• The contributing risk of tobacco use for ARDS development in burn-injured adults with inhalation injury

      Afshar, M.; Netzer, G.; Mosier, M.J. (American Association for Respiratory Care, 2017)
      BACKGROUND: This study aims to determine the relationship between tobacco use, inhalation injury, and ARDS in burn-injured adults. METHODS: This study was an observational cohort of 2,485 primary burn admissions to a referral burn center between January 1, 2008 and March 15, 2015. Subjects were evaluated by methods used to account for mediation and traditional approaches (multivariable logistic regression and propensity score analysis). Mediation analysis examined both the (1) indirect effect of tobacco use via inhalation injury as the mediator on ARDS development and (2) the direct effect of tobacco use alone on ARDS development. RESULTS: ARDS development occurred in 6.8% (n = 170) of the cohort. Inhalation injury occurred in 5.0% (n = 125) of the cohort, and ARDS developed in 48.8% (n = 83) of the subjects with inhalation injury. Tobacco use was 2-fold more common in subjects with ARDS. In the mediated model, the direct effect of tobacco use on ARDS, including interaction between tobacco use and inhalation injury, was not significant (odds ratio [OR] 1.63, 95% CI 0.91-2.92, P =.10). However, the indirect effect of tobacco use via inhalation injury as the mediator was significant (OR 1.61, 95% CI 1.25-2.07, P <.001), and the proportion of the total effect of tobacco use operating through the mediator was 55.6%. In the non-mediation models (multivariable logistic regression and propensity score analysis), which controlled for inhalation injury and other covariables, the OR for the association between tobacco use and ARDS was 1.84 (95% CI 1.22-2.81, P <.001) and 1.69 (95% CI 1.04-2.75, P =.03), respectively. CONCLUSIONS: In mediation analysis, inhalation injury was the overwhelming predictor for ARDS development, whereas tobacco use has its strongest effect indirectly through inhalation injury. Patients with at least moderate inhalation injury are at greatest risk for ARDS development despite baseline risk factors like tobacco use. Copyright 2017 by Daedalus Enterprises.
    • Effects of prey densities and dietary supplementation on the larval development of the blue crab Callinectes sapidus Rathbun, 1896 (Brachyura: Portunidae)

      Maurer, L.; Liang, D.; Sook, Chung, J. (Oxford University Press, 2017)
      Variation in larval development related to duration and number of stages is common among arthropods. This variation appears to be influenced largely by environmental factors such as prey availability and temperature, but the primary causes are poorly understood. We examined the effects of prey density and the use of polyhydroxybutyrate (PHB), an energy-storage compound, on larval duration and survival during the early development of the blue crab, Callinectes sapidus (Rathbun, 1896), using hatchery-raised animals at constant temperature (21–23 °C). We also determined the daily food consumption by zoeae and the number of zoeal stages that are required to reach the final megalopa stage. Newly-hatched zoeae of C. sapidus were reared until megalopae in 24-well plates under high and low prey density with and without PHB supplementation (50 and 100 mg/l). Food consumption only was significantly different when a high density of Artemia, used as food, during later development. The zoeae raised under a high prey density had a shorter duration by having fewer zoeal stages and greater survival rate than those with a low prey density. PHB supplementation, with a combination of a high prey density, increased the incidences of stage skipping without changing the duration of zoeal development. Prey density, possibly affecting the nutritional status of larvae, is a critical factor that influences the zoeal development of C. sapidus. Copyright 2017 The Author.
    • Paradigms for Assessing Hedonic Processing and Motivation in Humans: Relevance to Understanding Negative Symptoms in Psychopathology

      Barch, D.M.; Gold, J.M.; Kring, A.M. (Oxford University Press, 2017)
      Clinicians and researchers have long known that one of the debilitating aspects of psychotic disorders is the presence of "negative symptoms," which involve impairments in hedonic and motivational function, and/or alterations in expressive affect. We have a number of excellent clinical tools available for assessing the presence and severity of negative symptoms. However, to better understand the mechanisms that may give rise to negative symptoms, we need tools and methods that can help distinguish among different potential contributing causes, as a means to develop more targeted intervention pathways. Using such paradigms is particularly important if we wish to understand whether the causes are the same or different across disorders that may share surface features of negative symptoms. This approach is in line with the goals of the Research Diagnostic Criteria Initiative, which advocates understanding the nature of core dimensions of brain-behavior relationships transdiagnostically. Here we highlight some of the emerging measures and paradigms that may help us to parse the nature and causes of negative symptoms, illustrating both the research approaches from which they emerge and the types of constructs that they can help elucidate. Copyright The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
    • FLT3 Inhibitors in acute myeloid leukemia: Current status & future directions

      Larrosa-Garcia, M.; Baer, M.R. (American Association for Cancer Research Inc., 2017)
      The receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy produces clinical responses, they are usually incomplete and transient, and resistance develops rapidly. Diverse combination therapies have been suggested to potentiate the efficacy of FLT3 inhibitors and to prevent development of resistance or overcome resistance. Combinations with epigenetic therapies, proteasome inhibitors, downstream kinase inhibitors, phosphatase activators, and other drugs that alter signaling are being explored. This review summarizes the current status of translational and clinical research on FLT3 inhibitors in AML, and discusses novel combination approaches.
    • The metabolic phenotype of prostate cancer

      Eidelman, E.; Twum-Ampofo, J.; Ansari, J. (Frontiers Media S.A., 2017)
      Prostate cancer is the most common non-cutaneous cancer in men in the United States. Cancer metabolism has emerged as a contemporary topic of great interest for improved mechanistic understanding of tumorigenesis. Prostate cancer is a disease model of great interest from a metabolic perspective. Prostatic tissue exhibits unique metabolic activity under baseline conditions. Benign prostate cells accumulate zinc, and this excess zinc inhibits citrate oxidation and metabolism within the citric acid cycle, effectively resulting in citrate production. Malignant cells, however, actively oxidize citrate and resume more typical citric acid cycle function. Of further interest, prostate cancer does not exhibit the Warburg effect, an increase in glucose uptake, seen in many other cancers. These cellular metabolic differences and others are of clinical interest as they present a variety of potential therapeutic targets. Furthermore, understanding of the metabolic profile differences between benign prostate versus low- and high-grade prostate cancers also represents an avenue to better understand cancer progression and potentially develop new diagnostic testing. In this paper, we review the current state of knowledge on the metabolic phenotypes of prostate cancer.
    • Patterns of Systemic Hypertension among Adults with Perinatally Acquired HIV

      Ryscavage, P.; Macharia, T.; Trinidad, L.R. (SAGE Publications Inc., 2017)
      Patients with perinatally acquired HIV may be at risk for the development of age-related non-AIDS diseases. The primary aim of this study was to describe patterns of systemic hypertension among a cohort of adults (≥18 years) with perinatally acquired HIV. A retrospective cohort study was conducted among adults (≥18 years) with perinatally acquired HIV infection. Primary outcomes included documentation of systemic hypertension as well as several additional non-AIDS-associated illnesses. Systemic hypertension incidence rates and rate ratios (RRs) were calculated among groups aged ≥18 and <18 years at the time of hypertension diagnosis. The overall prevalence of hypertension in the cohort (N = 109) was 26.6%, and the incidence rate of hypertension was significantly higher among those aged ≥18 years compared to those who are aged <18 years at the time of diagnosis (RR: 10.0, CI: 7.29-13.71). By multivariable analysis, only coexisting renal disease was associated with an increased risk of hypertension diagnosis. Copyright The Author(s) 2016.
    • Family Medical History

      Bontempo, L.J. (Blackwell Publishing Inc., 2017)
    • Devices for preventing percutaneous exposure injuries caused by needles in healthcare personnel

