Photochemical Uncaging of Aldehydes and Ketones via Photocyclization/Fragmentation Cascades of Enyne Alcohols: An Unusual Application for a Cycloaromatization Process.

We utilized a cycloaromatization reaction driven by relief of excited state antiaromaticity to photouncage aldehydes and ketones. We developed several synthetic routes towards the synthesis of photocaged carbonyls as allylically substituted 3-(2-(arylethynyl)phenyl)prop-2-en-1-ols. A library of photocaged aryl aldehydes and ketones containing donors and acceptors, as well as several photocaged fragrance aldehydes and the steroid 5α-cholestan- 3 -one, were synthesized and demonstrated photouncaging in good to excellent yields.

Photochemical Activation of Enediyne Warheads: A Potential Tool for Targeted Antitumor Therapy.

Spatial and temporal control over DNA cleavage by photoactivated enediynes can be complemented by additional factors such as the release of internal strain, chelation, pH changes, intramolecular H-bonds, and substituent effects. This review presents design and reactivity of photoactivated enediynes/enynes and analyses the chemical, biological, and photophysical challenges in their applications.

The reduction of gunshot noise and auditory risk through the use of firearm suppressors and low-velocity ammunition.

OBJECTIVE: This research assessed the reduction of peak levels, equivalent energy and sound power of firearm suppressors. DESIGN: The first study evaluated the effect of three suppressors at four microphone positions around four firearms. The second study assessed the suppressor-related reduction of sound power with a 3 m hemispherical microphone array for two firearms. RESULTS: The suppressors reduced exposures at the ear between 17 and 24 dB peak sound pressure level and reduced the 8 h equivalent A-weighted energy between 9 and 21 dB depending upon the firearm and ammunition. Noise reductions observed for the instructor's position about a metre behind the shooter were between 20 and 28 dB peak sound pressure level and between 11 and 26 dB LAeq,8h. Firearm suppressors reduced the measured sound power levels between 2 and 23 dB. Sound power reductions were greater for the low-velocity ammunition than for the same firearms fired with high-velocity ammunition due to the effect of N-waves produced by a supersonic bullet. CONCLUSIONS: Firearm suppressors may reduce noise exposure, and the cumulative exposures of suppressed firearms can still present a significant hearing risk. Therefore, firearm users should always wear hearing protection whenever target shooting or hunting.

Depression symptoms and lost productivity in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is associated with significant losses of patient productivity that cost billions of dollars every year. The causative factors for decreases in productivity in patients with CRS have yet to be determined. OBJECTIVE: To determine which patterns of CRS symptoms drive lost productivity. METHODS: Prospective, cross-sectional cohort study of 107 patients with CRS. Sinonasal symptom severity was measured using the 22-item Sinonasal Outcomes Test, from which sleep, nasal, otologic or facial pain, and emotional function subdomain scores were calculated using principal component analysis. Depression risk was assessed with the 2-item Patient Health Questionnaire (PHQ-2), whereas nasal obstruction was assessed with the Nasal Obstruction Symptom Evaluation (NOSE) instrument. Lost productivity was assessed by asking participants how many days of work and/or school they missed in the last 3 months because of CRS. Associations were sought between lost productivity and CRS symptoms. RESULTS: A total of 107 patients were recruited. Patients missed a mean (SD) of 3.1 (12.9) days of work or school because of CRS. Lost productivity was most strongly associated with the emotional function subdomain (ß = 7.48; 95% confidence interval [CI], 5.71-9.25; P < .001). Reinforcing this finding, lost productivity was associated with PHQ-2 score (ß = 4.72; 95% CI, 2.62-6.83; P < .001). Lost productivity was less strongly associated with the nasal symptom subdomain score (ß = 2.65; 95% CI, 0.77-4.52; P = .007), and there was no association between lost productivity and NOSE score (ß = 0.01; 95% CI, -0.12 to 0.13; P = .91). CONCLUSION: Symptoms associated with depression are most strongly associated with missed days of work or school because of CRS. Further treatment focusing on depression-associated symptoms in patients with CRS may reduce losses in productivity.

Nitric oxide coupling to generate N2O promoted by a single-heme system as examined by density functional theory.

