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We sought to characterize the unique role of somatostatin (SST) in the prelimbic (PL) cortex in mice. We performed slice electrophysiology in pyramidal and GABAergic neurons to characterize the pharmacological mechanism of SST signaling and fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We used local delivery of a broad SST receptor (SSTR) agonist and antagonist to test causal effects of SST signaling. SSTR activation hyperpolarizes layer 2/3 pyramidal neurons, an effect that is recapitulated with optogenetic stimulation of SST neurons. SST neurons in PL are activated during EPM and OFT exploration, and SSTR agonist administration directly into the PL enhances open arm exploration in the EPM. This work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.

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BACKGROUND: Up to 40% of patients suffering from anxiety disorders do not benefit from currently available pharmacological treatments. Overactivity of the orexin-1 receptor (OX1R) has been implicated in anxiety- and panic-related states. AIM & METHODS: We investigated the pharmacokinetics and characterized the pharmacodynamic (PD) profile of the OX1R antagonist JNJ-61393215 using a battery of central nervous system assessments investigating relevant functional domains such as alertness, attention, (visuo)motor coordination, balance, subjective effects and resting-state electroencephalography in a single ascending dose placebo-controlled study in doses from 1 to 90 mg inclusive, assessing PD up to 10 h after dosing, safety and pharmacokinetic in 48 healthy male subjects. RESULTS: Average time to maximal plasma concentration (Tmax) ranged between 1.0 and 2.25 h; average half-life ranged from 13.6 to 24.6 h and average maximum plasma concentration ranged from 1.4 to 136.8 ng/mL in the 1 and 90 mg groups, respectively. JNJ-61393215 did not demonstrate any statistically significant or clinically meaningful effects on any PD endpoint at any dose investigated at Tmax nor over the total period up to 10 h post-dose and was well tolerated. The reported somnolence rate was 16.7% (which was attributable to the cohorts receiving 6 mg and higher doses) compared to 12.5% in placebo. CONCLUSION: This observation is in line with our knowledge about the OX1R in preclinical studies, where only inconsistent and non-dose-dependent changes in electroencephalography or other behavioural measures were observed under non-challenged conditions, potentially exemplifying the need for a challenged subject.

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Alcohol use disorder (AUD) is characterized by alcohol use coupled with chronic relapse and involves brain regions including the bed nucleus of the stria terminalis (BNST). Here, we explore whether a subpopulation of BNST neurons, somatostatin (SST) expressing GABAergic neurons, play a role in an animal model of binge-like alcohol consumption, the Drinking in the Dark (DID) model. Chemogenetic activation of BNST SST neurons reduced binge alcohol consumption in female but not male SST-Cre mice, while inhibition of these neurons in the same mice had no effect. In addition, chemogenetic activation of these neurons did not cause apparent changes in models of anxiety-like behavior in either sex. Basal SST cell counts and intrinsic excitability of SST neurons were compared to attempt to understand sex differences in DREADD-induced changes in drinking, and while males had a greater number of BNST SST neurons, this effect went away when normalizing for total BNST volume. Together, these results suggest SST neurons in the BNST should be further explored as a potential neuronal subtype modulated by AUD, and for their therapeutic potential.

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Blunt cerebrovascular injury is a very rare complication of blunt trauma and a diagnostic challenge. A 14 year old male fell 10 m sustaining multi system trauma. The atypical Glasgow Coma Score was six with a fully preserved eye component. Initial whole-body CT scanning demonstrated multiple injuries but no obvious brain injury. Trauma management involved non-operative resuscitation and was successful, however profound coma occurred and brain stem reflexes disappeared on day two. Repeat brain CT scan demonstrated multiple cerebral and cerebellar ischemic lesions and no opacification of the vertebral or basilar arteries. Secondary analysis of the first CT scan demonstrated a small focal basilar artery dissection not initially reported. Our case report highlights an unusual cause of coma after traumatic brain injury where the clinical scenario mimics locked in syndrome. In such circumstances cerebrovascular injury, and in particular traumatic basilar artery dissection, must be actively excluded.

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Forced abstinence (FA) from alcohol has been shown to produce a variety of anxiety- and depression-like symptoms in animal models. Somatostatin (SST) neurons, a subtype of GABAergic neurons found throughout the brain, are a novel neural target with potential treatment implications in affective disorders, yet their role in alcohol use disorders (AUD) remains to be explored. Here, we examined the neuroadaptations of SST neurons during forced abstinence from voluntary alcohol consumption. Following 6 weeks of two-bottle choice alcohol consumption and protracted forced abstinence, male and female C57BL/6J mice exhibited a heightened, but sex-specific, depressive-like behavioral profile in the sucrose preference test (SPT) and forced swim test (FST), without changes in anxiety-like behaviors in the elevated plus maze (EPM) and open field test (OFT). FST-induced cFos expressions in the prefrontal cortex (PFC) and ventral bed nucleus of the stria terminalis (vBNST) were altered in FA-exposed female mice only, suggesting a sex-specific effect of forced abstinence on the neural response to acute stress. SST immunoreactivity in these regions was unaffected by forced abstinence, while differences were seen in SST/cFos co-expression in the vBNST. No differences in cFos or SST immunoreactivity were seen in the lateral central nucleus of the amygdala (CEA) and the basolateral amygdala (BLA). Additionally, SST neurons in female mice displayed opposing alterations in the PFC and vBNST, with heightened intrinsic excitability in the PFC and diminished intrinsic excitability in the vBNST. These findings provide an overall framework of forced abstinence-induced neuroadaptations in these key brain regions involved in emotional regulation and processing.

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BACKGROUND: Patients with recurrent oropharyngeal cancer often require extensive salvage surgery. For patients with clinically N0 necks, the indication for concurrent neck dissection remains unclear. This study aimed to determine predictors, prevalence, and distribution of nodal disease in patients treated with salvage oropharyngectomy. METHODS: In a case series with data collection at a single tertiary academic National Cancer Institute (NCI)-designated comprehensive cancer center, this study analyzed patients treated with prior radiation or chemoradiation who had persistent, recurrent, or second primary squamous cell carcinoma of the oropharynx requiring oropharyngeal resection between 1998 and 2017 (n = 95). Clinical and oncologic characteristics and treatment outcomes were collected, and statistical analyses were performed. RESULTS: The overall rate of nodal positivity was 21% (24/95), and the rate of occult nodal disease was 6% (4/65). Ipsilateral and contralateral level 2 were the most common areas harboring positive nodes. Bivariate analysis showed female sex (p = 0.01), initial overall stage (p = 0.02), and N status (p = 0.03), as well as recurrent overall and T stage (p = 0.05) to be predictors of nodal disease. In the multivariate analysis, recurrent T stage continued to be significantly predictive of pathologic nodal disease. Both computed tomography (CT) and positron emission tomography-CT were moderately accurate in predicting nodal disease in the salvage setting (area under the curve, 0.79 and 0.80, respectively). CONCLUSION: Occult nodal disease is observed in few patients undergoing salvage oropharyngeal resection. This study identified factors predictive of nodal disease in patients undergoing salvage oropharyngectomy and appropriate diagnostic tests in this setting.

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BACKGROUND: The significance of cardiac troponin I (cTnI) elevation after trauma is debated. We therefore explored the association between cTnI elevation at admission after trauma and ICU mortality. METHODS: We performed a retrospective analysis from a prospectively constituted database, of patients admitted to ICU after trauma at a single centre, over a 36 month period. According to cTnI plasma concentration at admission, patients were categorised into three groups: normal (<0.05 ng ml-1), intermediate (0.05-0.99 ng ml-1), or high concentration (≥1.0 ng ml-1). Associations of pre-hospital conditions or cTnI elevation and mortality were analysed by multivariate logistic regression. RESULTS: Among the 994 patients, 177 (18%) had cTnI elevation at ICU admission. Of this total, 114 (11%) patients died in the ICU. The cTnI release was an independent predictor of ICU mortality with a concentration-response relationship [odds ratio (OR) 4.90 (2.19-11.16) and 14.83 (4.68-49.90) for intermediate and high concentrations, respectively] and Day 2 mortality [OR 2.23 (1.18-5.80) and 7.49 (2.77-20.12) for intermediate and high concentrations, respectively]. The severity of thoracic trauma [OR 2.25 (1.07-4.55) and 3.23 (2.00-5.27) for Abbreviated Injury Scale scores 1-2 and ≥3, respectively], out-of-hospital maximal heart rate ≥120 beats min-1 [OR 2.22 (1.32-3.69)], and out-of-hospital shock [OR 2.02 (1.20-3.38)] were independently associated with cTnI elevation. CONCLUSIONS: Release of cTnI was an independent predictor of ICU mortality, suggesting that this biomarker can be used in daily practice for early stratification of the risk of ICU death. Thoracic trauma was strongly associated with cTnI elevation.