      Reddy, V.K.; Lavoie, M.-C.; Verbeek, J.H. (John Wiley and Sons Ltd, 2017)
      Background: Percutaneous exposure injuries from devices used for blood collection or for injections expose healthcare workers to the risk of blood borne infections such as hepatitis B and C, and human immunodeficiency virus (HIV). Safety features such as shields or retractable needles can possibly contribute to the prevention of these injuries and it is important to evaluate their effectiveness. Objectives: To determine the benefits and harms of safety medical devices aiming to prevent percutaneous exposure injuries caused by needles in healthcare personnel versus no intervention or alternative interventions. Search methods: We searched CENTRAL, MEDLINE, EMBASE, NHSEED, Science Citation Index Expanded, CINAHL, Nioshtic, CISdoc and PsycINFO (until 11 November 2016). Selection criteria: We included randomised controlled trials (RCT), controlled before and after studies (CBA) and interrupted time-series (ITS) designs of the effect of safety engineered medical devices on percutaneous exposure injuries in healthcare staff. Data collection and analysis: Two of the authors independently assessed study eligibility and risk of bias and extracted data. We synthesized study results with a fixed-effect or random-effects model meta-analysis where appropriate. Main results: We included six RCTs with 1838 participants, two cluster-RCTs with 795 participants and 73,454 patient days, five CBAs with approximately 22,000 participants and eleven ITS with an average of 13.8 data points. These studies evaluated safe modifications of blood collection systems, intravenous (IV) systems, injection systems, multiple devices, sharps containers and legislation on the implementation of safe devices. We estimated the needlestick injury (NSI) rate in the control groups to be about one to five NSIs per 1000 person-years. There were only two studies from low- or middle-income countries. The risk of bias was high in 20 of 24 studies. Safe blood collection systems: We found one RCT that found a safety engineered blood gas syringe having no considerable effect on NSIs (Relative Risk (RR) 0.2, 95% Confidence Interval (95% CI) 0.01 to 4.14, 550 patients, very low quality evidence). In one ITS study, safe blood collection systems decreased NSIs immediately after the introduction (effect size (ES) -6.9, 95% CI -9.5 to -4.2) but there was no further decrease over time (ES -1.2, 95% CI -2.5 to 0.1, very low quality evidence). Another ITS study evaluated an outdated recapping shield, which we did not consider further. Safe Intravenous systems There was very low quality evidence in two ITS studies that NSIs were reduced with the introduction of safe IV devices, whereas one RCT and one CBA study provided very low quality evidence of no effect. However, there was moderate quality evidence produced by four other RCT studies that these devices increased the number of blood splashes when the safety system had to be engaged actively (relative risk (RR) 1.6, 95% CI 1.08 to 2.36). In contrast there was low quality evidence produced by two RCTs of passive systems that showed no effect on blood splashes. Yet another RCT produced low quality evidence that a different safe active IV system also decreased the incidence of blood leakages. Safe injection devices There was very low quality evidence provided by one RCT and one CBA study showing that introduction of safe injection devices did not considerably change the NSI rate. One ITS study produced low quality evidence showing that the introduction of safe passive injection systems had no effect on NSI rate when compared to safe active injection systems. Multiple safe devices There was very low quality evidence from one CBA study and two ITS studies. According to the CBA study, the introduction of multiple safe devices resulted in a decrease in NSI,whereas the two ITS studies found no change. Safety containers One CBA study produced very low quality evidence showing that the introduction of safety containers decreased NSI. However, two ITS studies evaluating the same intervention found inconsistent results. Legislation There was low to moderate quality evidence in two ITS studies that introduction of legislation on the use of safety-engineered devices reduced the rate of NSIs among healthcare workers. There was also low quality evidence which showed a decrease in the trend over time for NSI rates. Twenty out of 24 studies had a high risk of bias and the lack of evidence of a beneficial effect could be due to both confounding and bias. This does not mean that these devices are not effective. Authors' conclusions: For safe blood collection systems, we found very low quality evidence of inconsistent effects on NSIs. For safe passive intravenous systems, we found very low quality evidence of a decrease in NSI and a reduction in the incidence of blood leakage events but moderate quality evidence that active systems may increase exposure to blood. For safe injection needles, the introduction of multiple safety devices or the introduction of sharps containers the evidence was inconsistent or there was no clear evidence of a benefit. There was low to moderate quality evidence that introduction of legislation probably reduces NSI rates. More high-quality cluster-randomised controlled studies that include cost-effectiveness measures are needed, especially in countries where both NSIs and blood-borne infections are highly prevalent.
    • Effects of long-term water-aging on novel anti-biofilm and protein-repellent dental composite

      Zhang, N.; Zhang, K.; Melo, M.A.S. (MDPI AG, 2017)
      The aims of this study were to: (1) synthesize an anti-biofilm and protein-repellet dental composite by combining 2-methacryloyloxyethyl phosphorylcholine (MPC) with quaternary ammonium dimethylaminohexadecyl methacrylate (DMAHDM); and (2) evaluate the effects of water-aging for 180 days on protein resistance, bacteria-killing ability, and mechanical properties of MPC-DMAHDM composite. MPC and DMAHDM were added into a resin composite. Specimens were stored in distilled water at 37 °C for 1, 30, 90, and 180 days. Mechanical properties were measured in three-point flexure. Protein attachment onto the composite was evaluated by a micro bicinchoninic acid approach. An oral plaque microcosm biofilm model was employed to evaluate oral biofilm viability vs. water-aging time. Mechanical properties of the MPC-DMAHDM composite after 180-day immersion matched those of the commercial control composite. The composite with 3% MPC + 1.5% DMAHDM had much stronger resistance to protein adhesion than control (p < 0.05). MPC + DMAHDM achieved much stronger biofilm-eradicating effects than MPC or DMAHDM alone (p < 0.05). Biofilm colony-forming units on the 3% MPC + 1.5% DMAHDM composite were three orders of magnitude lower than commercial control. The protein-repellent and antibacterial effects were durable and showed no loss in water-aging from 1 to 180 days. The novel MPC-DMAHDM composite possessed strong and durable resistance to protein adhesion and potent bacteria-eradicating function, while matching the load-bearing ability of a commercial dental composite. The novel MPC-DMAHDM composite represents a promising means of suppressing oral plaque growth, acid production, and secondary caries. Copyright 2017 by the authors; licensee MDPI, Basel, Switzerland.
    • Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity

      Ono-Moore, K.D.; Zhao, L.; Huang, S. (Wiley-Blackwell, 2017)
      Introduction: Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenousmolecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)- induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance. Methods: We generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance. Results: TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet. Conclusions: Together, these results suggest that constitutively active TLR4- induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation. Copyright 2017 The Authors.
    • Unabated occupational risk in a patient with rheumatoid pulmonary fibrosis

      Holden, V.K.; Kligerman, S.J.; Hastings, T.G. (Oxford University Press, 2017)
      Background This case highlights the importance of considering hypersensitivity pneumonitis (HP) in the differential diagnosis of interstitial lung disease (ILD) and of obtaining an occupational history so that remediable risk factors may be identified and managed. Aims To report a case of a chicken sexer with severe rheumatoid arthritis (RA) who developed progressively worsening dyspnoea and restrictive lung disease associated with pulmonary fibrosis. Methods Clinical investigation included physical examination, occupational history, pulmonary function tests (PFTs), chest imaging and bronchoalveolar lavage (BAL), as well as serological tests including standard IgE bird feather mixture and local IgG precipitin preparation to chicken excrement. Lung histopathology was examined post-mortem. Results The patient had worked as a chicken sexer for 29 years with limited control of exposure to chicken bioaerosols. PFTs initially showed mild restriction with a moderate gas transfer defect and computerized tomography of the chest exhibited extensive interstitial infiltrates throughout with severe honeycombing at the bases. Cytology from a BAL revealed multinucleated giant cells (MNGs). Specific serologic tests for bird antigens were negative. Histopathology demonstrated diffuse interstitial fibrosis with honeycombing, poorly formed granulomas and MNGs. Conclusions Findings were consistent with a diagnosis of HP with RA-associated ILD. The patient's history of severe RA biased the diagnosis to one of RA-associated ILD and her occupational risk had been less emphatically addressed. Obtaining a thorough occupational history can uncover exposures to workplace respiratory hazards and may create opportunities for intervention to limit morbidity from chronic lung disease. Copyright The Author 2017.
    • Subplate neurons are the first cortical neurons to respond to sensory stimuli

