An investigation of the effects of fentanyl on respiratory control

Respiration is a complex rhythmic motor behaviour that metabolically supports all physiological processes in the body and is continuous throughout the life of mammals. A failure to generate a respiratory rhythm can be fatal. Understanding how the respiratory rhythm is generated by the brainstem presents a substantial challenge within the field of respiratory neurobiology. Studies utilising in vitro and in vivo rodent models have provided compelling evidence that a small bilateral region of the ventrolateral medulla, known as the preBötzinger complex (preBötC), is the site for respiratory rhythmogenesis. There is also evidence to suggest a second distinct neuronal group, the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), plays a specialised role in respiratory rhythm generation in the neonatal rodent. During early life in rodents and humans, the respiratory system is immature and an irregular breathing pattern is generated, making this period of life potentially vulnerable to external perturbations. However a step in maturity occurs early in life after which breathing becomes regular. Currently, the underlying mechanisms involved in respiratory rhythm generation during early life are not fully understood. It is hypothesised that the RTN/pFRG functions as the dominant respiratory rhythm generating oscillator during early life when the respiratory system is immature, after which the preBötC becomes the dominant rhythm generator. However, how the preBötC and the RTN/pFRG interact in vivo to produce rhythmic breathing during postnatal development remains elusive. The first aim of this thesis was to assess postnatal maturation of breathing patterns in the mouse using non-invasive whole body plethysmography. Between postnatal day (P) 2 and P3, a critical maturation step occurred, whereby breathing transitioned from an unstable and dysrhythmic pattern to a regular and robust pattern. The second aim of the thesis was to investigate the influence of this postnatal maturation on central respiratory control. Mu (μ) opioid receptor agonists are known respiratory depressants. The activity of the preBötC is depressed by μ opioids in vitro. Furthermore, fentanyl, a potent μ opioid receptor agonist, evokes respiratory frequency depression in vivo by exclusively targeting and depressing preBötC neurons. Conversely, the RTN/pFRG is insensitive to μ opioids. Accordingly, fentanyl was utilised as a pharmacological tool to selectively perturb the preBötC in vivo throughout postnatal development and through to early adulthood. The acute respiratory depressive effects of fentanyl were measured in order to investigate the level of involvement of the preBötC in respiratory rhythm generation throughout this critical developmental time period. Based on the general hypothesis that the preBötC functions as the dominant respiratory rhythm generator when the respiratory system has matured, it was hypothesised that mice would be more susceptible to the respiratory depressive effects of fentanyl after the maturation step has occurred i.e. the respiratory sensitivity to fentanyl would be age-dependent. Initially, mice were repeatedly exposed to fentanyl throughout postnatal development. However, fentanyl failed to induce a respiratory depression at all postnatal ages, suggesting repeated exposure had induced a rapid desensitisation to fentanyl’s respiratory effects. The study design was consequently altered to allow the hypothesis to be sufficiently tested, whereby different mice were studied on each postnatal day i.e. each mouse was only exposed to fentanyl once. This study revealed a trend towards an age-dependent increase in respiratory sensitivity to fentanyl, where mice displayed a heightened respiratory frequency depression in response to fentanyl after the maturation step had occurred from P3 onwards. This data therefore lends support to the hypothesis that the preBötC functions as the dominant respiratory rhythm generator post-maturation. In the clinical setting fentanyl is widely utilised for treating chronic and acute pain. However, despite the potent respiratory depressive actions of fentanyl, the long-term respiratory consequences of repeated exposure remain unexplored both clinically and pre-clinically. Owing to the immaturity of the respiratory system and the corresponding fragile nature of breathing patterns during neonatal life in mammals, a further aim of the thesis was to determine the long-term effects of fentanyl exposure during this vulnerable respiratory time period in the mouse. To establish if the postnatal age of fentanyl-exposure influences long-term respiratory effects, fentanyl exposure during juvenile life, which is regarded as being post-respiratory maturation, was also assessed. Neonatal mice were exposed to fentanyl (0.04 mg/kg daily) from P1-P5 and juvenile mice were exposed from P9-P13. When mice reached adulthood, baseline respiratory activity and the respiratory response to a subsequent fentanyl challenge were assessed during wakefulness and under anaesthesia. When awake, neonatal-exposed mice exhibited a reduced baseline respiratory frequency and an attenuated respiratory sensitivity to fentanyl. Under anaesthesia, neonatal-exposed mice displayed a depressed baseline minute ventilation and a high frequency of spontaneous augmented breaths. In direct contrast to the wakeful state, when anaesthetised, neonatal-exposed mice exhibited a striking hypersensitivity to the acute respiratory depressive actions of fentanyl. In all neonatal-exposed mice, fentanyl evoked a respiratory failure. In juvenile-exposed mice, baseline respiratory activity remained unaltered in the wakeful state and fentanyl also failed to induce a respiratory depression. When anaesthetised, baseline minute ventilation remained unchanged and the high occurrence of augmented breaths exhibited by the neonatal-exposed mice was not observed. Unlike the wakeful state, fentanyl evoked a depression of respiratory activity in the juvenile-exposed mice when anaesthetised, however the augmented sensitivity to fentanyl and consequential respiratory arrest displayed by the neonatal-exposed was not observed. This data indicates that the anaesthetised state is more susceptible to respiratory depression. Furthermore, the data suggests that neonatal life represents a time period that is particularly vulnerable to the respiratory effects of opioid depression. The final aim of the thesis was to determine the long-term effects of neonatal fentanyl exposure on neurokinin-1 (NK1R) and μ opioid receptor expression within the ventral respiratory column (VRC), a region of the ventrolateral medulla comprising the preBötC. Neonatal-exposed mice exhibited significantly less NK1R and μ opioid receptor expressing cells in the region of the preBötC. This data suggests that repeated fentanyl exposure in neonatal life induces a long-term downregulation of these receptors. In conclusion, fentanyl’s acute respiratory effects were age-dependent, which lends supports to the hypothesis that the preBötC functions as the dominant rhythm generator post-maturation. Furthermore, this thesis highlights the vulnerabilities of neonatal life to the lasting effects of opioid respiratory depression, whilst also providing invaluable insight into state-dependent respiratory modulation and depression

