Biomedical subjects
Publications and source records attributed to J Powell.
We report a simple system for producing [15O]H2O from 15N in a nitrogen/hydrogen gas target with recycling of the target nitrogen, allowing production on low-energy proton-only accelerators with minimal consumption of isotopically enriched 15N. The radiolabeled water is separated from the target gas and radiolytically produced ammonia by temporary freezing in a small trap at -40 degrees C.
Although 14C-labelling has been routinely used for small molecules, this technique is not routinely applied to therapeutic proteins due to difficulties of incorporating the label into the protein to a sufficiently high specific activity. An analytical method known as accelerator mass spectrometry (AMS) offers an extremely sensitive method of 14C quantification, thereby enabling (14)C-labeling methods to be applied to therapeutic protein detection. The therapeutic protein CAT-192 (metelimumab), a human anti-TGFss1 monocloncal antibody was manufactured in the presence of 14C-precursors resulting in a low specific activity product (1.4% 14C incorporation). [14C]-CAT-192 was administered to rats (1mg/kg and 222, 22 and 2.2 dpm/kg) and serum samples were collected. 14C in serum samples from the 2.2 dpm dosing was not detectable but samples from the 22 and 2220 dpm doses were measured by AMS and by ELISA for comparison. By both ELISA and AMS bioassay, the half-lives approximated 140 h (S.E.M. 15 h). The estimates of clearance were also comparable, 7.3 and 4.6 x 10(-4)ml/h/g (S.E.M. 6.6 and 5.1 x 10(-5)) for ELISA and AMS, respectively. The estimated limit of quantification (LOQ) was approximately 1 ng/ml, about 15 times lower than the ELISA LOQ of 15.6 ng/ml.
In order to achieve an accurate understanding of the crystal structure of 6-line ferrihydrite (6LFh) and ferritin molecule cores within a human liver biopsy using transmission electron microscopy (TEM), electron beam damage should be considered. For the case of 6LFh, the electron energy loss near-edge structure (ELNES) of core ionisation edges in the electron energy loss spectrum (EELS) combined with multiple linear least-square (MLLS) fitting of reference spectra together with analysis of selected area electron diffraction (SAED) patterns suggests that the iron in 6LFh is solely octahedrally coordinated Fe3+. With increasing electron dose, an increasing percentage of this octahedrally coordinated Fe3+ migrates to tetrahedral sites. When the dose exceeds 3 x 10(8) electrons/nm2, Fe2+ is found to be present in the material. This method also indicates that the iron in ferritin molecule cores within a human liver biopsy is the same as in 6LFh, entirely Fe3+ in octahedral coordination with oxygen. Again the percentage of octahedrally coordinated Fe3+ decreases as the accumulated electron dose increases and Fe2+ is produced in the liver biopsies when the electron dose exceeds 10(6)electrons/nm2.
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Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and alpha-2-macroglobulin (alpha-2M). Using semi-quantitative immunoblotting, the elevation of CFH and alpha-2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as alpha-2M may be a specific markers of this illness.
OBJECTIVES: To review systematically the evidence on the performance of diagnostic tests used to identify infection in diabetic foot ulcers (DFUs) and of interventions to treat infected DFUs. To use estimates derived from the systematic reviews to create a decision analytic model in order to identify the most effective method of diagnosing and treating infection and to identify areas of research that would lead to large reductions in clinical uncertainty. DATA SOURCES: Electronic databases covering period from inception of the database to November 2002. REVIEW METHODS: Selected studies were assessed against validated criteria and described in a narrative review. The structure of a decision analytic model was derived for two groups of patients in whom diagnostic tests were likely to be used. RESULTS: Three studies that investigated the performance of diagnostic tests for infection on populations including people with DFUs found that there was no evidence that single items on a clinical examination checklist were reliable in identifying infection in DFUs, that wound swabs perform poorly against wound biopsies, and that semi-quantitative analysis of wound swabs may be a useful alternative to quantitative analysis. However, few people with DFUs were included, so it was not possible to tell whether diagnostic performance differs for DFUs relative to wounds of other aetiologies. Twenty-three studies investigated the effectiveness (n = 23) or cost-effectiveness (n = 2) of antimicrobial agents for DFUs. Eight studied intravenous antibiotics, five oral antibiotics, four different topical agents such as dressings, four subcutaneous granulocyte colony stimulating factor (G-CSF), one evaluated oral and topical Ayurvedic preparations and one compared topical sugar versus antibiotics versus standard care. The majority of trials were underpowered and were too dissimilar to be pooled. There was no strong evidence for recommending any particular antimicrobial agent for the prevention of amputation, resolution of infection or ulcer healing. Topical pexiganan cream may be as effective as oral antibiotic treatment with ofloxacin for the resolution of local infection. Ampicillin and sulbactam were less costly than imipenem and cilastatin, a growth factor (G-CSF) was less costly than standard care and cadexomer iodine dressings may be less costly than daily dressings. A decision analytic model was derived for two groups of people, those for whom diagnostic testing would inform treatment--people with ulcers which do not appear infected but whose ulcer is not progressing despite optimal concurrent treatment--and those in whom a first course of antibiotics (prescribed empirically) have