Bacteria utilize a heme/non-heme enzyme system to detoxify nitric oxide (NO) to N2O. In order to probe the capacity of a single-heme system to mediate this NO-to-N2O transformation, various scenarios for addition of electrons, protons, and a second NO molecule to a heme nitrosyl to generate N2O were explored by density functional theory calculations. We describe, utilizing this single-heme system, several stepwise intermediates along pathways that enable the critical N-N bond formation step yielding the desired Fe-N2O product. We also report a hitherto unreported directional second protonation that results in either productive N2O formation with loss of water, or formation of a non-productive hyponitrous acid adduct Fe{HONNOH}.

Long-term glycemic control with hepatic insulin gene therapy in streptozotocin-diabetic mice.

BACKGROUND: Insulin self-administration is burdensome and can produce dangerous hypoglycemia. Insulin gene therapy may improve and simplify the treatment of diabetes mellitus. In rats, metabolically responsive hepatic insulin gene therapy (HIGT) delivered by adenovirus normalizes random blood sugars but with a limited duration. To prolong glycemic control, we delivered a metabolically regulated insulin transgene by adeno-associated virus (AAV). METHODS: We administered increasing doses of self-complementary (SC), pseudotyped AAV8 expressing the (GlRE)3 BP1-2xfur insulin transgene to streptozotocin-diabetic CD-1 mice, and monitored blood sugar and body weight. We also compared responses to intraperitoneal glucose and chow withdrawal, assessed for viral genomes in liver by Southern blotting, and measured hepatic glycogen. RESULTS: Glucose lowering required the combination of SC genomes and AAV capsid pseudotyping. HIGT controlled glycemia in diabetic mice (DM) for > 1 year. However, glycemic responses were variable. Approximately 30% of mice succumbed to hypoglycemia, and approximately 30% of mice again became hyperglycemic. During an intraperitoneal glucose tolerance test, blood sugars declined to normal within 180 min in HIGT-treated DM compared to 90 min in control mice. Hypoglycemia was common among HIGT-treated mice during a 24-h fast. However, HIGT mice lost less weight than either diabetic or nondiabetic controls as a result of increased water intake. HIGT treatment reduced the hepatic glycogen content of fed mice. CONCLUSIONS: Our studies demonstrate the possibility for long-term glycemic correction following AAV-mediated HIGT in mice. However, the dose-response relationship is irregular, and metabolic responsiveness may be less than that observed in rats.

The Relationship Between Cochleovestibular Orientation, Age, and Sensorineural Hearing Loss: Implications for Cochlear Implantation.

OBJECTIVES: To determine if spatial orientation of the cochlea within the temporal bone is related to age or sensorineural hearing loss (SNHL) and describe the implications for cochlear implantation. METHODS: Five angles of cochlear orientation were determined from computed tomography (CT) imaging of the temporal bones in adults with (n = 55) and without (n = 27) sensorineural hearing loss (SNHL) and children with (n = 45) and without (n = 12) SNHL: facial recess versus basal turn, posterior semicircular canal versus basal turn, round window versus basal turn (axial view), round window versus basal turn (coronal view), and the cochlear axis versus the mastoid facial nerve. RESULTS: All angles showed substantial variation between subjects and between ears. The angles between the round window and basal turn (coronal view) and the posterior semicircular canal and basal turn were significantly correlated with age for all subjects with SNHL (r = 0.22, P = .002 and r = 0.15, P = .03, respectively). Patients with SNHL had significantly more acute angles (46.6° vs 55.8°) between the round window versus basal turn (axial orientation) compared to controls (P < .001). CONCLUSIONS: Cochlear orientation within the temporal bone changes with age and the degree of SNHL. These results suggest that the approach to the round window for electrode insertion might differ between children and adults.

The experience of having psoriasis through the lens of the International Classification of Functioning, Disability and Health (ICF).

BACKGROUND/OBJECTIVE: The International Classification of Functioning, Disability and Health (ICF) was developed by the World Health Organization to comprehensively describe the ways that health conditions can affect people. The identification of ICF categories of most relevance to people with a particular disease can increase the usefulness of the ICF and create a reference for outcome studies. This study aimed to ascertain, through focus group interviews with psoriasis patients and an online Delphi survey with health professionals, the impacts of psoriasis as categorised by the ICF. METHODS: We conducted and transcribed verbatim focus group interviews with 32 outpatients with psoriasis from two New Zealand cities. The interview transcripts were analysed to yield meaning units and concepts contained in the meaning units were extracted. These concepts were linked to ICF categories. An online Delphi survey among 23 health professionals was conducted to obtain similar information. The ICF categories were rated for their perceived relevance to psoriasis by health professionals over three iterations. RESULTS: In total, 32 patients participated in six focus groups. Interview saturation was reached after five focus groups. The concepts were linked to 83 ICF categories and two separate health conditions. Among health professionals, 167 ICF categories were rated, mostly in the moderately relevant (four to six) range. CONCLUSION: Applying the established method of meaning condensation to focus group interview transcripts allowed the accurate linking of concepts to ICF categories. This will be of use to researchers developing the first ICF core set for psoriasis in the future.