A family of nitrogen enriched metal organic frameworks with CCS potential

Materials with enhanced carbon capture capacities are required to advance post-combustive amelioration methods; these are necessary to reduce atmospheric carbon dioxide emissions and the associated rate of global temperature increase. Current technologies tend to be very energy intensive processes with high levels of waste produced; this work presents three new metal organic framework materials with embedded Lewis base functionalities, imparted by the nitrogen-rich ligand, demonstrating an affinity for carbon dioxide. Thus , we report the synthesis and characterization of a series of metal organic framework materials using a range of metal centers (Co, Ni, and Zn) with the 1,4-bis(pyridin-4-yl)-1,2,4,5-tetrazine organic linker, in the presence of ammonium hexafluorosilicate. Three distinct crystal structures are reported for Zn-pytz(hydro) 1D chains, and Ni-pytz and Co-pytz isostructural 1D Ladders. Co-pytz shows an uptake of 47.53mg CO2/g of sorbent, which equates to 15 wt % based on available nitrogen sites within the structure, demonstrating potential for carbon capture applications

Unexpected selective gas adsorption on a 'non-porous' metal organic framework

A metal organic framework Cu(tpt)BF 4· 3 4 H 2O was synthesized as a potential carbon capture material, with the aim being to exploit the Lewis base interaction of the incorporated ligand functionalities with acidic gas. The material displays high thermal stability but an exceptionally low surface area; however, this contrasts starkly with its ability to capture carbon dioxide, demonstrating significant activated diffusion within the framework. The full characterization of the material shows a robust structure, where the CO 2 sorption is 120% greater than current industrial methods using liquid amine solutions; the thermal energy required for sorbent regeneration is reduced by 65%, indicating the true industrial potential of the synthesized material

Emergency Department Use Among Vermont Homeless Families

Background: Committee on Temporary Shelter (COTS) houses homeless individuals and families from the Burlington area. COTS believes that a high proportion of their residents use the Fletcher Allen Health Care Emergency Department (FAHCED) for their health care more frequently compared to the general population. There are many other primary care services offered in the Burlington area, such as Safe Harbor Clinic, Community Health Center, and private offices, which are more appropriate for non-emergent health concerns and are readily accessible to the homeless population. By surveying the population of homeless families in Burlington and conducting a focus group with the COTS staff, we hoped to discover the reasons for ED usage, potential barriers to primary health care, and any possible changes that could ameliorate the health care of this populationhttps://scholarworks.uvm.edu/comphp_gallery/1053/thumbnail.jp

Diagnostic utility of endoscopy and biopsy in suspected acute gastrointestinal graft-versus-host disease after hematopoietic progenitor cell transplantation