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Given the serious nature of suicidal ideation and behavior (SIB) and the possibility of treatment-emergent SIB, pharmaceutical companies are now applying more proactive approaches in clinical trials and are considering the value of nonclinical models to predict SIB. The current review summarizes nonclinical approaches to modeling three common risk factors associated with SIB: aggression, impulsivity, and anhedonia. For each risk factor, a general description, advantages and disadvantages, species considerations, nonclinical to clinical translation, and pharmacological validation with respect to treatments associated with SIB are summarized. From this review, several gaps were identified that need to be addressed before use of these nonclinical models can be considered a viable option to predict the relative risk for SIB. Other future directions that may compliment these nonclinical approaches, including the use of selectively-bred or genetically-modified rodent models, transgenic models, gene expression profiling, and biomarker analysis, are discussed. This article was developed with the support of the DruSafe Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org).

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BACKGROUND: Medical and educational partnerships between high- and low-resourced countries provide opportunities to have a long-term meaningful impact on medical training and healthcare delivery. METHODS: An otolaryngology partnership between Komfo Anokye Teaching Hospital in Kumasi, Ghana, and the University of Michigan Department of Otolaryngology/Head and Neck Surgery has been undertaken to enhance healthcare delivery at both institutions. RESULTS: A temporal bone dissection laboratory, with the equipment to perform dedicated otological surgery, and academic platforms for clinical and medical education and residency training have been established. CONCLUSION: This article describes the details of this partnership in otological surgery and hearing health, with an emphasis on creating in-country surgical simulation, training on newly acquired medical equipment and planning regarding the formulation of objectified metrics to gauge progress going forward.

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BACKGROUND: We reviewed our experience with tracheal extubation in the operating room (E-OR) among cystic fibrosis patients requiring bilateral lung transplantation to evaluate safety and determine predictive factors of E-OR. METHODS: The charts of 89 recipients (from May 2007 to June 2013) were analysed. Patients were divided into E-OR and E-ICU (intensive care unit extubation) groups. Data are expressed as numbers (percentages) or medians [25th-75th percentiles]. RESULTS: There were 41 patients in the E-OR group (46%). Donor and recipient characteristics were similar between groups. Intraoperative complications occurred less frequently in the E-OR group, and fluid and transfusion requirements were lower. Postoperative courses were different in the E-OR group, including a lower rate of grade 3 primary graft dysfunction (0 compared with 19 patients, P<0.0001) and shorter ICU (5.0 [3.7-7.2] compared with 11.5 [7.0-15.5] days) and hospital stays (22.0 [18.0-25.5] compared with 33.0 [25.0-56.5] days, respectively; P<0.0001 for both). The 1 yr survival rates were similar: 95% in the E-OR group and 98% in the E-ICU group. A statistical model built on a development cohort of 60 randomly selected patients predicted 95% of E-OR instances in this cohort and 82% of E-OR instances in the validation cohort (28 patients). Predictive factors were complications during single-lung ventilation (second graft implantation), complications during bipulmonary ventilation (end of surgery), and the ratio of arterial partial pressure of oxygen to fractional inspired oxygen (end of surgery). CONCLUSIONS: Our protocol allowed for extubation of 46% of bilateral lung transplant patients without increased postoperative risks.

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The development path described for JNJ-26489112 provides perspectives on interpretation of retinal effects observed in nonclinical studies and their implications for clinical development. JNJ-26489112 is a CNS-active investigational drug that has potential as a novel treatment for treatment-resistant and bipolar depression, epilepsy, and neuropathic/inflammatory pain. In a 6-month toxicity study in albino rats, retinal atrophy was observed at supratherapeutic exposures to JNJ-26489112. The histopathological changes and topography of the lesions were characteristic of light-induced damage specific to albino rats. The species/strain specificity is supported by an absence of any ocular effects in dogs and in pigmented and albino rats, housed under standard and reduced lighting, respectively. To further evaluate its potential to cause ocular effects, in vivo functional and structural ocular analyses were included in a 9-month monkey toxicity study. Reductions in rod- and cone-mediated electroretinograms were observed at supratherapeutic exposures but without any histopathologic changes. These data suggested that the effects of JNJ-26489112 in monkeys were neuromodulatory and not neurotoxic. Taken together, data related to the light-induced atrophy in albino rats and reversible neuromodulatory effects in monkeys, supported the safe evaluation of JNJ-26489112 in a clinical proof-of-concept study that included comprehensive functional and structural ocular monitoring.

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We have combined hard X-ray photoelectron spectroscopy with angular dependent O K-edge and V L-edge X-ray absorption spectroscopy to study the electronic structure of metallic and insulating end point phases in 4.1 nm thick (14 units cells along the c-axis of VO2) films on TiO2(001) substrates, each displaying an abrupt MIT centered at ~300 K with width <20 K and a resistance change of ΔR/R > 10(3). The dimensions, quality of the films, and stoichiometry were confirmed by a combination of scanning transmission electron microscopy with electron energy loss spectroscopy, X-ray spectroscopy, and resistivity measurements. The measured end point phases agree with their bulk counterparts. This clearly shows that, apart from the strain induced change in transition temperature, the underlying mechanism of the MIT for technologically relevant dimensions must be the same as the bulk for this orientation.

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Evaluating sweetpotato (Ipomoea batatas) genotypes for resistance to sweetpotato virus disease (SPVD) has been slow and inefficient. Ipomoea setosa plants, normally used as the source of scions for graft-infecting sweetpotatoes with viral diseases, are often severely stunted and their mortality is 10 to 30% when infected with SPVD, making them unsuitable as scions. Tanzania, a landrace of I. batatas widely grown in East Africa, was found to be a superior host for maintaining and increasing SPVD inoculum (scions) for mass grafting. Modifications to a cleft-grafting technique also increased survival of grafted SPVD-affected scions from 5 to 100%. These modifications, coupled with an efficient SPVD scoring technique, allowed rapid screening of large sweetpotato populations for SPVD resistance. Plant recovery from SPVD is reported here as a component of SPVD resistance. Differences in recovery from SPVD were detected among progenies, indicating its genetic basis. Plant tip dieback, a hypersensitivity response, was observed only in families with cv. Wagabolige as a parent. These findings may open up new opportunities for improved understanding and control of this devastating disease.

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We describe the design and operation of a modified commercial rheometer to simultaneously perform rheological measurements and structural studies by small angle neutron scattering (SANS). The apparatus uses a Couette geometry shear cell allowing two of the three scattering planes to be observed by performing experiments in either the radial or tangential geometries. The device enables small angle neutron scattering patterns to be obtained simultaneously with a wide variety of rheological measurements such as stress/strain flow curves, oscillatory deformations, and creep, recovery and relaxation tests, from -20 °C to 150 °C, for samples with viscosities varying by several orders of magnitude. We give a brief report of recent experiments performed on a dispersion of acicular nanoparticles and biopolymer network under stress demonstrating the utility of such measurements. This device has been developed at the National Institute of Standards and Technology's Center for Neutron Research (NCNR) and made available to the complex fluids community as part of the standard sample environment equipment.