New Zealand land search and rescue operations: an analysis of medical and traumatic conditions.

OBJECTIVE: The aim of this study was to describe the range and types of medical and traumatic conditions encountered in land search and rescue operations in New Zealand. METHODS: Twenty months (May 2010 to December 2011) of land search and rescue operations were analyzed. Data on medical and traumatic conditions were extracted from the New Zealand Police search and rescue database. RESULTS: During the period audited, New Zealand Police coordinated 1490 land-based search and rescue operations, from which 611 persons fulfilled the study inclusion criteria. Males accounted for 60.5% of the subjects, and a trauma-related injury was the most commonly encountered condition (37.3% of all). The lower limb was the most commonly injured body site, and most injuries occurred as the result of a slip or fall. Medical conditions were recorded in 11.6% of operations and included a wide spread of conditions, with cardiovascular events being seen most frequently. Hypothermia was diagnosed in 9.3% of all operations, and fatalities made up 5.6% of the sample. Thirty percent of all operations were for persons with cognitive impairment who had wandered away from their usual place of residence. These were almost entirely urban searches and concentrated in districts with large populations. CONCLUSIONS: Search and rescue personnel are exposed to a broad range of medical and traumatic conditions. In New Zealand, they include preexisting cognitive impairment that results in persons lost in urban environments. Notwithstanding this, many subjects will also need to be managed in remote, resource-limited environments for extended periods. First aid training and field equipment should reflect these demands.

Leveraging a Safety Event Management System to Improve Organizational Learning and Safety Culture.

BACKGROUND AND OBJECTIVES: Safety event management systems (SEMS) are rich sources of patient safety information, which can be used to improve organizational safety culture. An ideal SEMS can accomplish this when the system is improved with the intention of increasing learning and engagement across the organization. To support a global aim of improving overall patient safety and becoming a highly reliable learning health system, focus was directed toward increasing event review and follow-up completion and using this information to drive resource allocation and improvement efforts. METHODS: A new integrated SEMS was customized, tested, and implemented based on identified organizational need. Revised policies were developed to define expectations for event review and follow-up. The new SEMS incorporated a closed-loop communication process which ensured information from events was shared with the event submitters and facilitated shared learning. The expected impacts, improved event reporting, and follow-up were studied and guided ongoing improvements. RESULTS: After transitioning to a new SEMS, we experienced increased overall reporting by 8.6% and improved event follow-up, demonstrated by documentation on specified system forms, by 53.7%. CONCLUSIONS: By implementing a new, efficient, and standardized SEMS, which decentralized event management processes, the organization saw increased reporting and better engagement with patient safety event review and follow-up. Overall, these results demonstrated a stronger reporting culture, which allowed for local problem solving and improved learning from every event reported. A robust reporting culture positively impacted the overall organizational culture of safety.

Picbreeder: a case study in collaborative evolutionary exploration of design space.

For domains in which fitness is subjective or difficult to express formally, interactive evolutionary computation (IEC) is a natural choice. It is possible that a collaborative process combining feedback from multiple users can improve the quality and quantity of generated artifacts. Picbreeder, a large-scale online experiment in collaborative interactive evolution (CIE), explores this potential. Picbreeder is an online community in which users can evolve and share images, and most importantly, continue evolving others' images. Through this process of branching from other images, and through continually increasing image complexity made possible by the underlying neuroevolution of augmenting topologies (NEAT) algorithm, evolved images proliferate unlike in any other current IEC system. This paper discusses not only the strengths of the Picbreeder approach, but its challenges and shortcomings as well, in the hope that lessons learned will inform the design of future CIE systems.

Antiaromaticity Gain Activates Tropone and Nonbenzenoid Aromatics as Normal-Electron-Demand Diels-Alder Dienes.

We propose a carbonyl umpolung strategy for activating tropone as a normal-electron-demand Diels-Alder diene. Tropone has low reactivity for Diels-Alder reactions because of its [4n+2] π-aromaticity. Conversion of the carbonyl group into a hydrazone ion (═N-NR-) reverses the polarity of the exocyclic double bond, increases the [4n] ring π-antiaromaticity, and raises the HOMO energy. Computed gas-phase activation free energies for a Diels-Alder reaction with maleimide suggest a billion-fold rate increase when the tropone C═O is replaced by ═N-NR- (R = H or SO2CH3). Other nonbenzenoid aromatics can be activated as normal-electron-demand Diels-Alder dienes in the same way.

A stable hyponitrite-bridged iron porphyrin complex.

The coupling of two nitric oxide (NO) molecules in heme active sites is an important contributor to the conversion of NO to nitrous oxide (N(2)O) by heme-containing enzymes. Several formulations for the presumed heme-Fe{N(2)O(2)}(n-) intermediates have been proposed previously, however, no crystal structures of heme-Fe{N(2)O(2)}(n-) systems have been reported to date. We report the first isolation and characterization of a stable bimetallic hyponitrite iron porphyrin, [(OEP)Fe](2)(mu-N(2)O(2)), prepared from the reaction of [(OEP)Fe](2)(mu-O) with hyponitrous acid. Density functional theoretical calculations were performed on the model compound [(porphine)Fe](2)(mu-N(2)O(2)) to characterize its electronic structure and properties.

Hepatic insulin gene therapy diminishes liver glycogen despite insulin responsive transcriptional effects in diabetic CD-1 mice.

BACKGROUND: Hepatic insulin gene therapy (HIGT) produces near-normal glycemia in diabetic rats. Hepatic insulin production is expected to stimulate glycogen storage. However, the effect of HIGT on hepatic glycogen metabolism in vivo is unknown. METHODS: After administration of an adenoviral vector capable of inducing glucose responsive insulin production from hepatocytes, we evaluated circulating hormones, cytokines, hepatic gene expression and hepatic glycogen content in diabetic CD-1 mice receiving intravenous streptozotocin. Nondiabetic mice and diabetic mice treated with empty adenovirus served as controls. RESULTS: Peripheral concentrations of human insulin in HIGT mice were less than concentrations of mouse insulin among controls. However, expression of insulin responsive genes in HIGT livers indicated a significant intra-hepatic insulin effect, with expression changes reflecting appropriate responses to fed-fasting transitions. Transcription factors (hepatocyte nuclear factor-4alpha and peroxisome proliferator-activated receptor gamma co-activator-1alpha), as well as target genes (phospho-enol-pyruvate carboxykinase, glucose-6-phosphatase and glucokinase) exhibited insulin responsive expression. Despite producing near normal glycemia, HIGT diminished hepatic glycogen content in both fasted and fed mice. Serum cytokine responses revealed both vector-related (monocyte chemoatractant protein-1, interleukin-6) and transgene specific (resistin, tumor necrosis factor alpha) effects. CONCLUSIONS: HIGT produces low circulating concentrations of insulin, but produces significant intra-hepatic effects on gene expression. Despite controlling hyperglycemia, HIGT exerts unexpected insulin effects on hepatic carbohydrate metabolism. Although the precise mechanisms remain to be determined, they may relate to vector-induced cytokine effects.

The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats.

Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT(2C) receptor antagonist. As stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without predator stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no stress) or near a cat (predator stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the predator stress-induced impairment of spatial memory; (2) agomelatine-treated stressed, as well as non-stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both stressed and non-stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.

Hepatic insulin gene therapy normalizes diurnal fluctuation of oxidative metabolism in diabetic BB/Wor rats.

Previous studies of hepatic insulin gene therapy (HIGT) focused on glycemic effects of insulin produced from hepatocytes. In this study, we extend the observations of glycemic control with metabolically regulated HIGT to include systemic responses and whole-body metabolism. An insulin transgene was administered with an adenoviral vector [Ad/(GlRE)(3)BP1-2xfur] to livers of BB/Wor rats made diabetic with polyinosinic polycytidilic acid (poly-I:C) (HIGT group), and results compared with nondiabetic controls (non-DM), and diabetic rats receiving different doses of continuous-release insulin implants (DM-low BG and DM-high BG). Blood glucose and growth normalized in HIGT, with lower systemic insulin levels, elevated glucagon, and increased heat production compared with non-DM. Minimal regulation of systemic insulin levels were observed with HIGT, yet the animals maintained normal switching from carbohydrate to lipid metabolism determined by respiratory quotients (RQs), and tolerated 24-hour fasts without severe hypoglycemia. HIGT did not restore serum lipids as we observed increased triglycerides (TGs) and increased free fatty acids, but reduced weight of visceral fat pads despite normal total body fat content and retroperitoneal fat depots. HIGT favorably affects blood glucose, normalizes metabolic switching in diabetic rats, and reduces intra-abdominal fat deposition.

The influence of postural threat on the cortical response to unpredictable and predictable postural perturbations.

This study investigated the effects of postural threat on the cortical response associated with postural reactions to predictable and unpredictable perturbations to upright stance. Postural threat was manipulated by having individuals stand on an elevated surface to alter the context in which the postural task was performed. Ten healthy young adults experienced a series of predictable and unpredictable trunk perturbations when standing at ground level and at the edge of a platform located 3.2 m above the ground. Participants felt less confident, more fearful of falling, more anxious and less stable when standing at the high surface height. Unpredictable perturbations generated a large negative potential (N1) which was increased by 84% when standing at the high compared to low surface height. The magnitude of change in this potential was related to the magnitude of change in balance perceptions, such as confidence and fear. Predictable perturbations did not generate a N1 potential but instead produced an anticipation-related potential prior to the perturbation. This cortical activity observed in response to predictable perturbations was not influenced by postural threat. A large N1 potential was observed for a 'surprise' perturbation that followed a series of predictable perturbations. There was a trend for the amplitude of this potential to be increased when standing at the high compared to low surface height. The results of this study provide evidence for the modulating influence of psychological factors related to postural threat on the cortical activity associated with postural reactions to unpredictable perturbations.

Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by predator stress.

Extensive research has shown that the antidepressant tianeptine blocks the adverse effects of chronic stress on hippocampal functioning. The current series of experiments extended this area of investigation by examining the influence of tianeptine on acute stress-induced impairments of spatial (hippocampus-dependent) memory. Tianeptine (10 mg/kg, ip) administered to adult male rats before, but not after, water maze training blocked the amnestic effects of predator stress (occurring between training and retrieval) on memory. The protective effects of tianeptine on memory occurred in rats which had extensive pre-stress training, as well as in rats which had only a single day of training. Tianeptine blocked stress effects on memory without altering the stress-induced increase in corticosterone levels. Propranolol, a beta-adrenergic receptor antagonist (5 and 10 mg/kg, ip), in contrast, did not block stress-induced amnesia. These findings indicate that treatment with tianeptine, unlike propanolol, provides an effective means with which to block the adverse effects of stress on cognitive functions of the hippocampus.

Association between Asthma and Chronic Rhinosinusitis Severity in the Context of Asthma Control.

Objective Comorbid asthma is associated with decreased quality of life (QOL) in chronic rhinosinusitis (CRS). It is unclear whether this association is independent of the patients' clinical asthma status. We therefore sought to determine if asthma is associated with lower QOL in CRS, independent of asthma control. Study Design Cross-sectional cohort study of 350 patients with CRS. Setting Tertiary academic rhinology clinic. Subjects and Methods In total, 350 participants with CRS were recruited and 28.3% were asthmatic. CRS-specific QOL was measured using the 22-item Sinonasal Outcome Test (SNOT-22). Asthma control was assessed with the Asthma Control Test (ACT). General health-related QOL was assessed with the EuroQoL 5-dimensional general health-related quality of life survey visual analog scale (EQ-5D VAS). Associations were sought between SNOT-22 and EQ-5D VAS (dependent variables) and asthma (independent variable), while controlling for ACT. ACT score for patients with CRS without asthma was set at 25 (indicating completely controlled, asymptomatic asthma). Results Comorbid asthma was associated with SNOT-22 (ß = 11.8; 95% confidence interval [CI], 6.2-17.3; P < .001) and EQ-5D VAS (ß = -6.2; 95% CI, -11.2 to -1.3; P = .014). After controlling for ACT, asthma was no longer associated with SNOT-22 ( P = .147) or EQ-5D VAS ( P = .994). Instead, ACT score was associated with SNOT-22 (ß = -2.1; 95% CI, -3.2 to -1.1; P < .001) and EQ-5D VAS (ß = 2.1; 95% CI, 1.1 to 3.0; P < .001). ACT score completely drove the association between asthma and worse QOL. Conclusion Comorbid asthma is not necessarily reflective of decreased QOL in CRS. The association of comorbid asthma with lower QOL in CRS is related to the clinical status (eg, control) of asthma.