Biomedical subjects

D Lowe

Publications and source records attributed to D Lowe.

At least 55 records · Page 3Linked to original sources

PubMed2001

Expression of the tumour necrosis factor receptor-associated factors 1 and 2 in Hodgkin's disease.

The tumour necrosis factor receptor-associated factors (TRAFs) 1 and 2 participate in the signal transduction of various members of the tumour necrosis factor receptor (TNFR) family, including TNFR1, TNFR2, CD40, CD30, and the Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP1). Previous in situ hybridization studies have demonstrated TRAF1 transcripts in the malignant cells of the majority of Hodgkin's disease (HD) tumours, where the expression of TRAF1 was higher in EBV-associated tumours than in their EBV-negative counterparts. In order to determine whether TRAF1 and also TRAF2 were expressed at the protein level in HD and whether there was any relationship to EBV status, immunohistochemistry has been used to detect these proteins in a series of HD specimens. TRAF1 protein was detected more frequently in Hodgkin/Reed-Sternberg (HRS) cells from EBV-positive tumours than in their EBV-negative counterparts. This difference was statistically significant (p=0.01). In contrast, TRAF2 expression by HRS cells appeared to be independent of EBV status. Using a sequential labelling approach, co-localization of LMP1 with either TRAF1 or TRAF2 was also demonstrated in HRS cells from EBV-positive tumours.

Blotting, Western↗

PubMed2001

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

Alzheimer Disease↗

PubMed2001

Reliability and validity of the Intercollegiate Stroke Audit Package.

The aim of this study was to assure the validity and reliability of the Intercollegiate Stroke Audit Package as used in the National Sentinel Audit of Stroke. The Intercollegiate Working Party for Stroke, which included most stakeholders, including patients, devised the audit standards. These were submitted to a formal consensus (modified Delphi) survey before the audit questions were developed and piloted for validity and reliability. Following the pilot, Help Booklets were developed to promote the involvement of all disciplines as auditors in the national sentinel audit of stroke and ensure inter-rater reliability. During the national audit each Trust was asked to double rate the first five cases with auditors of different disciplines working independently. A total of 886 case notes were double-rated in 184 separate sites (median 5, range 1-5 per site). Trusts used auditors from different disciplines in 77% of cases. After excluding the 'No answer' cases the kappa score for items ranged from 0.49 to 0.87 (median 0.70, IQR 0.63-0.78). Very good agreement was found for seven of the 45 items, good agreement for 30 items, and moderate agreement for eight items. This large study, across a range of hospital sites and involving many disciplines, demonstrates that careful piloting of audit tools, with use of clear instructions to auditors, promotes the reliability of data.

Delphi Technique↗

PubMed2001

National audit of the blood transfusion process in the UK.

The objectives of this initiative were to produce nationally tested audit tools, to influence the content of national guidelines, and to enable performance indicators to be set for the clinical transfusion process. Audit tools were developed for blood transfusion practice through a collaboration between Royal Colleges and specialist Societies with an interest in blood transfusion. National audits were carried out involving 50 hospitals in the first audit and 23 of the same hospitals in the second. Over 20% of participating hospitals did not have Hospital Transfusion Committees. Most hospitals had written policies for the taking of blood samples for grouping and compatibility testing. Formal training for the phlebotomists and nurses who took blood samples was almost universal, but only one-third gave training to doctors. The audits of transfusion practice demonstrated considerable variation in the performance of standard procedures in relation to the administration of blood, and little change in practice between the two audits. The first two objectives have been met in that audit tools were developed and published, and information from the first audits was used in the development of national guidelines for the administration of blood. A significant shortfall in the systems for monitoring and delivering transfusions is present in many hospitals. This justifies pursuing the third objective but this will require a new initiative. The type of analysis and the method used for the presentation of audit data developed in this study may be useful for setting performance indicators for the clinical transfusion process.

Blood Transfusion↗

PubMed2001

Frequent expression of the tumor necrosis factor receptor-associated factor 1 in latent membrane protein 1-positive posttransplant lymphoproliferative disease and HIV-associated lymphomas.

The tumor necrosis factor receptor-associated factor 1 (TRAF1) participates in the signal transduction of various members of the tumor necrosis factor receptor (TNFR) family, including TNFR2, CD40, CD30, and the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1). In vitro, TRAF1 is induced by LMP1, and previous studies have suggested that expression of TRAF1 is higher in EBV-associated tumors than in their EBV-negative counterparts. To determine whether this was the case in posttransplant lymphoproliferative disease (PTLD) and related disorders, we used immunohistochemistry to analyze expression of TRAF1 in a total of 42 such lesions arising in a variety of immunosuppressive states. The specimens consisted of 22 PTLD lesions, 18 acquired immunodeficiency syndrome-associated lymphomas, including 6 primary central nervous system lymphomas, and 2 cases of Hodgkin disease. The presence of latent EBV infection was determined by EBER in situ hybridization, and expression of EBV-LMP1 was detected by immunohistochemistry. Latent EBV infection, as determined by a positive EBER signal, was detected in 36 of 42 tumors. Of the EBER-positive specimens, 30 of 36 also expressed LMP1. Twenty-four of 30 LMP1-positive tumors, including both Hodgkin disease specimens, expressed TRAF1, compared with only 3 of 12 LMP1-negative tumors. This difference was statistically significant (P <.005). These results show frequent expression of TRAF1 at the protein level in LMP1-positive PTLD and related disorders and suggest an important role for LMP1-mediated TRAF1 signaling in the pathogenesis of EBV-positive tumors arising in immunosuppressive states.

Epstein-Barr Virus Infections↗

PubMed2001

Death certification in patients whose primary treatment for oral and oropharyngeal carcinoma was operation: 1992-1997.

The aim of this study was to report the cause and place of death of patients with oral cancer as recorded by death certification and their survival with regard to comorbidity and age. From the departmental head and neck oncology database, 322 patients were identified with previously untreated oral and oropharyngeal squamous cell carcinoma diagnosed between 1992 and 1997 inclusive. Three-hundred were matched with the Office for National Statistics (ONS) and copies of death certificates generated on 6 March 1999. Of the 286 patients primarily treated by operation, 203 were alive and 83 had died. In 56 (68%), oral cancer was a contributory factor to the patient's death. Patients with a medical history recorded on their admission for operation had similar survival curves compared to those having no problems recorded. Although most patients (n= 46 55%) died in hospital, only 13 (16%) died in the Regional Maxillofacial Unit. Almost half of those patients who died were not recorded as dead on the departmental oncology database. This study shows that it is useful to link with the ONS to obtain accurate data on date and place of death. The death certificate also gives a useful indication of the cause of death and this seems unrelated to preoperative comorbidity.

Age Factors↗

PubMed2001

The relationship between length of stay and health-related quality of life in patients treated by primary surgery for oral and oropharyngeal cancer.

A patient's length of hospital admission is simple to measure, whilst their health related quality of life (HRQOL) is much more challenging. Similar clinical and demographic factors may exist between an increased length of stay (LOS) and a worse HRQOL outcome. The aim of this study was to assess whether LOS could serve as a proxy marker of HRQOL. One hundred and thirty consecutive patients with previously untreated oral and oropharyngeal squamous cell carcinoma were recruited. All had primary surgery. The University of Washington questionnaire (UW-QOL) and the European Organisation for Research and Treatment core cancer questionnaire (EORTC C30) were self-completed preoperatively, after 6 months and 1 year. The median LOS following laser/primary closure/split skin grafts (21 patients) was 2 days compared to 16 days following microvascular free flap reconstruction (105 patients). In the free flap group the best predictors of LOS were age, tumour size and early medical/surgery complications. Patients with a LOS greater than 16 days (median) reported significantly worse chewing (P = 0.008), swallowing (P = 0.002) and cumulative UW-QOL score (P = 0.01). No significant differences were seen in the EORTC C30. Length of stay is potentially a useful indicator of health related quality of life because it is linked by tumour size, however, the relationship is confounded by age, which tends to influence length of stay more than health related quality of life.

Adult↗

PubMed2001

Measuring the quality of urinary continence care in long-term care facilities: an analysis of outcome indicators.

BACKGROUND: the National Centre for Health Outcomes Development has produced outcome indicators for the assessment of quality of care in the management of urinary incontinence. Three measures relate to the management of older people in long-term care: the prevalence of incontinence, the use of indwelling catheters and clinical assessment rates. OBJECTIVE: to evaluate the recommended outcome measures in clinical practice. METHOD: participating centres included residential homes, nursing homes and long-stay wards. We sent a structured questionnaire to each centre for qualitative assessment of the acceptability of the outcome indicators. We analysed data collected by nurses and other staff who used the urinary incontinence section of the Royal College of Physicians Continuous Assessment Review and Evaluation scheme audit tool for long-term care. RESULTS: there were 1125 residents in 17 residential homes, 14 nursing homes and five long-stay wards. The overall prevalence of urinary incontinence was 34% in residential homes (range 2-86%), 70% in nursing homes (38-100%) and 71% in long-stay wards (4-97%). Catheterization rates were 5% in residential homes (0-20%), 10% in nursing homes (0-44%) and 6% in long-stay wards (0-20%). Rates of full clinical assessment were 48, 24 and 36% respectively. CONCLUSION: there is great variability in these outcome measures within and between settings. Interpretation of outcome results requires more precise details on case-mix and the definition of outcome measures. Individual units found the audit tool helpful, but we advise caution with interpretation of outcomes between units.

Aged↗

PubMed2001

Gender may affect the action of garlic oil on plasma cholesterol and glucose levels of normal subjects.

Early trials of garlic preparations on blood lipids mainly supported a lipid-lowering effect, whereas later well-designed garlic tablet trials were mainly entirely null. However, enteric simulation tests suggest that this discordance may result from ineffective delivery of bioactive agents from the brands of garlic powder (GP) and cyclodextrin-bound garlic oil (GO) tablets tested in some recent negative trials. In contrast, enteric simulation tests show that the preformed bioactive agents present in "traditional" gelatin capsules of GO are efficiently released, although such capsules have rarely been investigated in lipid-lowering trials. It was hypothesized that gelatin capsules of GO given to normal subjects would improve specified coronary heart disease risk factors. Effects of a GP preparation were also investigated. Subjects (n = 51; men and women, mean age 27 y) were randomly assigned to receive either 8.2 mg/d of GO (allyl sulfides) or placebo for 11 wk. Another 27 subjects received garlic powder (GP) of similar biopotential (7.8 mg allicin/d). Outcome measures were 95% confidence intervals (CI) between GO and placebo groups for differences between baseline and subsequent sample times. Men and women combined showed no significant differences save for an improved total antioxidant capacity at 6 wk (P = 0.01). Hence, no benefit from GO after 11 wk is one plausible conclusion. However, there were significant differences in effect of GO between men and women for HDL cholesterol (HDL-C) (P = 0.004) and total cholesterol (TC)/HDL-C (P = 0.003). Women showed favorable effects in terms of CHD risk factors (i.e., increases in HDL-C and reductions in TC/HDL-C), whereas men had small adverse effects. There was a significant difference in the GO effect for glucose (P = 0.006), with a reduction seen for men and an increase for women. The gender effects were unexpected and such analyses were not planned in advance. Confirmation of these findings with larger numbers of subjects would have importance for the use of garlic against CHD and for the design of future garlic studies.

Adult↗

PubMed2001

A randomized trial of the effects of garlic oil upon coronary heart disease risk factors in trained male runners.

Most trials of bulb garlic and garlic powder tablets indicate reduced coronary heart disease (CHD) risk in elevated-risk subjects. Most persons taking garlic supplements lack overt risk of CHD. However, no trials have tested steam-distilled garlic oil (GO) capsules with healthy subjects. The objectives of the present randomized, double-blind, placebo-controlled study were to determine whether GO capsules reduce CHD risk in trained male runners. Twenty-seven volunteers (mean age, 28.8 years) completed the study. Each took 12.3 mg/day GO (or placebo) capsules for 16 weeks. Main outcome measures were 95% confidence intervals (CIs) between GO and placebo groups for differences in changes of blood pressure (BP), plasma lipids, total antioxidant status (TAS), low-density lipoprotein (LDL) composition and blood clotting factors. Principal results as mean differences (95% CI) between GO and placebo are: pulse, 2.9 beats/min (-0.8 to 6.7), P = 0.12; systolic BP, -4.5 mmHg (-10.8 to 1.9), P = 0.16; plasma total cholesterol, 0.01 mmol/l (-0.34 to 0.37), P = 0.95; plasma triglycerides, -0.20 mmol/l (-0.43 to 0.03), P = 0.09; plasma TAS, 45 micromol Trolox equivalent/l (-35 to 124), P = 0.26; LDL density, 0.0019 g/ml (-0.0005 to 0.0043), P = 0.12; LDL triglycerides/protein, -0.078 mg/mg (-0.149 to -0.007), P = 0.03; LDL cholesterol/protein, -0.24 mg/mg (-0.69 to 0.22), P = 0.3; LDL TAS/triglycerides, 29 nmol/mg (11, 68), P = 0.15; prothrombin time, 0.99 s (-0.36 to 2.35), P = 0.14; partial thromboplastin time, 3.0 s (-1.0 to 7.1), P = 0.13. Results were null statistically. Trends with GO were mostly towards lower CHD risk, and a larger study (approximately 150 subjects) is required to test their validity.

Adolescent↗

PubMed2001

National stroke audit: a tool for change?

OBJECTIVES: To describe the standards of care for stroke patients in England, Wales and Northern Ireland and to determine the power of national audit, coupled with an active dissemination strategy to effect change. DESIGN: A national audit of organisational structure and retrospective case note audit, repeated within 18 months. Separate postal questionnaires were used to identify the types of change made between the first and second round and to compare the representativeness of the samples. SETTING: 157 trusts (64% of eligible trusts in England, Wales, and Northern Ireland) participated in both rounds. PARTICIPANTS: 5589 consecutive patients admitted with stroke between 1 January 1998 and 31 March 1998 (up to 40 per trust) and 5375 patients admitted between 1 August 1999 and 31 October 1999 (up to 40 per trust). Audit tool-Royal College of Physicians Intercollegiate Working Party stroke audit. RESULTS: The proportion of patients managed on stroke units rose between the two audits from 19% to 26% with the proportion managed on general wards falling from 60% to 55% and those managed on general rehabilitation wards falling from 14% to 11%. Standards of assessment, rehabilitation, and discharge planning improved equally on stroke units and general wards, but in many aspects remained poor (41% formal cognitive assessment, 46% weighed once during admission, 67% physiotherapy assessment within 72 hours, 24% plan documented for mood disturbance, 36% carers' needs assessed separately). CONCLUSIONS: Nationally conducted audit linked to a comprehensive dissemination programme was effective in stimulating improvements in the quality of care for patients with stroke. More patients are being managed on stroke units and multidisciplinary care is becoming more widespread. There remain, however, many areas where standards of care are low, indicating a need for investment of skills and resources to achieve acceptable levels.

Data Interpretation, Statistical↗

PubMed2001

Relationship between anxiety, depression, and morbidity in adult asthma patients.

BACKGROUND: Symptoms of disease reported by patients reflect the effects of the disease process within the individual and the person's physical and mental ability to tolerate or otherwise cope with the limitations on their functioning. This study examines the relationship between asthma symptoms, disease severity, and psychological status in patients being managed in routine primary healthcare settings. METHODS: One hundred and fourteen subjects from four GP practices, two inner city and two suburban, were studied. Symptoms were assessed by means of the Asthma Quality of Life questionnaire (AQLQ) and a locally devised Q score, and psychological status with the Hospital Anxiety and Depression (HAD) scale. Spirometric values and details of current asthma treatment (BTS asthma guidelines treatment step) were recorded as markers of asthma severity. RESULTS: Symptoms as measured by AQLQ correlated with peak expiratory flow (r(S) = 0.40) and with BTS guidelines treatment step (r(S) = 0.25). Similarly, the Q score correlated with peak expiratory flow (r(S) = 0.44) and with BTS guidelines treatment step (r(S) = 0.42). Similar levels of correlation of forced expiratory volume in one second (FEV(1)) with symptoms were reported. HAD anxiety and depression scores also correlated to a similar extent with these two symptom scores, but there was hardly any correlation with lung function. Logistic regression analysis showed that HAD scores help to explain symptom scores over and above the effects of lung function and BTS guidelines treatment step. Symptoms, depression, and anxiety were higher for inner city patients while little difference was observed in objective measures of asthma. CONCLUSIONS: Asthma guidelines suggest that changing levels of symptoms should be used to monitor the effectiveness of treatment. These data suggest that reported symptoms may be misleading and unreliable because they may reflect non-asthma factors that cannot be expected to respond to changes in asthma treatment.

Administration, Inhalation↗

PubMed2001

Investigating familial endocrine neoplasia syndromes in children.

Familial endocrine neoplasia syndromes multiple endocrine neoplasia (MEN) type 1, MEN type 2 and von Hippel Lindau (VHL) can now be diagnosed genetically in childhood. Paediatric endocrinologists must therefore be prepared to investigate and manage these children. This paper provides an overview of the major features of these syndromes and suggests protocols for regular screening of children known to be at risk of developing these disorders.

Child, Preschool↗

PubMed2001

Audit of acute admissions of COPD: standards of care and management in the hospital setting.

Despite publication of several management guidelines for COPD, relatively little is known about standards of care in clinical practice. Data were collected on the management of 1400 cases of acute admission with Chronic Obstructive Pulmonary Disease in 38 UK hospitals to compare clinical practice against the recommended British Thoracic Society standards. Variation in the process of care between the different centres was analysed and a comparison of the management by respiratory specialists and nonrespiratory specialists made. There were large variations between centres for many of the variables studied. A forced expiratory volume in one second measurement was found in only 53% of cases. Of the investigations recommended in the acute management arterial blood gases were performed in 79% (interhospital range 40-100%) of admissions and oxygen was formally prescribed in only 64% (range 9-94%). Of those cases with acidosis and hypercapnia 35% had no further blood gas analysis and only 13% received ventilatory support. Long-term management was also deficient with 246 cases known to be severely hypoxic on admission yet two-thirds had no confirmation that oxygen levels had returned to levels above the requirements for long-term oxygen therapy. Only 30% of current smokers had cessation advice documented. To conclude, the median standards of care observed fell below those recommended by the guidelines. The lowest levels of performance were for patients not under the respiratory specialists, but specialists also have room for improvement. The substantial variation in the process of care between hospitals is strong evidence that it is possible for other centres with poorer performance to improve their levels of care.

Acute Disease↗

PubMed2001

Regional variations in stroke care in England, Wales and Northern Ireland: results from the National Sentinel Audit of Stroke. Royal College of Physicians Intercollegiate Stroke Working Party.

STUDY OBJECTIVE: To identify the variations between regions in England, Wales and Northern Ireland in the case-mix, organization and process of care for stroke. DESIGN: Retrospective audit of case notes and service organization. SETTING: Two hundred and ten Trust sites from 197 Trusts in 10 Health Regions in England, Wales and Northern Ireland. PATIENTS: The 6894 consecutive stroke patients admitted between 1 January and 31 March 1998 (up to 40 per Trust). Audit tool: The Intercollegiate Stroke Audit. RESULTS: There are significant differences in stroke care between regions that cannot be explained by known case-mix or clinical variables. The proportion of patients spending more than half their hospital stay in stroke unit care varied between regions from 10% to 27%. Thirty-day mortality in different regions ranged between 21% and 33%. Institutionalization rates for those admitted from home varied between 6% and 19%. Similar variations existed in discharge disability and length of stay. CONCLUSIONS: There were widespread variations in specialist service provision for stroke in different regions. Regional variation in 30-day mortality and in institutionalization after stroke is not explained by clinical factors and therefore may represent different local health care policies and expectations.

Aged↗

PubMed2001

Generation of a humanized, high affinity anti-tissue factor antibody for use as a novel antithrombotic therapeutic.

Blocking the cofactor function of human tissue factor may be beneficial in various coagulation-mediated diseases. The murine antibody D3 binds to the membrane proximal substrate interaction region of human tissue factor and blocks tissue factor function even in the presence of bound factor VIIa. The cloned murine D3 antibody was humanized and affinity matured by exchanging amino acids in the complementarity determining regions as well as in the antibody framework. The humanized antibody, D3H44, bound to tissue factor with a 100-fold increased affinity (KD 0.1 nM) as compared to the original murine and chimeric versions. Depending on the particular disease, different pharmacokinetic properties of the antibody may be required and, therefore, several antibody variants-- F(ab), F(ab')2, IgG2, IgG4 and IgG4b-were generated. In vitro, the humanized D3 antibodies displayed potent inhibition of plasma clotting and tissue factor: factor VIIa-mediated activation of factors IX and X (e.g. D3H44-F(ab')2, IC50(F.X) 47 pM). In addition, D3H44-F(ab')2 completely prevented fibrin deposition in a human ex vivo thrombosis model under venous blood flow conditions (IC50 37 nM). The humanized D3 antibodies may be utilized for treatment of cardiovascular diseases which involve tissue factor activity, e.g. acute coronary syndrome and venous thrombosis.

Amino Acid Sequence↗

PubMed2000

Effects of subdural haematoma on sensorimotor functioning and spatial learning in rats.

Twenty per cent of all strokes are haemorrhagic in character and are associated with severe disturbances in sensorimotor behaviour and cognition. Although spontaneous recovery of pre-stroke functioning occurs in some cases, the process is demanding, slow, and often incomplete. A first step in the preclinical testing of new putative, neuroprotective and recovery-supporting therapeutics is to validate animal models of brain injury. In a series of four experiments we evaluated the behavioural impairments and the time course of recovery of functional deficits in rats with an experimentally induced subdural haematoma. We found that unilateral subdural haematoma resulted in dysfunction in both simple reflexive (experiment 1) and skilled sensorimotor behaviour (experiment 2). Reflexive behaviour did not recover, or recovered only marginally, and neither did the deficits in skilled forepaw use. Bilateral subdural haematoma impaired the learning and memory performance of adult (experiment 3) and old rats (experiment 4) in the Morris water escape task. Considering the diversity of the deficits found in our experiments, we conclude that different models are needed to cover the broad range of deficits seen in stroke patients.

Age Factors↗

PubMed2000

LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine.

LY354740 ¿(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylate monohydrate¿, a selective group II metabotropic glutamate (mGlu) receptor agonist, was recently reported to attenuate the behavioral effects of phencyclidine (PCP) in rats. In the present study, LY354740 failed to attenuate the discriminative stimulus properties of PCP and its disruption of prepulse inhibition of the acoustic startle response, at a dose range which decreased startle responding. The suggestion that mGlu group II receptor activation induces antipsychotic effects may be premature.

Acoustic Stimulation↗