The Influence of the Endothelium on the Response of Vascular Smooth Muscle

This project was carried out to examine the influence of the vascular endothelium on the responses of the underlying smooth muscle. I have examined the influence of the endothelium on sensitivity of the smooth muscle to calcium and the interaction of a Ca2+-channel activator and blocker. A further study was carried out to examine how the initial tone affects the responses to both contractile and relaxatory agents and how the size of the induced tone affects the ability of Ach to cause relaxation. I studied the changes, if any, in this relationship in certain cardiovascular diseases. These effects were studied in an isolated aortic ring from the rat and also a complete vascular bed, the perfused rat tail. The following is a summary of the results: 1) Removal of the vascular endothelium from isolated aortic rings affects the sensitivity of the tissue to various agonists. The influence on the responses is greater for some agonists than for others. The agonists influenced to the greatest extent had both the pD2 and the maximum response significantly changed by removal of the endothelium: these agonists were either alpha1-adrenoceptor partial agonists or alpha2-adrenoceptor agonists in other tissues. The agonist affected to the least extent, the thromboxane mimetic drug U46619 showed no significant change on removal of the endothelium in either the maximum response or the pD2 value. 2) The presence of the vascular endothelium had no influence on the actions at alpha1-adrenoceptors, of the selective antagonists prazosin and corynanthine, or the alpha2-adrenoceptor antagonist, Wyeth 26703. The results using Wyeth 26703 did not support the possibility of alpha2-adrenoceptor stimulation releasing EDRF, since it had the same effect on responses to NA in tissues with both an intact and disrupted endothelium. 3) Increasing the initial length in aortic ring segments caused a length-dependent increase in the resting tension. The absence of the endothelium had no significant effect on the resting tensions compared with intact tissues. The size of the contraction to Phe (1uM) and relaxation to Ach (1uM) (tone induced by Phe) were dependent on the initial length of the preparation. The optimum stretch to demonstrate the proportionate effect of Ach (1uM) did not coincide with the optimum for Phe-induced contractions. 4) The size of the induced tone against which Ach produced relaxation affected the sensitivity to this agent. The greater the size of the induced tone the less sensitive the tissue was to relaxation. Atropine did not affect the size of the tone induced by NA but inhibited the relaxation to Ach. BAY-K 8644, a calcium channel facilitator, increased the tone induced by NA and inhibited the relaxation to Ach to a greater extent than would be expected by increase in tone alone. The cx2-antagonist drug Wyeth 26703, at concentrations where it acts selectively at alpha2-adrenoceptors (in other tissues), had no effect on NA-induced tone or on Ach-induced relaxation. 5) Using a maximal concentration of NA (3uM) in rat aortic rings, with either an intact or disrupted endothelium, in both a buffered and unbuffered calcium system, the contractile response was shown to be dependent on the concentration of extracellular calcium. At concentrations of calcium greater than 1.25mM the response started to fall off. This response was not potentiated using either system in the presence of BAY-K 8644 (1uM) but was significantly inhibited in the presence of nifedipine (1muM). 6) Using a submaximal concentration of NA (30nM) in the rat aortic rings either intact or disrupted, in an unbuffered system, again the response was shown to be dependent on the concentration of extracellular calcium. In this system the responses to NA (30nM) were potentiated by BAY-K 8644 (1-100nM). The potentiation was similar regardless of the presence of the endothelium and reached a maximum at BAY-K (10nM). In the presence of this drug the drop in maximum response at high concentrations of calcium was still evident. 7) In the presence of nifedipine (0.1-1muM) the responses to NA (30nM) were inhibited to a similar extent in both intact and disrupted rings. With this drug the drop in the maximum response at high calcium concentrations was not seen

Reproductive outcomes following induced abortion : a national register-based cohort study in Scotland

PMID: 22869092 [PubMed] Free full textPeer reviewedPreprin

Outpatient Treatment with AZD7442 (Tixagevimab/Cilgavimab) Prevented COVID-19 Hospitalizations over 6 Months and Reduced Symptom Progression in the TACKLE Randomized Trial

INTRODUCTION: We assessed effects of AZD7442 (tixagevimab/cilgavimab) on deaths from any cause or hospitalizations due to coronavirus disease 2019 (COVID-19) and symptom severity and longer-term safety in the TACKLE adult outpatient treatment study. METHODS: Participants received 600 mg AZD7442 (n = 452) or placebo (n = 451) ≤ 7 days of COVID-19 symptom onset. RESULTS: Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 (key secondary endpoint) occurred in 20/399 (5.0%) participants receiving AZD7442 versus 40/407 (9.8%) receiving placebo [relative risk reduction (RRR) 49.1%; 95% confidence interval (CI) 14.5, 69.7; p = 0.009] or 50.7% (95% CI 17.5, 70.5; p = 0.006) after excluding participants unblinded before day 169 for consideration of vaccination). AZD7442 reduced progression of COVID-19 symptoms versus placebo through to day 29 (RRR 12.5%; 95% CI 0.5, 23.0) and improved most symptoms within 1-2 weeks. Over median safety follow-up of 170 days, adverse events occurred in 174 (38.5%) and 196 (43.5%) participants receiving AZD7442 or placebo, respectively. Cardiac serious adverse events occurred in two (0.4%) and three (0.7%) participants receiving AZD7442 or placebo, respectively. CONCLUSIONS: AZD7442 was well tolerated and reduced hospitalization and mortality through 6 months, and symptom burden through 29 days, in outpatients with mild-to-moderate COVID-19. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04723394. ( https://beta. CLINICALTRIALS: gov/study/NCT04723394 )

Hepatitis C reinfection following treatment induced viral clearance among people who have injected drugs

Background: Although people who inject drugs (PWID) are an important group to receive Hepatitis C Virus (HCV) antiviral therapy, initiation onto treatment remains low. Concerns over reinfection may make clinicians reluctant to treat this group. We examined the risk of HCV reinfection among a cohort of PWID (encompassing all those reporting a history of injecting drug use) from Scotland who achieved a sustained virological response (SVR). Methods: Clinical and laboratory data were used to monitor RNA testing among PWID who attained SVR following therapy between 2000 and 2009. Data were linked to morbidity and mortality records. Follow-up began one year after completion of therapy, ending on 31st December, 2012. Frequency of RNA testing during follow-up was calculated and the incidence of HCV reinfection estimated. Cox proportional hazards regression was used to examine factors associated with HCV reinfection. Results: Among 448 PWID with a SVR, 277 (61.8%) were tested during follow-up, median 4.5 years; 191 (69%) received one RNA test and 86 (31%) received at least two RNA tests. There were seven reinfections over 410 person years generating a reinfection rate of 1.7/100 py (95% CI 0.7–3.5). For PWID who have been hospitalised for an opiate or injection related cause post SVR (11%), the risk of HCV reinfection was greater [AHR = 12.9, 95% CI 2.2–76.0, p = 0.002] and the reinfection rate was 5.7/100 py (95% CI 1.8–13.3). Conclusion: PWID who have been tested, following SVR, for HCV in Scotland appear to be at a low risk of reinfection. Follow-up and monitoring of this population are warranted as treatment is offered more widely

Late Ebola virus relapse causing meningoencephalitis: a case report

Background: There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods: A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings: On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation: Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis (DEFINE):A Phase Ib/IIa Randomised Controlled Trial

RATIONALE: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. OBJECTIVES: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. METHODS: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. MEASUREMENTS AND MAIN RESULTS: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2–7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. CONCLUSIONS: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020–002230–32)

Patient-, organization-, and system-level barriers and facilitators to preventive oral health care:A convergent mixed-methods study in primary dental care

Background: Dental caries is the most common chronic disease of adult and childhood, a largely preventable yet widespread, costly public health problem. This study identified patient-, organization-, and system-level factors influencing routine delivery of recommended care for prevention and management of caries in primary dental care. Methods: A convergent mixed-methods design assessed six guidance-recommended behaviours to prevent and manage caries (recording risk, risk-based recall intervals, applying fluoride varnish, placing preventive fissure sealants, demonstrating oral health maintenance, taking dental x-rays). A diagnostic questionnaire assessing current practice, beliefs, and practice characteristics was sent to a random sample of 651 dentists in National Health Service (NHS) Scotland. Eight in-depth case studies comprising observation of routine dental visits and dental team member interviews were conducted. Patient feedback was collected from adult patients with recent checkups at case study practices. Key informant interviews were conducted with decision makers in policy, funding, education, and regulation. The Theoretical Domains Framework within the Behaviour Change Wheel was used to identify and describe patient-, organization-, and system-level barriers and facilitators to care. Findings were merged into a matrix describing theoretical domains salient to each behaviour. The matrix and Behaviour Change Wheel were used to prioritize behaviours for change and plan relevant intervention strategies. Results: Theoretical domains associated with best practice were identified from the questionnaire (N-196), case studies (N = 8 practices, 29 interviews), and patient feedback (N = 19). Using the study matrix, key stakeholders identified priority behaviours (use of preventive fissure sealants among 6–12-year-olds) and strategies (audit and feedback, patient informational campaign) to improve guidance implementation. Proposed strategies were assessed as appropriate for immediate implementation and suitable for development with remaining behaviours. Conclusions: Specific, theoretically based, testable interventions to improve caries prevention and management were coproduced by patient-, practice-, and policy-level stakeholders. Findings emphasize duality of behavioural determinants as barriers and facilitators, patient influence on preventive care delivery, and benefits of integrating multi-level interests when planning interventions in a dynamic, resource-constrained environment. Interventions identified in this study are actively being used to support ongoing implementation initiatives including guidance, professional development, and oral health promotion

Neural networks for genetic epidemiology: past, present, and future

During the past two decades, the field of human genetics has experienced an information explosion. The completion of the human genome project and the development of high throughput SNP technologies have created a wealth of data; however, the analysis and interpretation of these data have created a research bottleneck. While technology facilitates the measurement of hundreds or thousands of genes, statistical and computational methodologies are lacking for the analysis of these data. New statistical methods and variable selection strategies must be explored for identifying disease susceptibility genes for common, complex diseases. Neural networks (NN) are a class of pattern recognition methods that have been successfully implemented for data mining and prediction in a variety of fields. The application of NN for statistical genetics studies is an active area of research. Neural networks have been applied in both linkage and association analysis for the identification of disease susceptibility genes