Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 32
Filter
1.
Disabil Rehabil ; : 1-7, 2024 May 13.
Article in English | MEDLINE | ID: mdl-38738835

ABSTRACT

PURPOSE: To explore patient and clinician perceptions of blunt chest trauma management and recovery, when discharged directly home from the Emergency Department (ED). METHODS: This was a qualitative study, completed in a trauma unit in Wales. Blunt chest trauma was defined as an isolated blunt injury to the chest wall, resulting in bruising or rib fractures. Data collection involved semi-structured telephone interviews and focus groups with patients and clinicians respectively. Data analysis was completed using reflexive thematic coding. RESULTS: Twelve patient interviews and three focus groups (23 clinicians) were conducted. In the interviews, seven males and five females participated, with a mean age of 54 years (range 28-74). Clinicians included nurses, doctors, and therapists. Two main themes emerged; 1) the ED experience and 2) recovery once home; each with a number of sub-themes. Results highlighted the significant impact of pain on recovery, and that there is a disjuncture between organisational perspectives of clinicians, and the individual personal perspective of patients. DISCUSSION: Recovery from blunt chest trauma for patients discharged directly home from the ED is a challenging and complex process. Protocol-driven care does not always lead to good patient experience, as it focuses primarily on hospital services and resources.


Recovery from blunt chest trauma is a complex process, leading to poor outcomes including pain and disability.Protocol-driven care of blunt chest trauma does not always lead to a good patient experience.Patients with blunt chest trauma benefit from reassurance that their severity of pain is normal, prior to discharge home from the Emergency Department (ED).Education regarding pacing activity, rest, and reliance on others for a period of time following injury can lead to an improved recovery experience.

2.
Front Neurol ; 15: 1364217, 2024.
Article in English | MEDLINE | ID: mdl-38682037

ABSTRACT

Introduction: Diabetes is associated with an increased risk of stroke. In many cases, a diabetes diagnosis may predate a stroke; however, diabetes is often diagnosed during the hospital admission following a stroke. To explore the experiences of stroke survivors as they cope with a new diabetes diagnosis, particularly regarding developing an effective strategy for managing the disease. Methods: A qualitative grounded theory approach was used that employed focus group interviews with participants, including clinicians and stroke survivors, to develop a holistic understanding of primary and secondary stroke care services and the experiences of those accessing them. Results: Clinicians believed they were not optimally equipped to manage diabetes as a condition. They believed more emphasis should be placed on self-management, which would be better managed by lifestyle changes than medication alone. Conversely, stroke survivors with diabetes experienced an additional burden associated with the diagnoses but relied on clinicians to manage their diabetes and believed the clinicians were failing if they were unwilling or unable to achieve this. Discussion: The research highlights the tensions between stroke survivors and healthcare professionals. Stroke survivors relied on the healthcare teams to provide the optimal treatment when they had recently undergone a significant health event where they had experienced a stroke and received a diabetes diagnosis. However, the healthcare teams, while recognizing the importance of a holistic and comprehensive treatment package, struggled to provide it due to resource limitations. To optimize post-stroke diabetes self-management education, a strategic framework that prioritizes patient empowerment and interdisciplinary collaboration is paramount. Tailoring educational interventions to align with individual patient profiles-considering their unique health status, personal preferences, and cultural context-is essential for fostering self-efficacy. Such a strategy not only empowers patients to take an active role in managing their diabetes post-stroke but also contributes to superior health outcomes and an elevated standard of living.

3.
Elife ; 132024 Mar 01.
Article in English | MEDLINE | ID: mdl-38426402

ABSTRACT

Investigating how, when, and what subjects learn during decision-making tasks requires tracking their choice strategies on a trial-by-trial basis. Here, we present a simple but effective probabilistic approach to tracking choice strategies at trial resolution using Bayesian evidence accumulation. We show this approach identifies both successful learning and the exploratory strategies used in decision tasks performed by humans, non-human primates, rats, and synthetic agents. Both when subjects learn and when rules change the exploratory strategies of win-stay and lose-shift, often considered complementary, are consistently used independently. Indeed, we find the use of lose-shift is strong evidence that subjects have latently learnt the salient features of a new rewarded rule. Our approach can be extended to any discrete choice strategy, and its low computational cost is ideally suited for real-time analysis and closed-loop control.


Subject(s)
Choice Behavior , Learning , Humans , Rats , Animals , Bayes Theorem , Reward , Primates
4.
Neurosciences (Riyadh) ; 29(1): 44-50, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38195138

ABSTRACT

OBJECTIVES: To explore the barriers preventing pioglitazone use in stroke survivors and primary and secondary stroke care services. METHODS: A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its side effects (SEs) associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022. RESULTS: A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its SEs associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022. CONCLUSION: These strategies might allow greater treatment adherence by stroke survivors and increased confidence of the health care professionals in their practice. The findings suggest that further research will be needed to facilitate wider usage of pioglitazone in treating people with stroke and health education is necessitate when using diabetes drugs post-stroke.


Subject(s)
Diabetes Mellitus , Stroke , Humans , Pioglitazone/therapeutic use , Comorbidity , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology , Stroke/complications , Stroke/drug therapy , Survivors
5.
Injury ; 52(9): 2565-2570, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34246478

ABSTRACT

INTRODUCTION: There is no universal agreement or supporting evidence for the content or format of a standardised guidance document for patients with blunt chest wall trauma. The aim of this study is to investigate current UK Emergency Medicine practice of the management of patients with blunt chest wall trauma, who do not require admission to hospital. METHODS: This was a cross-sectional survey study, with mixed quantitative / qualitative analysis methods. A convenience sample of all professions working in the Emergency Departments / Urgent Care Centres in the UK was used. A combination of closed and open-ended questions were included, covering demographics and current practice in the respondent's main place of work. Themes explored included management strategies for safe discharge home, risk prediction and variables considered relevant for inclusion in patient guidance. RESULTS: A total of 113 clinicians responded from all UK trauma networks, including all devolved nations. A total of 20 different risk prediction tools / pathways were reported to be used when assessing whether a patient is safe for discharge home, with over 35 different variables listed by respondents as being important to highlight to patients. Qualitative analysis revealed that a small number of respondents believe patients can be better managed through the improvement of the following; identification of the high-risk patient, initial assessment and current management strategies used in the ED / UCC. DISCUSSION: The wide variation in practice highlighted in this study may be due in part to a lack of national consensus guidelines on how to manage this complex patient group. Further research is needed into whether structured national guidelines for the assessment and management of such patients could potentially lead to an overall improvement in outcomes. Such guidelines should be developed by not only expert clinicians and researchers, but also and more importantly by those service-users who have lived experience of blunt chest wall trauma.


Subject(s)
Thoracic Wall , Cross-Sectional Studies , Emergency Service, Hospital , Hospitals , Humans , Surveys and Questionnaires , United Kingdom/epidemiology
6.
7.
Kidney Int Rep ; 6(2): 449-459, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33615070

ABSTRACT

INTRODUCTION: We aimed to determine the mortality rate, cause of death, and rate of end-stage kidney disease (ESKD) in adults with nephrotic syndrome (NS). METHODS: We conducted a national registry-based study, including all 522 adults who had a kidney biopsy for NS in Scotland in 2014-2017. We linked the Scottish Renal Registry to death certificate data. We performed survival and Cox proportional hazards analyses, accounting for competing risks of death and ESKD. We compared mortality rates with those in the age- and sex-matched general population. RESULTS: A total of 372 patients had primary NS; 150 had secondary NS. Over a median follow-up of 866 days, 110 patients (21%) died. In patients with primary NS, observed versus population 3-year mortality was 2.1% (95% CI 0.0%-4.6%) versus 0.9% (0.8%-1.0%) in patients aged <60 years and 24.9% (18.4%-30.8%) versus 9.4% (8.3%-10.5%) in those aged ≥60 years. In secondary NS, this discrepancy was 17.1% (5.6%-27.2%) versus 1.1% (0.9%-1.2%) in <60-year-olds and 49.4% (36.6%-59.7%) versus 8.1% (6.6%-9.6%) in ≥60-year-olds. In primary NS, cardiovascular causes accounted for 28% of deaths, compared with 18% in the general population. Eighty patients (15%) progressed to ESKD. Incidence of ESKD by 3 years was 8.4% (95% CI 4.9%-11.7%) in primary and 35.1% (24.3%-44.5%) in secondary NS. Early remission of proteinuria and the absence of early acute kidney injury (AKI) were associated with lower rates of death and ESKD. CONCLUSIONS: Adults with NS have high rates of death and ESKD. Cardiovascular causes account for excess mortality in primary NS.

8.
BMC Nephrol ; 21(1): 419, 2020 10 01.
Article in English | MEDLINE | ID: mdl-33004002

ABSTRACT

BACKGROUND: Infection with the severe acute respiratory coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic with coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, overwhelming healthcare systems globally. Preliminary reports suggest a high incidence of infection and mortality with SARS-CoV-2 in patients receiving kidney replacement therapy (KRT). The aims of this study are to report characteristics, rates and outcomes of all patients affected by infection with SARS-CoV-2 undergoing KRT in Scotland. METHODS: Study design was an observational cohort study. Data were linked between the Scottish Renal Registry, Health Protection Scotland and the Scottish Intensive Care Society Audit Group national data sets using a unique patient identifier (Community Health Index (CHI)) for each individual by the Public Health and Intelligence unit of Public Health, Scotland. Descriptive statistics and survival analyses were performed. RESULTS: During the period 1st March 2020 to 31st May 2020, 110 patients receiving KRT tested positive for SARS-CoV-2 amounting to 2% of the prevalent KRT population. Of those affected, 86 were receiving haemodialysis or peritoneal dialysis and 24 had a renal transplant. Patients who tested positive were older and more likely to reside in more deprived postcodes. Mortality was high at 26.7% in the dialysis patients and 29.2% in the transplant patients. CONCLUSION: The rate of detected SARS-CoV-2 in people receiving KRT in Scotland was relatively low but with a high mortality for those demonstrating infection. Although impossible to confirm, it appears that the measures taken within dialysis units coupled with the national shielding policy, have been effective in protecting this population from infection.


Subject(s)
Betacoronavirus/isolation & purification , Communicable Disease Control/organization & administration , Coronavirus Infections , Kidney Failure, Chronic , Kidney Transplantation/statistics & numerical data , Pandemics , Pneumonia, Viral , Renal Replacement Therapy , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Female , Humans , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/surgery , Kidney Failure, Chronic/therapy , Male , Middle Aged , Mortality , Outcome and Process Assessment, Health Care , Pandemics/prevention & control , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Public Health/methods , Registries/statistics & numerical data , Renal Replacement Therapy/methods , Renal Replacement Therapy/statistics & numerical data , SARS-CoV-2 , Scotland/epidemiology
9.
Wellcome Open Res ; 5: 276, 2020.
Article in English | MEDLINE | ID: mdl-33585703

ABSTRACT

Background: The impact of the coronavirus disease 2019 (COVID-19) pandemic on people with multiple sclerosis (MS) is a major current concern, in particular the risk of death. Here we describe the impact of the first wave of COVID-19 infections (Mar 2020-July 2020) on the Scottish MS Register (SMSR) population, a cohort of 4702 individuals with MS, all newly diagnosed in the past decade. Methods: We established a clinician alert system, linking the SMSR with the Electronic Communication of Surveillance in Scotland (ECOSS). This allows identification of patients within this cohort who had a positive SARS-CoV-2 PCR test. The SMSR was also linked to death records from National Records Scotland. Results: Of 4702 people with MS, 246 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR tests were performed, of which 17 were positive. The proportion of positive tests were similar to the general Scotland population (Observed PCR confirmed cases = 17, expected = 17.5, O/E = 0.97, 95% CI: 0.60 - 1.56, p=.90). Between 1 st March - 31 st July 2020 12 individuals on the SMSR died, 5 of which were linked to COVID-19 (1 PCR confirmed, 4 clinical diagnoses without PCR confirmation). This number of COVID-19-related deaths was higher than expected (observed deaths = 5, expected deaths = 1.2, O/E = 4.03, 95% CI = 1.48 - 8.94, p=.01). All COVID-19-related deaths in the SMSR occurred in individuals with advanced disability (Expanded Disability Status Scale ≥7), and no deaths occurred in patients receiving disease modifying therapy (DMT) therapies. Conclusion: In this nationally comprehensive cohort of MS patients diagnosed in Scotland within the past 10 years, we observed similar rates of PCR-confirmed SARS-CoV-2 infection compared to the general Scottish population, but a small number of excess COVID-19 related deaths. These deaths occurred in individuals with advanced disability who were not receiving DMTs.

10.
J Neurol ; 266(10): 2376-2386, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31187189

ABSTRACT

BACKGROUND: Fifteen regional studies published over the last six decades surveying prevalence, mortality and hospital admissions have suggested that Scotland is amongst the highest risk nations for multiple sclerosis (MS) in the world. However, substantial intranational variation in rates (between regions) has been described in numerous countries, including in the only previous Scottish national survey, which used hospital admission data, to address this issue. Against this backdrop, the Scottish Multiple Sclerosis Register (SMSR) was established in 2010 to prospectively collect nationally comprehensive incidence data and to allow for regional comparisons. METHODS: Here, we present the SMSR and analyse the variation in crude and age-sex standardized incidence rates, lifetime risk (cumulative incidence), and the sex distribution of cases and rates, between the 14 administrative Health Boards or regions of Scotland: 01 January 2010 to 31 December 2017. RESULTS: The overall incidence rate for Scotland was 8.76/100,000 person-years (standardized: 8.54). Regional incidence rates varied significantly-up to threefold-between Health Boards (p < 1 × 10-13). The national female-to-male sex ratio was 2.3:1, but this too varied regionally (outlier regions result in a range from 1.0 to 4.2:1). Lifetime risk ranged from 19.9/1000 for females in Orkney (58.98°N) to 1.6/1000 for males in the Borders (55.60°N). Comparison with a previous national survey suggests that these differences are longstanding. In 6 of 14 regions the lifetime risk for women exceeds 1%. CONCLUSIONS: This study introduces a national incidence register: a valuable research tool and the result of substantial public investment. The wide variation in incidence rates and sex ratios between regions, in a relatively homogenous population, raises questions for future study.


Subject(s)
Multiple Sclerosis/epidemiology , Registries/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Incidence , Male , Middle Aged , Scotland/epidemiology , Sex Factors , Young Adult
12.
Behav Brain Res ; 355: 90-94, 2018 12 14.
Article in English | MEDLINE | ID: mdl-29709608

ABSTRACT

Uncertain reward outcomes are characterised by statistical parameters that capture the numerical values of the underlying probability distributions of reward values, including the expected value, risk (variance) and probability. Here we show coding of an integrated expected value signal by single orbitofrontal neurons in response to visual cues predicting uncertain rewards. Separate subpopulations of orbitofrontal neurons predominantly code the prediction of one statistical parameter with few neurons showing combined coding. These signals are likely combined with subjective value signals to inform learning and decision making under conditions of uncertainty.


Subject(s)
Anticipation, Psychological/physiology , Neurons/physiology , Prefrontal Cortex/physiology , Reward , Uncertainty , Animals , Cues , Macaca mulatta , Male , Models, Statistical , Saccades/physiology , Visual Perception/physiology
13.
Disaster Med Public Health Prep ; 12(5): 563-566, 2018 10.
Article in English | MEDLINE | ID: mdl-29552993

ABSTRACT

Ebola is a high consequence infectious disease-a disease with the potential to cause outbreaks, epidemics, or pandemics with deadly possibilities, highly infectious, pathogenic, and virulent. Ebola's first reported cases in the United States in September 2014 led to the development of preparedness capabilities for the mitigation of possible rapid outbreaks, with the Centers for Disease Control and Prevention (CDC) providing guidelines to assist public health officials in infectious disease response planning. These guidelines include broad goals for state and local agencies and detailed information concerning the types of resources needed at health care facilities. However, the spatial configuration of populations and existing health care facilities is neglected. An incomplete understanding of the demand landscape may result in an inefficient and inequitable allocation of resources to populations. Hence, this paper examines challenges in implementing CDC's guidance for Ebola preparedness and mitigation in the context of geospatial allocation of health resources and discusses possible strategies for addressing such challenges. (Disaster Med Public Health Preparedness. 2018;12:563-566).


Subject(s)
Disaster Planning/methods , Disease Outbreaks/prevention & control , Centers for Disease Control and Prevention, U.S./organization & administration , Communicable Diseases/epidemiology , Disaster Planning/legislation & jurisprudence , Disease Outbreaks/legislation & jurisprudence , Geographic Mapping , Humans , Policy Making , Public Health/legislation & jurisprudence , Public Health/methods , United States
14.
PLoS One ; 11(1): e0146350, 2016.
Article in English | MEDLINE | ID: mdl-26771551

ABSTRACT

Effective response planning and preparedness are critical to the health and well-being of communities in the face of biological emergencies. Response plans involving mass prophylaxis may seem feasible when considering the choice of dispensing points within a region, overall population density, and estimated traffic demands. However, the plan may fail to serve particular vulnerable subpopulations, resulting in access disparities during emergency response. For a response plan to be effective, sufficient mitigation resources must be made accessible to target populations within short, federally-mandated time frames. A major challenge in response plan design is to establish a balance between the allocation of available resources and the provision of equal access to PODs for all individuals in a given geographic region. Limitations on the availability, granularity, and currency of data to identify vulnerable populations further complicate the planning process. To address these challenges and limitations, data driven methods to quantify vulnerabilities in the context of response plans have been developed and are explored in this article.


Subject(s)
Disaster Planning , Emergency Responders , Humans
15.
J Emerg Manag ; 13(3): 227-38, 2015.
Article in English | MEDLINE | ID: mdl-26150366

ABSTRACT

OBJECTIVE: The study focused on the methodological advancement and analytical approach of using multilevel data to define population vulnerability and risk in bioemergency disaster planning. METHODS: The authors considered two types of vulnerabilities, transportation vulnerability that stems from lack of access to transportation (public or private) and communication vulnerability that stems from unavailability of needed language-specific communication resources. The authors used Transit Authority general transit feed data and the American Community Survey 5-year estimate data (2006-2010 summary files) to quantify these vulnerabilities. These data were integrated with Topologically Integrated Geographic Encoding and Referencing (TIGER) data for spatial analysis. A response plan was generated for Tarrant County, TX, and deemed feasible before consideration of vulnerable populations. RESULTS: The results point to the importance of integrating geographical and population demographic features that represent potential barriers to the optimum distribution and utilization of resources into the analysis of response plans. An examination of transportation vulnerabilities indicate that, of those vulnerable in Tarrant County, nearly 23,000 individuals will be at-risk of not being able to reach the Point Of Dispensing (POD) to obtain services as they are beyond walking distance to the POD and lack access to transportation resources. The analysis of language vulnerability depicts an uneven distribution resulting in nonuniform demand at PODs for translation resources. There are more than 11,000 at-risk households in the South East region of Tarrant County alone that are truly in need of translation services. CONCLUSIONS: The authors demonstrated that multiple vulnerabilities at each POD can be quantified by aggregating the vulnerability at the available granularity (ie, all blocks or block groups) in a given service area. The quantification of vulnerability at each service area facilitates a POD-based at-risk analysis for the response plan. Disparities stemming from social, behavioral, cultural, economic, and health characteristics of diverse subpopulations could induce the need for additional targeted resources to support emergency response efforts.


Subject(s)
Disaster Planning/organization & administration , Emergency Responders , Health Services Needs and Demand , Vulnerable Populations/statistics & numerical data , Data Collection , Health Services Accessibility , Humans
16.
J Physiol Paris ; 109(1-3): 70-7, 2015.
Article in English | MEDLINE | ID: mdl-24954027

ABSTRACT

Risk is a ubiquitous feature of the environment for all organisms. Very few things in life are achieved with absolute certainty. Therefore, it is essential that organisms process risky information efficiently to promote adaptive behaviour and enhance survival. Here we outline a clear definition of economic risk derived from economic theory and focus on two experiments in which we have shown subpopulations of single neurons in the orbitofrontal cortex of rhesus macaques that code either economic risk per se or an error-related risk signal, namely a risk prediction error. These biological risk signals are essential for processing and updating risky information in the environment to contribute to efficient decision making and adaptive behaviour.


Subject(s)
Decision Making/physiology , Neurons/physiology , Prefrontal Cortex/cytology , Reward , Animals , Prefrontal Cortex/physiology , Risk-Taking
17.
IEEE Trans Syst Man Cybern Syst ; 44(12): 1569-1583, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25419503

ABSTRACT

Computational tools are needed to make data-driven disaster mitigation planning accessible to planners and policymakers without the need for programming or GIS expertise. To address this problem, we have created modules to facilitate quantitative analyses pertinent to a variety of different disaster scenarios. These modules, which comprise the REsponse PLan ANalyzer (RE-PLAN) framework, may be used to create tools for specific disaster scenarios that allow planners to harness large amounts of disparate data and execute computational models through a point-and-click interface. Bio-E, a user-friendly tool built using this framework, was designed to develop and analyze the feasibility of ad hoc clinics for treating populations following a biological emergency event. In this article, the design and implementation of the RE-PLAN framework are described, and the functionality of the modules used in the Bio-E biological emergency mitigation tool are demonstrated.

18.
J Neurosci ; 33(40): 15810-4, 2013 Oct 02.
Article in English | MEDLINE | ID: mdl-24089488

ABSTRACT

Risk is a ubiquitous feature of life. It plays an important role in economic decisions by affecting subjective reward value. Informed decisions require accurate risk information for each choice option. However, risk is often not constant but changes dynamically in the environment. Therefore, risk information should be updated to the current risk level. Potential mechanisms involve error-driven updating, whereby differences between current and predicted risk levels (risk prediction errors) are used to obtain currently accurate risk predictions. As a major reward structure, the orbitofrontal cortex is involved in coding key reward parameters such as reward value and risk. In this study, monkeys viewed different visual stimuli indicating specific levels of risk that deviated from the overall risk predicted by a common earlier stimulus. A group of orbitofrontal neurons displayed a risk signal that tracked the discrepancy between current and predicted risk. Such neuronal signals may be involved in the updating of risk information.


Subject(s)
Action Potentials/physiology , Behavior, Animal/physiology , Decision Making/physiology , Frontal Lobe/physiology , Neurons/physiology , Animals , Cues , Learning/physiology , Macaca mulatta , Male , Reward , Risk
19.
Int J Pharm ; 456(2): 390-9, 2013 Nov 18.
Article in English | MEDLINE | ID: mdl-24016741

ABSTRACT

Local gene delivery represents a promising therapeutic approach for diseases of the intestine. However, the gastrointestinal tract poses significant challenges to successful gene delivery. Cyclodextrins (CDs) have been extensively investigated as non-viral vectors. Here, we assessed the suitability of an amphiphilic cationic CD for intestinal gene transfer, with particular focus on extracellular barriers. Stability and transfection efficiency of CD·DNA complexes were assessed post incubation in simulated gastric and intestinal fluids, bile salts and mucin, or with intestinal enzymes to represent extracellular barriers to intestinal gene delivery. Stability was determined by gel electrophoresis and transfection was measured by luciferase expression in intestinal epithelial cells (Caco-2). Transfection efficiency of CD·DNA complexes was enhanced after incubation in bile salts but was reduced after incubation in gastric and intestinal fluids and mucin. CD·DNA complexes were stable after incubation with pancreatic enzymes and with a model lower intestinal enzyme. Furthermore, the CD protected pDNA from degradation by DNase. In summary, physiologically relevant in vitro models were established and used to quantify the barriers posed by the intestinal extracellular environment to gene delivery. This systematic assessment identified the advantages and limitations of the CD vector and facilitated the proposal of formulation strategies to overcome these barriers.


Subject(s)
Cyclodextrins/administration & dosage , Extracellular Fluid/drug effects , Gastrointestinal Tract , Gene Transfer Techniques , Animals , Caco-2 Cells , Cell Survival/drug effects , Cell Survival/physiology , Cyclodextrins/genetics , Cyclodextrins/pharmacokinetics , Extracellular Fluid/metabolism , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/metabolism , Humans , Swine
20.
J Pharm Pharmacol ; 64(8): 1063-73, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22775209

ABSTRACT

OBJECTIVES: Achieving targeted delivery of gene medicines is desirable to maximise activity. Here, galactosylated amphiphilic cyclodextrins (CDs) are examined in terms of their ability to transfect asialoglycoprotein receptor-bearing HepG2 cells. METHODS: Cationic amphiphilic CDs were synthesised as well as amphiphilic CDs bearing galactose-targeting ligands with different linker lengths. Binding of galactosylated CDs to a galactose-specific lectin was examined by surface plasmon resonance. CDs were formulated with and without the helper lipid DOPE and complexed with plasmid DNA. Transfection was evaluated by luciferase assay. Intracellular trafficking was assessed by confocal microscopy. KEY FINDINGS: Binding of targeted CDs to a galactose-specific lectin was achieved. Binding decreased with linker length between the galactosyl group and the CD core. Contrary to the lectin binding results, transfection levels increased with an increase in linker length from 7 atoms to 15. Compared to non-targeted formulations, a significant increase in transfection was observed only in the presence of the helper lipid DOPE. Confocal microscopy revealed that DOPE caused a pronounced effect on cellular distribution. CONCLUSIONS: The galactose-targeting ligand induced substantial increases in transfection over non-targeted formulations when DOPE was included, indicating the potential for targeted gene delivery using CD-based delivery systems.


Subject(s)
Asialoglycoprotein Receptor/genetics , Cyclodextrins/metabolism , DNA/administration & dosage , Galactose/metabolism , Gene Targeting , Hepatocytes/metabolism , Transfection , Cations , Genetic Therapy , Hep G2 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Lectins/metabolism , Lipids , Luciferases/metabolism , Microscopy, Confocal , Phosphatidylethanolamines/metabolism , Plasmids
SELECTION OF CITATIONS
SEARCH DETAIL
...