ABSTRACT
Peer review has been widely employed within the NHS to facilitate health quality improvement but has not been rigorously evaluated. This article reports the largest randomised trial of peer review ever conducted in the UK. The peer review intervention was a reciprocal supportive exercise that included clinicians, hospital management, commissioners and patients which focused on the quality of the provision of four specific evidence-based aspects of chronic obstructive pulmonary disease care. Follow up at 12 months demonstrated few quantitative differences in the number or quality of services offered in the two groups. Qualitative data in contrast suggested many benefits of peer review in most but not all intervention units and some control teams. Findings suggest peer review in this format is a positive experience for most participants but is ineffective in some situations. Its longer term benefits and cost effectiveness require further study. The generic findings of this study have potential implications for the application of peer review throughout the NHS.
Subject(s)
Outcome Assessment, Health Care , Peer Review, Health Care , Pulmonary Disease, Chronic Obstructive/therapy , State Medicine/organization & administration , Evidence-Based Medicine , Humans , Quality of Health Care , State Medicine/standards , United KingdomABSTRACT
BACKGROUND: Case series and case-control studies have shown high rates of psychosocial and behavioural risk factors amongst patients admitted to hospital with severe asthma. General population studies have shown associations between psychosocial factors and prevalent asthma but few have investigated incident asthma outcomes. METHODS: Data on psychosocial factors and asthma hospital admissions were available for 20 854 participants, aged 41-80 years, in the Norfolk cohort of the European Prospective Investigation into Cancer study. Postal assessments included details of physical functioning, mood disorder history, social adversity and social support. RESULTS: A total of 686 asthma hospital admissions were recorded. Psychosocial factors present at baseline, including current mood disorders, adverse circumstances in childhood, the impact of life events experienced during adulthood and negative perceived support from a close confidant, were associated with increased rates of hospital admission independent of age, sex, indicators of socio-economic status, physical functional health, and obesity. Restricted to those participants who reported lifetime doctor-diagnosed asthma at baseline, the reported impact of adverse life events experienced in adulthood, and both confiding and negative aspects of support quality, were associated with asthma hospital admission. The magnitude of these associations was comparable to those involving indicators of socio-economic status and physical health. CONCLUSIONS: These results show that psychosocial factors are associated with incident asthma hospital admissions and highlight the potential importance of taking account of psychosocial factors, including availability and quality of support networks, in guiding long-term asthma management.
Subject(s)
Asthma/psychology , Patient Admission , Adult , Aged , Aged, 80 and over , Asthma/epidemiology , Cohort Studies , Female , Humans , Incidence , Male , Middle Aged , Mood Disorders/epidemiology , Mood Disorders/psychology , United KingdomSubject(s)
Community-Acquired Infections/diagnosis , Pneumonia, Bacterial/diagnosis , Severity of Illness Index , Urea/blood , Age Factors , Aged , Blood Pressure/physiology , Cohort Studies , Community-Acquired Infections/classification , Community-Acquired Infections/mortality , Confusion/diagnosis , Confusion/etiology , Female , Humans , Male , Pneumonia, Bacterial/classification , Pneumonia, Bacterial/mortality , Respiratory Function Tests , Sensitivity and SpecificityABSTRACT
Difficult asthma must be distinguished from severe asthma. It is then important in patients with suspected difficult asthma to ensure that the diagnosis is correct, and that if the patient has asthma that the attributed symptoms are indeed all genuinely due to the asthma and not to coexisting physical or psychogenic respiratory conditions. It is also important to be alert when there is discordance between symptoms and objective lung function in order to recognize both poor perceivers and over-reactors. Difficult asthma can occur in patients with objectively mild, moderate or severe disease, but the consequences are most dramatic in patients with severe asthma. Asthma may be difficult for the patient, for the clinician or both because of disease factors, doctor or nurse therapist factors, and/or patient factors. Investigation requires access to the full range of respiratory, imaging and allergy tests. It also requires a multidisciplinary approach involving ear, nose and throat specialists and speech therapists, and access to psychiatric and psychological assessment and therapies. Poor compliance is associated with significantly poorer asthma and asthma-related health outcomes. Poor compliance can be recognized in two-thirds of such patients by their not attending scheduled appointments. Poor compliance is significantly associated with anxiety, social deprivation and adverse family circumstances, and these characteristics and adversities probably contribute to the poorly compliant behaviour. In difficult asthma it is important to identify and manage the condition causing the symptoms rather than prescribing more and more asthma therapy. Recognizing psychosocial adversity is essential. A structured approach is essential. There remains a small number of patients with genuine steroid-resistant asthma, some with predominately neutrophilic rather than eosinophilic airway inflammation, and others for whom the secondary gain of continuing symptoms is overwhelming. There is a need for further research using agreed definitions, structured approaches and a full range of investigations in patients with difficult asthma.
