Corticosterone administration up-regulated expression of norepinephrine transporter and dopamine ß-hydroxylase in rat locus coeruleus and its terminal regions.

Stress has been reported to activate the locus coeruleus (LC)-noradrenergic system. In this study, corticosterone (CORT) was orally administrated to rats for 21 days to mimic stress status. In situ hybridization measurements showed that CORT ingestion significantly increased mRNA levels of norepinephrine transporter (NET) and dopamine ß-hydroxylase (DBH) in the LC region. Immunofluorescence staining and western blotting revealed that CORT treatment also increased protein levels of NET and DBH in the LC, as well as NET protein levels in the hippocampus, the frontal cortex and the amygdala. However, CORT-induced increase in DBH protein levels only appeared in the hippocampus and the amygdala. Elevated NET and DBH expression in most of these areas (except for NET protein levels in the LC) was abolished by simultaneous treatment with combination of corticosteroid receptor antagonist mifepristone and spironolactone (s.c. for 21 days). Also, treatment with mifepristone alone prevented CORT-induced increases of NET expression and DBH protein levels in the LC. In addition, behavioral tasks showed that CORT ingestion facilitated escape in avoidance trials using an elevated T-maze, but interestingly, there was no significant effect on the escape trial. Corticosteroid receptor antagonists failed to counteract this response in CORT-treated rats. In the open-field task, CORT treatment resulted in less activity in a defined central zone compared to controls and corticosteroid receptor antagonist treatment alleviated this increase. In conclusion, this study demonstrates that chronic exposure to CORT results in a phenotype that mimics stress-induced alteration of noradrenergic phenotypes, but the effects on behavior are task dependent. As the sucrose consumption test strongly suggests CORT ingestion-induced depression-like behavior, further elucidation of underlying mechanisms may improve our understanding of the correlation between stress and the development of depression.

A light-guiding urinary catheter for the inhibition of Proteus mirabilis biofilm formation.

Catheter-associated urinary tract infection (CAUTI) is a leading cause of hospital-acquired infections worldwide causing debilitating illness for patients as well as a significant financial and treatment burden on health services. CAUTI is linked with the build-up of biofilms on catheter surfaces which act as a reservoir for infection. Additionally, urease-producing bacteria such as Gram-negative Proteus mirabilis (PM), can form crystalline biofilms which encrust catheter surfaces ultimately leading to blockages which require immediate removal of the catheter. Currently there are limited treatments available to prevent the formation of biofilms by PM as well as other urinary tract infection causing bacteria. A novel concept for a light-guiding urinary catheter is presented where a silicone elastomer waveguide incorporated along the length of the catheter is used to irradiate the catheter surfaces with antimicrobial blue light (405 nm) to prevent biofilm formation in situ. The prototype device is mass producible while also easy to fabricate in a lab setting for research studies. The inhibitory effect of blue light on PM biofilm formation over a range of irradiances is described for the first time showing an LD90 at 192-345 J/cm2 and total inhibition at 1,700 J/cm2 In vitro studies show that the light-guiding catheter (LGC) prototypes exhibit a 98% inhibition in PM biofilm formation inside the catheter lumen at an average estimated irradiance of 30-50 mW/cm2 (324-540 J/cm2 fluence) showing that the concept is highly effective, promising to be a powerful and economical antimicrobial approach to prevent catheter associated biofilm development and blockage.

Transpharyngeal Approaches for Management of Oropharyngeal Squamous Cell Carcinoma: Mayo Clinic Institution Experience.

OBJECTIVE: Investigate oncologic and functional outcomes associated with transhyoid and lateral pharyngotomy (transpharyngeal) approaches in the treatment of oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective review. SETTING: Single institution (tertiary care center). METHODS: This is a retrospective case series of patients with OPSCC undergoing transpharyngeal resection from 1990 to 2017 at Mayo Clinic. Oncologic outcomes, postoperative complications, objective swallowing data, and rates of tracheostomy and percutaneous gastrostomy tube dependence were recorded. RESULTS: Of 83 patients meeting inclusion criteria, 56 (68%) were human papillomavirus positive. Overall survival rates at 5 and 10 years following surgery were 85% and 80%, respectively. Cancer-specific survival rates at these same time points were 90% and 88%. Following treatment, 35 of 49 patients (71%) had a Functional Oral Intake Scale score ≥5, indicating total oral intake of multiple consistencies; 79 of 82 (96%) were without tracheostomy or laryngectomy; and 71 of 81 (88%) were on a full oral diet. CONCLUSION: Transpharyngeal approaches provide adequate functional and oncologic outcomes in the majority of patients with OPSCC. These results may have important implications for patients who are not candidates for, or are unwilling to undergo, nonoperative therapy or for those without access to radiation therapy.

Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole.

Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D2-like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats.

Synergism versus Additivity: Defining the Interactions between Common Disinfectants.

Many of the most common disinfectant and sanitizer products are formulations of multiple antimicrobial compounds. Products claiming to contain synergistic formulations are common, although there is often little supporting evidence. The antimicrobial interactions of all pairwise combinations of common disinfectants (benzalkonium chloride, didecyldimethylammonium chloride, polyhexamethylene biguanide, chlorocresol, and bronopol) were classified via checkerboard assay and validated by time-kill analyses. Combinations were tested against Acinetobacter baumannii NCTC 12156, Enterococcus faecalis NCTC 13379, Klebsiella pneumoniae NCTC 13443, and Staphylococcus aureus NCTC 13143. Synergistic interactions were identified only for the combinations of chlorocresol with benzalkonium chloride and chlorocresol with polyhexamethylene biguanide. Synergism was not ubiquitously demonstrated against all species tested and was on the borderline of the synergism threshold. These data demonstrate that synergism between disinfectants is uncommon and circumstantial. Most of the antimicrobial interactions tested were characterized as additive. We suggest that this is due to the broad, nonspecific mechanisms associated with disinfectants not providing an opportunity for the combined activities of these compounds to exceed the sum of their parts. IMPORTANCE The scarcity of observed synergistic interactions suggests that in the case of many disinfectant-based products, combined mechanisms of interaction may be being misinterpreted. We emphasize the need to correctly differentiate between additivity and synergism in antimicrobial formulations, as inappropriate classification may lead to unnecessary issues in the event of regulatory changes. Furthermore, we question the need to focus on synergism and disregard additivity when considering combinations of disinfectants, as the benefits that synergistic interactions provide are not necessarily relevant to the application of the final product.

Neonatal quinpirole treatment enhances locomotor activation and dopamine release in the nucleus accumbens core in response to amphetamine treatment in adulthood.

Neonatal quinpirole treatment to rats produces long-term increases in D(2) receptor sensitivity that persists throughout the animal's lifetime, a phenomenon referred to as D(2) priming. Male and female Sprague-dawley rats were administered quinpirole (1 mg kg(-1)) or saline from postnatal days (P)1-11. At P60, all animals were given an injection of quinpirole (100 microg kg(-1)), and results showed that rats neonatally treated with quinpirole demonstrated enhanced yawning in response to quinprole, verifying D(2) receptor priming because yawning is a D(2) receptor mediated event. Beginning 1-3 days later, locomotor sensitization was tested through administration of d-amphetamine (1 mg kg(-1)) or saline every other day over 14 days, and horizontal activity and turning behavior were analyzed. Findings indicated that D(2)-priming enhanced horizontal activity in response to amphetamine in females compared to males at Days 1 and 4 of locomotor sensitization testing, and D(2)-priming enhanced turning in response to amphetamine. Seven to ten days after sensitization was complete, microdialysis of the NAcc core was performed using a cumulative dosing regimen of amphetamine (0.1-3.0 mg kg(-1)). D(2)-primed rats administered amphetamine demonstrated a 500% increase in accumbal DA overflow compared to control rats administered amphetamine. Additionally, amphetamine produced a significant increase in NE overflow compared to controls, but this was unaffected by D(2) priming. These results indicate that D(2) receptor priming as is produced by neonatal quinpirole treatment robustly enhances behavioral activation and accumbal DA overflow in response to amphetamine, which may underlie increases in psychostimulant use and abuse within the psychotic population where increased D(2) receptor sensitivity is a hallmark.

Nicotine sensitization and analysis of brain-derived neurotrophic factor in adolescent beta-arrestin-2 knockout mice.

Nicotine sensitization and levels of brain-derived neurotrophic factor (BDNF) were analyzed in adolescent beta-arrestin-2 knockout (betaA-2 KO) and wild type (WT) mice. The beta-arrestin-2 protein has been shown to be important in G-protein hydrolysis and receptor internalization. Four- to five-week-old adolescent betaA-2 KO and WT C57/Bl6 mice were administered either nicotine (0.5 mg/kg free base) or saline 10 min before being placed into a locomotor arena on each of 7 (Experiment 1) or 14 (Experiment 2) consecutive days. A nicotine challenge was given 7 days after sensitization was complete. In Experiment 1, betaA-2 KO mice administered nicotine or saline and WT mice administered nicotine demonstrated significant hypoactivity during early in testing, and neither WT nor betaA-2 KO mice administered nicotine demonstrated sensitization. On the nicotine challenge, WT mice administered nicotine demonstrated significantly higher activity levels compared to all groups, and this same group demonstrated significantly higher levels of accumbal BDNF compared to all groups. In Experiment 2, betaA-2 KO mice were again hypoactive compared to WT mice, whereas WT mice administered nicotine demonstrated significant hypoactivity during initial testing and significantly higher levels of activity compared to all other groups late in testing. On the nicotine challenge, WT mice that received nicotine demonstrated a significant increase in activity compared to all groups, and showed increased accumbal BDNF compared to all groups. These results show that the beta-arrestin-2 protein is important in induction and expression of nicotine sensitization as well as nicotine's effects on accumbal BDNF.

Secondary tracheoesophageal puncture using transnasal esophagoscopy in gastric pull-up reconstruction after total laryngopharyngoesophagectomy.

BACKGROUND: There is debate about the optimal voice restoration method and technique for patients who have undergone total laryngopharyngectomy, esophagectomy, and gastric pull-up. The purpose of this study was to report a series of patients who underwent awake, secondary tracheoesophageal puncture (TEP) after this procedure. METHODS: A retrospective chart review was performed at a tertiary referral center. All subjects who underwent TEP placement under transnasal esophagoscopy guidance between 2003 and 2013 were included. RESULTS: All patients underwent uncomplicated TEP in the clinic. At the time of last follow-up, all patients had functional TEP speech that they were using preferentially over an available electrolarynx. CONCLUSION: In-office placement of secondary TEP using transnasal esophagoscopy is an efficient means of providing a conduit for voice prostheses in patients who have undergone laryngopharyngectomy with gastric pull up reconstruction. This procedure can be performed with minimal complications and with expectation of voice outcomes comparable to that seen with standard laryngectomy.

Thyroplasty in the previously irradiated neck: A case series and short-term outcomes.

OBJECTIVES/HYPOTHESIS: External beam radiation to the neck is widely considered a contraindication for thyroplasty due to concern for infection and implant extrusion. We present a case series of our experience regarding thyroplasty performed in a previously radiated field. STUDY DESIGN: Retrospective case study at a tertiary academic referral center. METHODS: Using the institution's clinical notes search tool, records from 1999 through 2014 documenting thyroplasty and radiation were identified and reviewed. Patients who received external beam radiation to the operative field prior to thyroplasty were included. Data including duration of radiation, timing and specifics of thyroplasty, postoperative complications, risk factors, clinical voice outcomes, and length of follow-up were collected. RESULTS: Fourteen patients met criteria for the study. Of all thyroplasty performed, 11 were Silastic implants, two were Gore-Tex implants, six had concurrent arytenoid adduction, and one was a midline type II thyroplasty. In terms of risk factors for postoperative complications, two were diabetic, none were active smokers, and one had a splenectomy. All patients were given postoperative antibiotics. The median duration of follow-up after surgery was 14.2 months. No patients were found to have postoperative complications. Pre- and postoperative voice data were assessed. Overall, there was improvement in voice outcomes. CONCLUSIONS: Thyroplasty may be an option for patients who have previously undergone external beam radiation. Short-term and intermediate outcomes in our patients showed no postoperative complications, and generally voice or dysphagia improved. Careful selection is still warranted when considering thyroplasty in a previously irradiated neck, and long-term outcomes need further study. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1849-1853, 2016.

Ontario children have outgrown the Broselow tape.

OBJECTIVE: The Broselow Pediatric Emergency Tape (Armstrong Medical Industries, Inc., Lincolnshire, IL) (BT) is a well-established length-based tool for estimation of body weight for children during resuscitation. In view of pandemic childhood obesity, the BT may no longer accurately estimate weight. We therefore studied the BT in children from Ontario in a large recent patient cohort. METHODS: Actual height and weight were obtained from an urban and a rural setting. Children were prospectively recruited between April 2007 and July 2008 from the emergency department and outpatient clinics at the London Health Science Centre. Rural children from junior kindergarten to grade 4 were also recruited in the spring of 2008 from the Avon Maitland District School Board. Data for preschool children were obtained from three daycare centres and the electronic medical record from the Maitland Valley Medical Centre. The predicted weight from the BT was compared to the actual weight using Spearman rank correlation; agreement and percent error (PE) were also calculated. RESULTS: A total of 6,361 children (46.2% female) were included in the study. The median age was 3.9 years (interquartile range [IQR] 1.56-7.67 years), weight was 17.2 kg (IQR 11.6-25.4 kg), and height was 103.5 cm (IQR 82-124.4 cm). Although the BT weight estimate correlated with the actual weight (r  =  0.95577, p < 0.0001), the BT underestimated the actual weight by 1.62 kg (7.1% ± 16.9% SD, 95% CI -26.0-40.2). The BT had an ≥ 10% PE 43.7% of the time. CONCLUSIONS: Although the BT remains an effective method for estimating pediatric weight, it was not accurate and tended to underestimate the weight of Ontario children. Until more accurate measurement tools for emergency departments are developed, physicians should be aware of this discrepancy.

Eszopiclone facilitation of the antidepressant efficacy of fluoxetine using a social defeat stress model.

This study analyzed the interaction of the sleep aid eszopiclone (ESZ) and antidepressant fluoxetine (FLX) on social defeat stress (SDS) in the mouse. Beta adrenoreceptors, brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB) expression in the hippocampus and frontal cortex were also analyzed. Subjects were adult male 'intruder' C57/B6 mice that were exposed to a retired 'resident' male breeder ICR mouse in this animal's home cage for a 5 min period for each of 10 consecutive days, and the resident established physical dominance. The following day, all animals were assigned to one of four drug treatment groups, and treatment was given for up to 18 days: vehicle, ESZ only (3mg/kg), FLX (10mg/kg) only, or ESZ+FLX. A social interaction test was given on days 1, 5, 10, and 15 of drug treatment to assess SDS. Results showed that the ESZ+FLX group spent less time in avoidance zones during the interaction test at days 1 and 5, and more time in the interaction zone at day 5 compared to defeated mice given vehicle. All drug treatment groups spent more time in the interaction zone compared to defeated mice given vehicle on day 1 as well as day 10. SDS completely dissipated by the fourth interaction test according to both behavioral measures. Neurochemically, SDS did not produce changes in any marker analyzed. This study shows the combination of ESZ and FLX alleviated SDS, but a neurochemical correlate remains elusive.