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Exploring the genetic diversity and evolutionary history of plant viruses is critical to understanding their ecology and epidemiology. In this study, maximum-likelihood and population genetics-based methods were used to investigate the population structure, genetic diversity, and sources of genetic variation in field isolates of Tomato spotted wilt virus (TSWV) from peanut in North Carolina and Virginia. Selected regions of the nucleocapsid, movement, and RNA-dependent RNA polymerase genes were amplified and sequenced to identify haplotypes and infer genetic relationships between isolates of TSWV with heuristic methods. The haplotype structure of each locus consisted of 1 or 2 predominant haplotypes and >100 haplotypes represented by a single isolate. No specific haplotypes were associated with geographic area, peanut cultivar, or year of isolation. The population was panmictic at the regional level and high levels of genetic diversity were observed among isolates. There was evidence for positive selection on single amino acids in each gene on a background of predominant purifying selection acting upon each locus. The results of compatibility analyses and the persistence of specific gene sequences in isolates collected over three field seasons suggest that recombination was occurring in the population. Estimates of the population mutation rate suggest that mutation has had a significant effect on the shaping of this population and, together with purifying selection, these forces have been the predominant evolutionary forces influencing the TSWV population in peanut in North Carolina and Virginia.

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BACKGROUND AND PURPOSE: Head and neck cancer can cause substantial morbidity and mortality. Our aim was to evaluate the potential usefulness of a computerized system for segmenting lesions in head and neck CT scans and for estimation of volume change of head and neck malignant tumors in response to treatment. MATERIALS AND METHODS: CT scans from a pretreatment examination and a post 1-cycle chemotherapy examination of 34 patients with 34 head and neck primary-site cancers were collected. The computerized system was developed in our laboratory. It performs 3D segmentation on the basis of a level-set model and uses as input an approximate bounding box for the lesion of interest. The 34 tumors included tongue, tonsil, vallecula, supraglottic, epiglottic, and hard palate carcinomas. As a reference standard, 1 radiologist outlined full 3D contours for each of the 34 primary tumors for both the pre- and posttreatment scans and a second radiologist verified the contours. RESULTS: The correlation between the automatic and manual estimates for both the pre- to post-treatment volume change and the percentage volume change for the 34 primary-site tumors was 0.95, with an average error of -2.4 ± 8.5% by automatic segmentation. There was no substantial difference and specific trend in the automatic segmentation accuracy for the different types of primary head and neck tumors, indicating that the computerized segmentation performs relatively robustly for this application. CONCLUSIONS: The tumor size change in response to treatment can be accurately estimated by the computerized segmentation system relative to radiologists' manual estimations for different types of head and neck tumors.

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One hundred fifty-three isolates of Phytophthora nicotianae that were collected over a 4-year period from a single field were subjected to amplified fragment length polymorphism (AFLP) analysis to investigate the effect of different types of resistance in tobacco (Nicotiana tabacum) on genetic diversity in the pathogen population. No race 1 isolates were detected in the field prior to initiating the study, but the race was present in multiple plots by the end of the 4-year period. There were 102 race 0 isolates and 51 race 1 isolates characterized. Seventy-six of the 153 isolates had a unique AFLP profile, whereas the remaining 77 isolates were represented by 27 AFLP profiles shared by at least two isolates. Isolates of both races were found in both the unique and shared AFLP profile groups. Twenty-three of the AFLP profiles were detected in multiple years, indicating a clonal component to the pathogen population. Race 1 isolates that were detected over multiple years were always obtained from the same plot. No race 1 profile was found in more than one plot, confirming the hypothesis that the multiple occurrences of the race throughout the field were the result of independent events and not pathogen spread. Three identical race 0 AFLP profiles occurred in noncontiguous plots, and in each case, the plots contained the same partially resistant variety. Cluster analysis provided a high level of bootstrap support for 41 isolates in 19 clusters that grouped primarily by race and rotation treatment. Estimates of genetic diversity ranged from 0.365 to 0.831 and varied depending on tobacco cultivar planted and race. When averaged over all treatments, diversity in race 1 isolates was lower than in race 0 isolates at the end of each season. Deployment of single-gene resistance initially decreased genetic diversity of the population, but the diversity increased each year, indicating the pathogen was adapting to the host genotypes deployed in the field.