Acute gastrointestinal graft-versus-host disease (GI-GVHD) after hematopoietic progenitor cell transplantation (HPCT) is a common and life-threatening complication. Endoscopic biopsy of the GI tract (GIT) is required for diagnosis. However, clear evidence to optimize this diagnostic approach is lacking, leading to variation in diagnostic sensitivity between institutions. We aimed to assess the clinical, endoscopic, and histologic findings of endoscopies performed for suspected acute GI-GVHD at our institution to better define the optimal use of this strategy. We performed a retrospective cohort study of adults who had undergone endoscopy for suspected acute GI-GVHD within 180 days after allogeneic HPCT for hematologic malignancy between 2011 and 2016. Details included symptoms at time of referral for endoscopy, type of procedure performed, macroscopic findings on endoscopy, and histologic findings after gut biopsy. Correlation was made with clinical GVHD severity scores. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated and compared for each procedure. Predictors of histologic GVHD and overall survival were also compared. Of the 123 patients included, acute GI-GVHD occurred in 59 (48%). Lower endoscopy demonstrated greater sensitivity than upper endoscopy (50% versus 39%). Single upper endoscopy for upper symptoms alone had the lowest yield of GI-GVHD (14%). Combination upper and lower endoscopy demonstrated strong histologic concordance between upper and lower procedures. The addition of upper endoscopy to lower endoscopy only identified an extra 2 (4%) cases of GVHD. Advanced age and the presence of lower GIT symptoms were the only pre-endoscopy predictors of histologic GVHD on multivariate analysis. Patients with isolated upper histologic GVHD showed similar survival to patients with negative biopsies. Endoscopy and biopsy only identified 74% of those ultimately requiring treatment for acute GI-GVHD. Acute GI-GVHD remains a clinical diagnosis supported by available histologic evidence. Isolated upper GI-GVHD is rare, and in the absence of lower GIT symptoms, routine upper endoscopy does not significantly improve diagnostic yield for histologic GVHD. Overall, endoscopy and biopsy underdiagnoses 26% of clinical GI-GVHD, highlighting a need for research into novel diagnostic strategies

Improving the gas sorption capacity in lantern-type metal-organic polyhedra by a scrambled cage method

The synthesis of multivariate metal-organic frameworks (MOFs) is a well-known method for increasing the complexity of porous frameworks. In these materials, the structural differences of the ligands used in the synthesis are sufficiently subtle that they can each occupy the same site in the framework. However, multivariate or ligand scrambling approaches are rarely used in the synthesis of porous metal-organic polyhedra (MOPs) – the molecular equivalent of MOFs – despite the potential to retain a unique intrinsic pore from the individual cage while varying the extrinsic porosity of the material. Herein we directly synthesise scrambled cages across two families of lantern-type MOPs and find contrasting effects on their gas sorption properties. In one family, the scrambling approach sees a gradual increase in the BET surface area with the maximum and minimum uptakes associated with the two pure homoleptic cages. In the other, the scrambled materials display improved surface areas with respect to both of the original, homoleptic cages. Through analysis of the gas sorption isotherms, we attribute this effect to the balance of micro- and mesoporosity within the materials, which varies as a result of the scrambling approach. The gas uptake of the materials presented here underscores the tunability of cages that springs from their combination of intrinsic, extrinsic, micro- and meso- porosities

At-home blood collection and stabilization in high temperature climates using home RNA

Expanding whole blood sample collection for transcriptome analysis beyond traditional phlebotomy clinics will open new frontiers for remote immune research and telemedicine. Determining the stability of RNA in blood samples exposed to high ambient temperatures (\u3e30°C) is necessary for deploying home-sampling in settings with elevated temperatures (e.g., studying physiological response to natural disasters that occur in warm locations or in the summer). Recently, we have develope

Porous metal-organic cages based on rigid bicyclo[2.2.2]oct-7-ene type ligands : synthesis, structure, and gas uptake properties

Three new ligands containing a bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxydiimide unit have been used to assemble lantern-type metal-organic cages with the general formula [Cu4L4]. Functionalisation of the backbone of the ligands leads to distinct crystal packing motifs between the three cages, as observed with single-crystal X-ray diffraction. The three cages vary in their gas sorption behaviour, and the capacity of the materials for CO2 is found to depend on the activation conditions: softer activation conditions lead to superior uptake, and one of the cages displays the highest BET surface area found for lantern-type cages so far

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses