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"Harrison, Tim"
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Towards a personalised treatment approach for asthma attacks
Asthma attacks (exacerbations) are common, accounting for over 90 000 UK hospital admissions per annum. They kill nearly 1500 people per year in the UK, have significant associated direct and indirect costs and lead to accelerated and permanent loss of lung function. The recognition of asthma as a heterogeneous condition with multiple phenotypes has revolutionised the approach to the long-term management of the condition, with greater emphasis on personalised treatment and the introduction of the treatable traits concept. In contrast asthma attacks are poorly defined and understood and our treatment approach consists of bronchodilators and systemic corticosteroids. This review aims to explore the current limitations in the description, assessment and management of asthma attacks. We will outline the risk factors for attacks, strategies to modify this risk and describe the recognised characteristics of attacks as a first step towards the development of an approach for phenotyping and personalising the treatment of these critically important events. By doing this, we hope to gradually improve asthma attack treatment and reduce the adverse effects associated with recurrent courses of corticosteroids.
Journal Article
Who was Edgar Allan Poe?
Introduces the inventor of detective fiction and the father of American mystery writers, whose work continues to influence popular culture through films, music, literature, and television today.
BOOK
Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD
Inhaled corticosteroids (ICSs) treatment combined with long-acting β
-adrenoceptor agonists (LABAs) reduces the risk of exacerbations in COPD, but the use of ICSs is associated with increased incidence of pneumonia. There are indications that this association is stronger for fluticasone propionate than for budesonide. We have examined systematic reviews assessing the risk of pneumonia associated with fluticasone propionate and budesonide COPD therapy. Compared with placebo or LABAs, we found that fluticasone propionate was associated with 43%-78% increased risk of pneumonia, while only slightly increased risk or no risk was found for budesonide. We have evaluated conceivable mechanisms which may explain this difference and suggest that the higher pneumonia risk with fluticasone propionate treatment is caused by greater and more protracted immunosuppressive effects locally in the airways/lungs. These effects are due to the much slower dissolution of fluticasone propionate particles in airway luminal fluid, resulting in a slower uptake into the airway tissue and a much longer presence of fluticasone propionate in airway epithelial lining fluid.
Journal Article
The airways microbiome of individuals with asthma treated with high and low doses of inhaled corticosteroids
Inhaled corticosteroids (ICS) are the mainstay of asthma treatment, but evidence suggests a link between ICS usage and increased rates of respiratory infections. We assessed the composition of the asthmatic airways microbiome in asthma patients taking low and high dose ICS and the stability of the microbiome over a 2 week period.
We prospectively recruited 55 individuals with asthma. Of these, 22 were on low-dose ICS and 33 on high-dose ICS (16 on budesonide, 17 on fluticasone propionate). Sputum from each subject underwent DNA extraction, amplification and 16S rRNA gene sequencing of the bacterial component of the microbiome. 19 subjects returned for further sputum induction after 24 h and 2 weeks.
A total of 5,615,037 sequencing reads revealed 167 bacterial taxa in the asthmatic airway samples, with the most abundant being Streptococcus spp. No significant differences in sputum bacterial load or overall community composition were seen between the low- and high-dose ICS groups. However, Streptococcus spp. showed significantly higher relative abundance in subjects taking low-dose ICS (p = 0.002). Haemophilus parainfluenzae was significantly more abundant in subjects on high-dose fluticasone propionate than those on high-dose budesonide (p = 0.047). There were no statistically significant changes in microbiota composition over a 2-week period.
Whilst no significant differences were observed between the low- and high-dose ICS groups, increased abundance of the potential pathogen H. parainfluenzae was observed in patients taking high-dose fluticasone propionate compared to those taking high-dose budesonide. The microbiota were stable over fourteen days, providing novel evidence of the established community of bacteria in the asthmatic airways.
ClinicalTrials.gov NCT02671773.
Journal Article
Prolonged disorders of consciousness: Practice described by palliative and rehabilitation physicians
•63.5% of survey respondents cared for people with prolonged disorders of consciousness at the end of their lives.•44% of clinicians withdraw clinically assisted nutrition and hydration (CANH) in the patient’s usual place of care.•Where a decision to admit is taken, 43% will admit to a hospice inpatient unit.•87% of survey respondents do not arrange long line or central intravenous access prior to withdrawal of CANH.•In 81% of cases, there was no difficulty with symptom management.
National clinical guidelines for the management of prolonged disorders of consciousness (PDOC) following sudden-onset brain injury were updated in 2020. Since then, clinical experience has grown. This paper reports on current practice.
A questionnaire was developed, tested and sent to rehabilitation and palliative medicine specialists, via the British Society of Physical and Rehabilitation Medicine and Association for Palliative Medicine. Anonymised responses were analysed.
63.5% (n = 61) of respondents were involved in the care of people with PDOC, with two-thirds working in palliative medicine. 44% of clinicians withdraw clinically assisted nutrition and hydration (CANH) in the patient’s usual place of care. Where a decision to admit is taken, 43% will admit to a hospice inpatient unit. 87% of respondents do not arrange long line or central intravenous access prior to withdrawal of CANH.
Ninety-five per cent of clinicians prescribe opioids and 92% prescribe sedatives for prn use or directly convert regular medications to a continuous subcutaneous infusion when withdrawing CANH. Most clinicians titrate according to need. In 81% of cases, there was no difficulty with symptom management on withdrawal of CANH.
Forty-eight per cent of respondents worked with staff who expressed a conscientious objection to CANH, 40% in palliative medicine.
National guidance should be updated to reflect clinical practice with regard to place of care, the effectiveness of a subcutaneous route and the use of proportionate symptom management.
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Journal Article
Hepatitis E Virus Produced from Cell Culture Has a Lipid Envelope
The absence of a productive cell culture system hampered detailed analysis of the structure and protein composition of the hepatitis E virion. In this study, hepatitis E virus from a robust HEV cell culture system and from the feces of infected monkeys at the peak of virus excretion was purified by ultra-centrifugation. The common feature of the two samples after ultracentrifugation was that the ORF2 protein mainly remained in the top fractions. The ORF2 protein from cell culture system was glycosylated, with an apparent molecular weight of 88 kDa, and was not infectious in PLC/PRF/5 cells. The ORF2 protein in this fraction can bind to and protect HEV RNA from digestion by RNase A. The RNA-ORF2 product has a similar sedimentation coefficient to the virus from feces. The viral RNA in the cell culture supernatant was mainly in the fraction of 1.15 g/cm3 but that from the feces was mainly in the fraction of 1.21 g/cm3. Both were infectious in PLC/PRF/5 cells. And the fraction in the middle of the gradient (1.06 g/cm3) from the cell culture supernatant,but not that from the feces, also has ORF2 protein and HEV RNA but was not infectious in PLC/PRF/5.The infectious RNA-rich fraction from the cell culture contained ORF3 protein and lipid but the corresponding fraction from feces had no lipid and little ORF3 protein. The lipid on the surface of the virus has no effect on its binding to cells but the ORF3 protein interferes with binding. The result suggests that most of the secreted ORF2 protein is not associated with HEV RNA and that hepatitis E virus produced in cell culture differs in structure from the virus found in feces in that it has a lipid envelope.
Journal Article
Extra-Cellular Matrix Proteins Induce Matrix Metalloproteinase-1 (MMP-1) Activity and Increase Airway Smooth Muscle Contraction in Asthma
Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms.
Journal Article
Experimental Infection of Rabbits with Rabbit and Genotypes 1 and 4 Hepatitis E Viruses
A recent study provided evidence that farmed rabbits in China harbor a novel hepatitis E virus (HEV) genotype. Although the rabbit HEV isolate had 77-79% nucleotide identity to the mammalian HEV genotypes 1 to 4, their genomic organization is very similar. Since rabbits are used widely experimentally, including as models of infection, we investigated whether they constitute an appropriate animal model for human HEV infection.
Forty-two SPF rabbits were divided randomly into eleven groups and inoculated with six different isolates of rabbit HEV, two different doses of a second-passage rabbit HEV, and with genotype 1 and 4 HEV. Sera and feces were collected weekly after inoculation. HEV antigen, RNA, antibody and alanine aminotransferase in sera and HEV RNA in feces were detected. The liver samples were collected during necropsy subject to histopathological examination.
Rabbits inoculated with rabbit HEV became infected with HEV, with viremia, fecal virus shedding and high serum levels of viral antigens, and developed hepatitis, with elevation of the liver enzyme, ALT. The severity of disease corresponded to the infectious dose (genome equivalents), with the most severe hepatic disease caused by strain GDC54-18. However, only two of nine rabbits infected with HEV genotype 4, and none infected with genotype 1, developed hepatitis although six of nine rabbits inoculated with the genotype 1 HEV and in all rabbits inoculated with the genotype 4 HEV seroconverted to be positive for anti-HEV IgG antibody by 14 weeks post-inoculation.
These data indicate that rabbits are an appropriate model for rabbit HEV infection but are not likely to be useful for the study of human HEV. The rabbit HEV infection of rabbits may provide an appropriate parallel animal model to study HEV pathogenesis.
Journal Article
Persistent Hepatitis E Virus Genotype 4 Infection in a Child With Acute Lymphoblastic Leukemia
In general, the hepatitis E virus (HEV) causes acute, self-limiting hepatitis. Prolonged and chronic infections caused by HEV genotype 3 have been found in some immunosuppressed patients in developed countries.
Here we report a Chinese boy with acute lymphoblastic leukemia, who developed hepatitis E during a period of intensive chemotherapy. Twenty months after the initial infection, HEV viremia was reappeared in the patient, with detectable anti-HEV IgM and IgG and modestly elevated serum transaminases. Sequence analysis of the viral RNAs revealed the reactivation of the HEV genotype 4d strain, indicating viral persistence in the patient.
To our knowledge, this is the first chronic case confirmed by the prolonged presence of HEV RNA in china. It is also the first reported persistent hepatitis E infection caused by HEV genotype 4.
Journal Article