates (0.6% [n = 1] vs 4% [n = 7]; P = .03). Low-volume and HV surgeons had similar 30-day readmission rates (14% [n = 23] vs 7% [n = 12]; P = .12), in-hospital mortality (0% [n = 0] vs 0.6% [n = 1]; P = .33), and oncologic outcomes; 3-year recurrence-free survival was 95% versus 91%; P = .44, and 3-year overall survival was 94% versus 90%; P = 0. Charges were reduced by 28%, and direct costs were reduced by 23% (both P < .001) in the HV cohort. Conclusions: HV surgeons provide comprehensive value across a health system. This multidomain framework can be used to help drive oncologic care decisions within a health system