Subject(s)
Asthma , Adult , Asthma/diagnosis , Asthma/etiology , Asthma/therapy , Humans , Prognosis , Severity of Illness Index , Treatment OutcomeABSTRACT
BACKGROUND: Morbidity and mortality associated with severe asthma might be reduced by interventions that address psychosocial factors contributing to adverse outcomes. A study was undertaken to assess the effectiveness of a 6 month home based psychoeducational intervention delivered by a respiratory nurse specialist for adults at risk of adverse asthma outcomes. METHODS: A pragmatic randomised controlled trial was performed in 92 adults registered with hospital or primary care asthma clinics. All had previous hospital admissions and/or were on British Thoracic Society step 4-5 treatment and had failed to attend clinic appointments or were considered to have poor adherence to other aspects of their agreed management. Patients were visited in their homes for assessment and, where appropriate, intervention. The main outcomes measured were symptom control, asthma specific quality of life, and generic health status. RESULTS: At the 6 month primary time point there were no significant differences between usual care and intervention groups in mean symptom control, physical functioning, or mental health scores (differences (with 95% CI) -0.35 (-1.83 to 1.13), 3.10 (-11.42 to 17.63), 0.42 (-10.22 to 11.07), respectively). Small effects on asthma specific quality of life up to 12 months (e.g. adjusted difference at 12 months 0.13 (95% CI 0.02 to 0.25)) and short term effects on generic health status, which mirrored improvements in aspects of self-care observed at the end of the intensive phase of the intervention, were apparent only from fully adjusted analyses. CONCLUSIONS: A home based intervention provided by a nurse receiving psychological supervision may have effects on quality of life but is overall of limited long term benefit to adults at risk of adverse asthma outcomes.
Subject(s)
Adaptation, Psychological , Asthma/psychology , Psychotherapy/methods , Adult , Asthma/mortality , Asthma/nursing , Female , Home Care Services , Humans , Male , Patient Education as Topic/methods , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND: Studies have linked asthma death to either increased or decreased use of medical services. METHODS: A population based case-control study of asthma deaths in 1994-8 was performed in 22 English, six Scottish, and five Welsh health authorities/boards. All 681 subjects who died were under the age of 65 years with asthma in Part I on the death certificates. After exclusions, 532 hospital controls were matched to 532 cases for age, district, and date of asthma admission/death. Data were extracted blind from primary care records. RESULTS: The median age of the subjects who died was 53 years; 60% of cases and 64% of controls were female. There was little difference in outpatient attendance (55% and 55%), hospital admission for asthma (51% and 54%), and median inpatient days (20 days and 15 days) in the previous 5 years. After mutual adjustment and adjustment for sex, using conditional logistic regression, three variables were independently associated with asthma death: fewer general practice contacts (odds ratio 0.82 (95% confidence interval (CI) 0.74 to 0.91) per 5 contacts) in the previous year, more home visits (1.14 (95% CI 1.08 to 1.21) per visit) in the previous year, and fewer peak expiratory flow recordings (0.83 (95% CI 0.74 to 0.92) per occasion) in the previous 3 months. These associations were similar after adjustment for markers of severity, psychosocial factors, systemic steroids, short acting bronchodilators and antibiotics, although the association with peak flow was weakened and just lost significance. CONCLUSION: Asthma death is associated with less use of primary care services. Both practice and patient factors may be involved and a better understanding of these may offer possibilities for reducing asthma death.
Subject(s)
Asthma/mortality , Health Services Needs and Demand/statistics & numerical data , Administration, Inhalation , Adult , Anti-Asthmatic Agents/therapeutic use , Asthma/therapy , Case-Control Studies , Female , Forced Expiratory Volume/physiology , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Patient Acceptance of Health Care/statistics & numerical data , Peak Expiratory Flow Rate/physiology , Primary Health Care/statistics & numerical data , Steroids/administration & dosage , United Kingdom/epidemiologyABSTRACT
OBJECTIVES: Prior research has highlighted the importance of psychosocial factors in 'difficult' asthma. This study aimed to review the content, effectiveness and cost-effectiveness of psycho-educational interventions designed to address these factors in patients with severe and difficult asthma. DATA SOURCES: Thirty-two electronic databases and other sources were searched for studies of educational, self-management, psychosocial and multifaceted interventions. REVIEW METHODS: Abstracts were screened in duplicate, against prior definitions, to identify eligible interventions targeted to patients with forms of or risk factors for difficult asthma. Studies were classified by patient group (child, adult) and graded along two dimensions related to study design and relevance in terms of the degree to which they were judged to have targeted difficult asthma. Detailed data were extracted from studies meeting a minimum design and relevance threshold. Characteristics of studies were tabulated and results qualitatively synthesised. Where sufficiently similar studies reported adequate data about comparable outcomes, quantitative syntheses of results were undertaken using a random effects approach to calculate pooled relative risks (RR) or standardised mean differences (SMD), with 95% confidence intervals (CI). RESULTS: Searches identified over 23,000 citations. After initial screening and removal of duplicates, 4240 possibly relevant abstracts were assessed. Papers associated with 188 studies were initially obtained and classified. Fifty-seven studies including control groups and those that were judged to have at least 'possible' targeting of difficult asthma (35 in children, 21 in adults, 1 in both) were selected for in-depth review. The delivery, setting, timing and content of interventions varied considerably even within broad types. Reporting of interventions and methodological quality was often poor, but studies demonstrated some success in targeting and following up at-risk patients. Studies reporting data suitable for calculation of summary statistics were of higher quality than those that did not. There was evidence from these that, compared to usual or non-psycho-educational care, psycho-educational interventions reduced admissions when data from the latest follow-ups reported were pooled across nine studies in children (RR = 0.64, CI = 0.46-0.89) and six studies with possible targeting of difficult asthma in adults (RR = 0.57, CI = 0.34-0.93). In children, the greatest and only significant effects were confined to individual studies with limited targeting of difficult asthma and no long-term follow-up. Limited data in adults also suggested effects may not extend to those most at risk. There was no evidence of pooled effects of psycho-educational interventions on emergency attendances from eight studies in children (RR = 0.97, CI = 0.78-1.21) and four in adults (RR = 1.03, CI = 0.82-1.29). There were overall significant reductions in symptoms, similar in different sub-groups of difficult asthma, across four paediatric studies that could be combined (SMD = -0.45, CI = -0.68 to -0.22), but mixed results across individual adult studies. A few individual studies in children showed mainly positive effects on measures of self-care behaviour, but with respect to all other outcomes in adults and children, studies showed mixed results or suggested limited effectiveness of psycho-educational interventions. No studies of psychosocial interventions were included in any quantitative syntheses and it was not possible to draw clear conclusions regarding the relative effectiveness of educational, self-management and multifaceted programmes. Data on costs were very limited. Of the two well-designed economic evaluations identified, both of multifaceted interventions, one in children suggested an additional cost of achieving health gain in terms of symptom-free days. Provisional data from the other study suggested that in adults the significantly increased costs of providing an intervention were not offset by any short-term savings in use of healthcare resources or associated with improvements in health outcomes. CONCLUSIONS: There was some evidence of overall positive effects of psycho-educational interventions on hospital admissions in adults and children, and on symptoms in children, but limited evidence of effects on other outcomes. The majority of research and greatest effects, especially in adults, were confined to patients with severe disease but who lacked other characteristics indicative of difficult asthma or likely to put them at risk. A lack of good-quality research limited conclusions about cost-effectiveness. Although psycho-educational interventions may be of some benefit to patients with severe disease, there is currently a lack of evidence to warrant significant changes in clinical practice with regard to the care of patients with more difficult asthma. Further research is needed to: (1) standardise reporting of complex interventions; (2) extend and update this review; (3) improve identification of patients at risk from their asthma; (4) develop and test appropriate outcome measures for this group; and (5) design and evaluate, via the conduct of high-quality pragmatic RCTs, more powerful psycho-educational interventions that are conceptualised in terms of the ways in which psychosocial factors and asthma interact.
Subject(s)
Asthma , Patient Education as Topic , Psychotherapy , Self Care , Adult , Asthma/economics , Asthma/psychology , Asthma/therapy , Child , Cost of Illness , Cost-Benefit Analysis , Humans , Patient Education as Topic/economics , Psychotherapy/economics , Psychotherapy/methods , Self Care/economics , Self Care/methods , Treatment OutcomeABSTRACT
BACKGROUND: The Norfolk and Norwich University Hospital (NNUH) is situated in rural Norfolk, and ambulance journey times are often >30 min. Longer ambulance journeys could lead to a greater risk of hypercapnia, if inappropriately high concentrations of oxygen are given during an exacerbation of COPD. AIM: To investigate the effect of high concentration oxygen (HCO, FiO(2) > 0.28) on COPD patients, and the outcome of instituting a simple protocol to reduce such exposure. DESIGN: Retrospective audit. METHOD: An audit was conducted of all patients admitted with an exacerbation of COPD to the NNUH during the 2 months from 1 December 2001 to 31 January 2002 (n = 108). Results were shared with paramedics, and guidelines agreed for the initial provision of lower concentrations of oxygen (LCO, FiO(2) < or = 0.28). A second audit was conducted a year later between 1 December 2002 and 31 January 2003 (n = 103). RESULTS: HCO caused significant (p < 0.01) acidosis and inappropriately high PaO(2) and PaCO(2), compared to initial LCO therapy. There was a significantly increased complication rate during admission (p < 0.01) in those COPD patients receiving HCO compared to LCO, particularly when ambulance journeys exceeded 30 min. The second audit demonstrated a significant (p < 0.001) reduction in the number of patients initially receiving HCO, but the complication rate was unaltered. DISCUSSION: A simple intervention, such as providing paramedics with 28% Venturi masks, can reduce the number of COPD patients exposed to HCO. A randomized controlled trial is long overdue to establish whether HCO or LCO as initial management is associated with the most favourable prognosis in different hospital settings.
Subject(s)
Oxygen Inhalation Therapy/methods , Pulmonary Disease, Chronic Obstructive/therapy , Adult , Aged , Aged, 80 and over , Ambulances , Ambulatory Care/methods , Carbon Dioxide/physiology , Female , Humans , Male , Medical Audit/methods , Middle Aged , Oxygen/physiology , Oxygen Inhalation Therapy/adverse effects , Retrospective Studies , Time FactorsABSTRACT
OBJECTIVES: To assess any change in the microbiological profile of community-acquired pneumonia (CAP) in our region over the last 20 years. METHODS: We compared hospital admissions aged between 15 and 74 (n = 61) in Norfolk (UK) for CAP over a 19-month period in 1982-3 (ST1) with all admissions aged over 16 (n = 99) over a 14-month period in 1999-2000 (ST2). Data were collected for ST1 as part of a prospective multicentred research study, in a period of high Mycoplasma pneumoniae activity. ST2 was a prospective study of clinical practice. Chlamydophila species were differentiated in ST2 using whole-cell immunofluorescence. RESULTS: A microbiological diagnosis was made in 38 (62%) in ST1 compared with 48 (48%) in ST2. Streptococcus pneumoniae remained the most common pathogen (26% in ST1, 25% in ST2). The incidence of M. pneumoniae was 18% in ST1 and 4% in ST2. The proportion of viral pathogens identified was similar: nine (15%) in ST1 and 14 (14%) in ST2. No cases of Chlamydophila pneumoniae were diagnosed in ST2. CONCLUSIONS: The microbiological profile of CAP in Norfolk (UK) has not changed over the last 20 years and C. pneumoniae is not a frequent pathogen.