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The human basal ganglia, and in particular the subthalamic nucleus (STN), can oscillate at surprisingly high frequencies, around 300 Hz [G. Foffani, A. Priori, M. Egidi, P. Rampini, F. Tamma, E. Caputo, K.A. Moxon, S. Cerutti, S. Barbieri, 300-Hz subthalamic oscillations in Parkinson's disease, Brain 126 (2003) 2153-2163]. It has been proposed that these oscillations could contribute to the mechanisms of action of deep brain stimulation (DBS) [G. Foffani, A. Priori, Deep brain stimulation in Parkinson's disease can mimic the 300 Hz subthalamic rhythm, Brain 129 (2006) E59]. However, the physiological role of high-frequency STN oscillations is questionable, because they have been observed only in patients with advanced Parkinson's disease and could therefore be secondary to the dopamine-depleted parkinsonian state. Here, we report high-frequency STN oscillations in the range of the 300-Hz rhythm during intraoperative microrecordings for DBS in an awake patient with focal dystonia as well as in a patient with essential tremor (ET). High-frequency STN oscillations are therefore not exclusively related to parkinsonian pathophysiology, but may represent a broader feature of human STN function.

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Sweet potato chlorotic stunt virus (SPCSV) is the whitefly-transmitted component of the sweet potato virus disease (SPVD), a devastating disease originally described in Africa (4). Two isolates designated as G-01 and T-03 were obtained in North Carolina in July 2001 and October 2003, respectively, from plants of cv. Beauregard exhibiting symptoms typical of SPVD, including stunting, leaf narrowing and distortion, vein clearing, and chlorotic mosaic. Sap extract from symptomatic plants tested positive for SPCSV by nitrocellulose immuno-dot blot, using monoclonal antibodies specific for SPCSV obtained from the International Potato Center. Total RNA was extracted from 100 mg of symptomatic leaf tissue by using the PureLink Total RNA Purification System Kit from Invitrogen (Carlsbad, CA) with a minor modification (adding 2% PVP-40 and 1% 2-mercaptoethanol to the extraction buffer) (1). Results were confirmed by reverse transcription (RT)-PCR using primers CP1 and CP3 and HSP70-A/HSP70-B (2), corresponding to the capsid protein and 'heat shock' protein genes, respectively. HSP70 amplicons were cloned using the TOPO TA Cloning Kit (Invitrogen) and sequenced. At the nucleotide level, viral sequences from clones from both isolates were an average 99.4% similar to West Africa and 77.9% to East Africa sequences of SPCSV from Genbank (1). Although the isolates were collected from different fields, viral sequences generated from clones for T-03 and G-01 differed by only six nucleotides and were identical at the amino acid level. The neighbor-joining phylogenetic tree constructed using the HSP70 gene fragment (39 nt) delineated two major clusters with two subpopulations each: Cluster 1, "East Africa", consisted of East Africa and Peru subpopulations; Cluster 2, "West Africa", consisted of Argentina-Brazil and USA-West Africa subpopulations (1). In addition, SPCSV isolates from East Africa and West Africa clusters were sufficiently distant phylogenetically to suggest that they may correspond to two different criniviruses, with an average similarity between the populations of 78.14% and an average within the populations above 89%. Hudson's tests confirmed the presence of genetically distinct SPCSV groups with high statistical significance (1). Two groups (Peru and East Africa) were differentiated in the East Africa cluster, and three groups (Argentina-Brazil, USA, and West Africa) were differentiated in the West Africa cluster, suggesting that the USA population is not a recent introduction. Although SPCSV was previously reported in the United States, the source was a single accession of cv. White Bunch from the USDA Sweetpotato Germplasm Repository (3). Sweet potato feathery mottle virus (SPFMV) (family Potyviridae, genus Potyvirus), the other component of SPVD, was also detected in both cultivars. To our knowledge, this is the first report of SPCSV in sweetpotato fields in the United States. References: (1) J. A. Abad et al. Phytopathology (Abstr.) 96(suppl.):S1, 2006. (2) T. Alicai et al. Plant Pathol. 48:718, 1999. (3) G. Pio-Ribeiro et al. Plant Dis. 80:551, 1996. (4) G. A. Schaefer and E. R. Terry. Phytopathology 66:642, 1977.