      Wess, J.M.; Isaiah, A.; Watkins, P.V. (National Academy of Sciences, 2017)
      In utero experience, such as maternal speech in humans, can shape later perception, although the underlying cortical substrate is unknown. In adult mammals, ascending thalamocortical projections target layer 4, and the onset of sensory responses in the cortex is thought to be dependent on the onset of thalamocortical transmission to layer 4 as well as the ear and eye opening. In developing animals, thalamic fibers do not target layer 4 but instead target subplate neurons deep in the developing white matter. We investigated if subplate neurons respond to sensory stimuli. Using electrophysiological recordings in young ferrets, we show that auditory cortex neurons respond to sound at very young ages, even before the opening of the ears. Single unit recordings showed that auditory responses emerged first in cortical subplate neurons. Subsequently, responses appeared in the future thalamocortical input layer 4, and sound-evoked spike latencies were longer in layer 4 than in subplate, consistent with the known relay of thalamic information to layer 4 by subplate neurons. Electrode array recordings show that early auditory responses demonstrate a nascent topographic organization, suggesting that topographic maps emerge before the onset of spiking responses in layer 4. Together our results show that sound-evoked activity and topographic organization of the cortex emerge earlier and in a different layer than previously thought. Thus, early sound experience can activate and potentially sculpt subplate circuits before permanent thalamocortical circuits to layer 4 are present, and disruption of this early sensory activity could be utilized for early diagnosis of developmental disorders.
    • Review of breast screening: Toward clinical realization of microwave imaging

      Modiri, A.; Goudreau, S.; Rahimi, A. (John Wiley and Sons Ltd., 2017)
      Microwave imaging (MI) technology has come a long way to introduce a noninvasive, inexpensive, fast, convenient, and safe screening tool for clinical breast monitoring. However, there is a niche between the existing understanding of MI by engineers versus clinicians. Our manuscript targets that niche and highlights the state of the art in MI technology compared to the existing breast cancer detection modalities (mammography, ultrasound, molecular imaging, and magnetic resonance). The significance of our review article is in consolidation of up-to-date breast clinician views with the practical needs and engineering challenges of a novel breast screening modality. We summarize breast tissue abnormalities and highlight the benefits as well as potential drawbacks of the MI as a cancer detection methodology. Our goal is to present an article that MI researchers as well as practitioners in the field can use to assess the viability of the MI technology as a competing or complementary modality to the existing means of breast cancer screening.
    • A percutaneous strategy for safe femoral venoarterial extracorporeal life support

      Pasrija, C.; Mazzeffi, M.A.; Kon, Z.N. (Mosby Inc., 2017)
    • Commentary on symptom management of the patient with CKD: The role of dialysis

      Kestenbaum, B.; Seliger, S.L. (American Society of Nephrology, 2017)
    • Obesity and Survival With Heart Failure: Still a Paradox

      deFilippi, C.R.; Seliger, S.L. (Elsevier Inc., 2017)
    • Ventricular Tachycardia Ablation in the Elderly: An International Ventricular Tachycardia Center Collaborative Group Analysis

      Vakil, K.; Garcia, S.; Tung, R. (Lippincott Williams and Wilkins, 2017)
      Background: Successful ventricular tachycardia (VT) ablation is associated with improved survival in patients with heart failure. However, the safety and efficacy of VT ablation in the elderly, a population with higher competing nonsudden death risk and comorbidities, have not been well defined. Methods and Results: The International Ventricular Tachycardia Center Collaborative Study Group registry of 2061 patients who underwent VT ablation at 12 international centers was analyzed. Kaplan–Meier analysis was used to estimate survival of patients ≥70 years with and without VT recurrence. Of the 2049 patients who met inclusion criteria, 681 (33%) patients were ≥70 years of age (mean age, 75±4 years). Among these, 92% were men, 71% had ischemic VT, and 42% had VT storm at presentation. Mean (±SD) left ventricular ejection fraction was 30±11%. Compared with patients <70 years, patients ≥70 years had higher in-hospital (4.4% versus 2.3%; P=0.01) and 1-year mortality (15% versus 11%; P=0.002) but a similar incidence of VT recurrence at 1 year (26% versus 25%; P=0.74) and time to VT recurrence (280 versus 289 days; P=0.20). Absence of VT recurrence during follow-up was strongly associated with improved survival in patients ≥70 years. Conclusion: VT ablation in the elderly is feasible and reasonably safe with a modestly higher in-hospital and 1-year mortality, with similar rates of VT recurrence at 1 year compared with younger patients. Successful VT ablation, that is, lack of VT recurrence, is strongly associated with improved survival even in this elderly subgroup. Copyright 2017 American Heart Association, Inc.
    • Electrophysiological evidence for hyperfocusing of spatial attention in schizophrenia

      Kreither, J.; Lopez-Calderon, J.; Leonard, C.J. (Society for Neuroscience, 2017)
      A recently proposed hyperfocusing hypothesis of cognitive dysfunction in schizophrenia proposes that people with schizophrenia (PSZ) tend to concentrate processing resources more narrowly but more intensely than healthy control subjects (HCS). The present study tests a key prediction of this hypothesis, namely, that PSZ will hyperfocus on information presented at the center of gaze. This should lead to greater filtering of peripheral stimuli when the task requires focusing centrally but reduced filtering of central stimuli when the task requires attending broadly in the periphery. These predictions were tested in a double oddball paradigm, in which frequent standard stimuli and rare oddball stimuli were presented at central and peripheral locations while event-related potentials were recorded. Participants were instructed to discriminate between the standard and oddball stimuli at either the central location or at the peripheral locations. PSZ and HCS showed opposite patterns of spatial bias at the level of early sensory processing, as assessed with the P1 component: PSZ exhibited stronger sensory suppression of peripheral stimuli when the task required attending narrowly to the central location, whereas HCS exhibited stronger sensory suppression of central stimuli when the task required attending broadly to the peripheral locations. Moreover, PSZ exhibited a stronger stimulus categorization response than HCS, as assessed with the P3b component, for central stimuli when the task required attending to the peripheral region. These results provide strong evidence of hyperfocusing in PSZ, which may provide a unified mechanistic account of multiple aspects of cognitive dysfunction in schizophrenia. Copyright 2017 the authors.
    • Presence of ethanol-sensitive glycine receptors in medium spiny neurons in the mouse nucleus accumbens

      Forstera, B.; Munoz, B.; Lobo, M.K. (Blackwell Publishing Ltd, 2017)
      Alcohol abuse causes major social, economic and health‐related problems worldwide. Alcohol, like other drugs of abuse, increases levels of dopamine in the nucleus accumbens (nAc), facilitating behavioural reinforcement and substance abuse. Previous studies suggested that glycine receptors (GlyRs) are involved in the regulation of accumbal dopamine levels. Here, we investigated the presence of GlyRs in accumbal dopamine receptor medium spiny neurons (MSNs) of C57BL/6J mice, analysing mRNA expression levels and immunoreactivity of GlyR subunits, as well as ethanol sensitivity. We found that GlyR α1 subunits are expressed at higher levels than α2, α3 and β in the mouse nAc and were located preferentially in dopamine receptor 1 (DRD1)‐positive MSNs. Interestingly, the glycine‐evoked currents in dissociated DRD1‐positive MSNs were potentiated by ethanol. Also, the potentiation of the GlyR‐mediated tonic current by ethanol suggests that they modulate the excitability of DRD1‐positive MSNs in nAc. This study should contribute to understanding the role of GlyR α1 in the reward system and might help to develop novel pharmacological therapies to treat alcoholism and other addiction‐related and compulsive behaviours. Copyright 2017 The Authors. The Journal of Physiology Copyright 2017 The Physiological Society
    • Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

      Nagode, D.A.; Meng, X.; Winkowski, D.E. (Elsevier B.V., 2017)
      Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as “patches” of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD. Copyright 2017 The Author(s)