Subject(s)
Community-Acquired Infections/microbiology , Pneumonia, Bacterial/microbiology , Pneumonia, Viral/microbiology , Adolescent , Adult , Aged , Chlamydophila/isolation & purification , Humans , Middle Aged , Mycoplasma pneumoniae/isolation & purification , Prospective Studies , Streptococcus pneumoniae/isolation & purificationABSTRACT
In this retrospective pilot study we examine the feasibility of establishing a confidential enquiry into why some patients die after emergency admission to hospital. After excluding those who died in the first hour or who were admitted for palliative care, pairs of physicians were able to collect quantitative and qualitative data on 200 consecutive deaths. Both physicians reported shortfalls of care in 14 patients and one of the pair in 25 patients whose deaths would not have been the expected outcome. In 25, the shortfalls of care may have contributed to their deaths. Major problems were delays in seeing doctors, inaccurate diagnoses, delays in investigations and initiation of treatment. They occurred mostly in those admitted at night. It is possible that establishing the correct diagnosis and starting appropriate treatment may have been delayed in 64% of the 200 patients. The headline figures appear worse than some previous external assessment studies but this study did concentrate on those in whom problems were more likely. Nevertheless, the frequency is too high to be overlooked. In this feasibility study we have demonstrated that it is practicable for local staff to collect and assess data in hospitals and that the types of problems identified are relevant to anyone planning how to organise emergency care. A larger definitive study should be performed.
Subject(s)
Cause of Death , Emergency Medical Services/statistics & numerical data , Hospital Mortality , Quality of Health Care/statistics & numerical data , Aged , Aged, 80 and over , Databases as Topic , England , Feasibility Studies , Female , Humans , Male , Middle Aged , Pilot Projects , Retrospective Studies , Risk FactorsABSTRACT
Community-acquired pneumonia (CAP) is the most common reason for acute admission to hospital and the fourth most common cause of death in the UK. It is important to identify patients with severe pneumonia and the worst prognosis. We conducted this study to validate a rule designed to do this devised in New Zealand. CAP was defined by evidence of new shadowing on the chest X-ray and clinical features of pneumonia. A standardised proforma was completed documenting clinical features and investigation results. Severe pneumonia was identified by two or more of the following: confusion; respiratory rate > or = 30/min; diastolic blood pressure < or = 60 mmHg; urea >7 mmol/l. One hundred patients (mean age 58.8 years) were included; 32 satisfied the rule. Seven died, all of whom satisfied the rule. Ten patients received intensive care, including six who died. Of 11 patients who died and/or received intensive care, nine satisfied the rule. The sensitivity and specificity of the rule for predicting death and/or intensive care were 82% and 73% respectively.
Subject(s)
Community-Acquired Infections/diagnosis , Pneumonia/diagnosis , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Blood Pressure , Community-Acquired Infections/blood , Community-Acquired Infections/diagnostic imaging , Community-Acquired Infections/mortality , Community-Acquired Infections/physiopathology , Confusion/etiology , Critical Care , Diastole , Hospitalization , Humans , Middle Aged , Pneumonia/blood , Pneumonia/diagnostic imaging , Pneumonia/mortality , Pneumonia/physiopathology , Predictive Value of Tests , Prognosis , Radiography, Thoracic , Respiration , Risk Factors , Sensitivity and Specificity , United Kingdom , Urea/bloodABSTRACT
BACKGROUND: Uncontrolled studies suggest that psychosocial factors and health behaviour may be important in asthma death. METHODS: A community based case-control study of 533 cases, comprising 78% of all asthma deaths under age 65 years and 533 hospital controls individually matched for age, district and asthma admission date corresponding to date of death was undertaken in seven regions of Britain (1994-98). Data were extracted blind from anonymised copies of primary care records for the previous 5 years and non-blind for the earlier period. RESULTS: 60% of cases and 63% of controls were female. The median age in both groups was 53. Cases had an earlier age of asthma onset, more chronic obstructive lung disease, and were more obese. 48% of cases and 42% of controls had a health behaviour problem; repeated non-attendance/poor inhaler technique was related to increased risk of death. Overall, 85% and 86%, respectively, had a psychosocial problem. Four psychosocial factors were associated with increased risk of death (psychosis, alcohol/drug abuse, financial/employment problems, learning difficulties) and two with reduced risk (anxiety/prescription of antidepressant drugs and sexual problems). While alcohol/drug abuse lost significance after adjustment for psychosis, other associations appeared independent of each other and of indicators of severity and co-morbidity. None of the remaining 13 factors including family problems, domestic abuse, bereavement, and social isolation were significantly related to risk of asthma death. CONCLUSION: There was an apparently high burden of psychosocial problems in both cases and controls. The associations between health behaviour, psychosocial factors, and asthma death are varied and complex with a limited number of factors showing positive relationships.
Subject(s)
Asthma/mortality , Adolescent , Adult , Age of Onset , Asthma/psychology , Asthma/therapy , Case-Control Studies , Child , Child, Preschool , Female , Health Behavior , Humans , Infant , Infant, Newborn , Male , Middle Aged , Patient Compliance , Psychology, Social , Risk Factors , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Systemic corticosteroids and inhaled beta(2) agonists are accepted first line treatments for acute severe asthma, but there is no consensus on their optimum dosage and frequency of administration. American regimens include higher initial dosages of beta(2) agonists and corticosteroids than UK regimens. METHODS: In a prospective, pragmatic, randomised, parallel group study, 170 patients of mean (SD) age 37 (12) years with acute asthma (peak expiratory flow (PEF) 212 (80) l/min) presenting to hospital received treatment with either high dose prednisolone and continuous nebulised salbutamol as recommended in the US or lower dose prednisolone and bolus nebulised salbutamol as recommended in the UK by the BTS. RESULTS: Outcome measures were: deltaPEF at 1 hour (BTS 89 l/min, US 106 l/min, p=0.2, CI -8 to 41) and at 2 hours (BTS 49 l/min, US 101 l/min, p<0.0001, CI 28 to 77); time to discharge if admitted (BTS 4 days, US 4 days); rates of achieving discharge PEF (>60%) at 2 hours (BTS 64%, US 78%, p=0.04); time to regain control of asthma as measured by PEF >/=80% best with =20% variability (BTS 3 days, US 4 days, p=0.6); PEF at 24 hours in patients admitted (BTS 293 l/min, US 288 l/min, p=0.8); and control of asthma in the subsequent month (no significant differences). CONCLUSIONS: Treatment with higher doses of continuous nebulised salbutamol leads to a greater immediate improvement in PEF but the degree of recovery at 24 hours and speed of recovery thereafter is achieved as effectively with lower corticosteroid doses as recommended in the British guidelines.
Subject(s)
Adrenergic beta-Agonists/administration & dosage , Albuterol/administration & dosage , Asthma/drug therapy , Glucocorticoids/administration & dosage , Prednisolone/administration & dosage , Administration, Inhalation , Adult , Asthma/physiopathology , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Peak Expiratory Flow Rate/physiology , Prospective Studies , United Kingdom , United StatesABSTRACT
AIMS: The airways of patients with asthma are characterized by chronic inflammatory changes comprising mainly T-cells and eosinophils, and airway remodelling with goblet cell metaplasia and submucosal gland hyperplasia. Mucus hypersecretion is often a marked feature, particularly in status asthmaticus. The matrix of airway sputum consists of high molecular glycoproteins and mucins. In this study, the expression and distribution of the major gel-forming mucins MUC5AC and MUC5B were studied in fatal status asthmaticus tissues and bronchial biopsies of mild asthmatic patients. The effect of inhaled corticosteroids on the expression of these mucins was also investigated. METHODS AND RESULTS: Polyclonal antibodies specific for MUC5AC and MUC5B, and a monoclonal antibody for MUC5B were used to stain lung tissues and airway mucosal biopsies obtained from patients who died of status asthmaticus (n=5) and from mild asthmatics (n=4), respectively. Immunohistochemistry for MUC5AC revealed abundant staining of goblet cells situated in the epithelial surface lining and glandular ducts of tissues from patients with fatal asthma. MUC5B immunoreactivity was restricted to mucous cells of submucosal glands and to epithelial cells. In mild asthmatics, large amounts of MUC5B, but not MUC5AC, positive extracellular mucus was found in the airway lumen as plugs, adjacent to the epithelial lining and in the necks of glandular secretory ducts of mild asthmatics. The distribution of MUC5AC and MUC5B in bronchial biopsies of mild asthmatics was similar before and after inhaled steroid treatment. CONCLUSIONS: The expression of MUC5AC and MUC5B shares a similar distribution to normal airways in different states of asthma. The distribution is not affected by topical corticosteroid therapy.
Subject(s)
Asthma/pathology , Mucins/biosynthesis , Respiratory Mucosa/pathology , Asthma/metabolism , Humans , Immunohistochemistry , Mucin 5AC , Mucin-5B , Protein Isoforms/biosynthesis , Respiratory Mucosa/chemistry , Severity of Illness IndexABSTRACT
Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor alpha, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.
Subject(s)
Antigen Presentation , Dendritic Cells , Leukemia, Myeloid/immunology , T-Lymphocytes, Cytotoxic/immunology , Acute Disease , Antigens, Neoplasm , Cell Differentiation/immunology , Cytotoxicity, Immunologic , Dendritic Cells/immunology , Dendritic Cells/pathology , Humans , Leukemia, Myeloid/pathologyABSTRACT
Begomoviruses occur in many plant species in Pakistan and are associated with an epidemic of cotton leaf curl disease that has developed since 1985. PCR analysis with primer pairs specific for each of four already sequenced types of DNA-A of cotton leaf curl virus (CLCuV-PK types a, 26, 72b and 804a), or for okra yellow vein mosaic virus (OYVMV), indicated that many individual naturally infected plants of cotton and other malvaceous species contained two or three begomovirus sequences. Similarly, sequence differences among overlapping fragments of begomovirus DNA-A, amplified from individual naturally infected plants, indicated much multiple infection in malvaceous and non-malvaceous species. Some cotton plants contained DNA-A sequences typical of begomoviruses from non-malvaceous species, and some non-malvaceous plants contained sequences typical of CLCuV-PK. Some DNA-A sequences were chimaeric; they each included elements typical of different types of CLCuV-PK, or of different malvaceous and/or non-malvaceous begomoviruses. Often an apparent recombination site occurred at the origin of replication. No complete CLCuV-PK DNA-A sequence was found in malvaceous or non-malvaceous species collected in Pakistan outside the area of the cotton leaf curl epidemic but chimaeric sequences, including a part that was typical of CLCuV-PK DNA-A, did occur there. We suggest that recombination among such pre-existing sequences was crucial for the emergence of CLCuV-PK. Recombination, following multiple infection, could also explain the network of relationships among many of the begomoviruses found in the Indian subcontinent, and their evolutionary divergence, as a group, from begomoviruses causing similar diseases in other geographical regions.