failed. There was insufficient information from the systematic reviews or interviews with experts to populate the model with transition probabilities for the sensitivity and specificity of diagnosis of infection in DFUs. Similarly, there was insufficient information on the probabilities of healing, amputation or death in the intervention studies for the two populations of interest. Therefore, we were unable to run the model to inform the most effective diagnostic and treatment strategy. CONCLUSIONS: The available evidence is too weak to be able to draw reliable implications for practice. This means that, in terms of diagnosis, infection in DFUs cannot be reliably identified using clinical assessment. This has implications for determining which patients need formal diagnostic testing for infection, on whether empirical treatment with antibiotics (before the results of diagnostic tests are available) leads to better outcomes, and on identifying the optimal methods of diagnostic testing. With respect to treatment, it is not known whether treatment with systemic or local antibiotics leads to better outcomes or whether any particular agent is more effective. Limited evidence suggests that both G-CSF and cadexomer iodine dressings may be less expensive than 'standard' care, that ampicillin/sulbactam may be less costly than imipenem/cilastatin, and that an unlicensed cream (pexiganan) may be as effective as oral ofloxacin. Further research is needed to ascertain the characteristics of infection in people with DFUs that influence healing and amputation outcomes, to determine whether detecting infection prior to treatment offers any benefit over empirical therapy, and to establish the most effective and cost-effective methods for detecting infection, as well as the relative effectiveness and cost-effectiveness of antimicrobial interventions for DFU infection.
Use of moxidectin long-acting injectable and ivermectin injectable in female Bos taurus beef-type calves was evaluated in terms of efficacy (fecal egg counts) and performance parameters (weight gain). In this 150-day study, moxidectin-treated calves gained 20% more weight than did ivermectin-treated and control calves. Mean fecal egg count reductions ranged from 76.7 to 99.0 for moxidectin and -0.8 to 83.4 for ivermectin. Moxidectin long-acting injection provided efficacious (immediate as well as long-term) egg count suppressions as well as enhanced animal productivity (weight gains). The study also showed that Cooperia spp appear poised to present the most immediate challenges once long-acting macrocyclic lactone treatments become available.
Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
AIMS: To identify prevalence of delayed detection of cleft palate, and associated factors that could lead to improved identification at neonatal clinical examination. METHODS: Audit of hospital notes, parental questionnaire incorporating open ended questions, and telephone questionnaire of junior doctors in the referring hospitals incorporating fixed choice questions. RESULTS: Of 344 cleft palate patients without cleft lip or submucous cleft palate, the day the cleft was detected was recorded in 92%. Delayed detection, after the first day, was 28% overall, distributed as 37% with isolated cleft palate and 23% with syndromic cleft palate. Narrow V shaped clefts were more likely to be delayed in detection compared with broad U shaped clefts, as were soft palate clefts compared with hard palate clefts. Five with isolated cleft palates were not detected until after the first year. Babies born at home were unlikely to be detected on day 1. Symptoms were significantly increased in the delayed detection group for feeding problems and nasal regurgitation. A telephone questionnaire of trainee paediatricians in referring units revealed that digital examination was more commonly practised than visual inspection, and few recalled receiving specific instruction on examination of the palate. CONCLUSION: Delayed detection of cleft palate was not uncommon, and the features of those more likely to be missed suggested digital examination was related. Trainee doctors and midwives should be instructed to inspect visually using a light and tongue depressor, then digitally if submucous cleft palate is suspected.
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INTRODUCTION: With the rising incidence of oesophageal cancer, palliative treatment has an increasingly important role. With median survival unlikely to exceed 6 months, in advanced disease the palliative therapy chosen must not hasten patient's demise. AIM: To establish the outcome of both modern and historical palliative treatment in oesophageal tumours, with emphasis on the aetiology and outcome of iatrogenic perforation. METHODS: Patients with oesophageal or cardia carcinoma treated within the West Midlands between 1992 and 1996 were identified retrospectively. Information was gathered from hospital case notes and the regional cancer intelligence unit with hospitals visited to capture data. All episodes were entered into a dedicated database. RESULTS: Of the 3660 patients who were treated, 2529 received palliation as primary treatment, with 5259 palliative procedures performed; 164 iatrogenic perforations were recorded; 83 were due to diagnostic endoscopy (endoscopic perforation) with the reminder due to interventional palliative procedures. Median survival from all forms of palliation was 138 days. Following perforation survival was 95 days after interventional palliative procedure and 58 days after endoscopic perforation (P > 0.05). Thirty-day mortality after emergency surgery was 11.8% with mean survival of 7.5 months. CONCLUSION: Perforation at diagnostic endoscopy is associated with substantial mortality despite rapid intervention. Patients with suspected cancer must be investigated with extreme care to reduce iatrogenic complications.
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OBJECTIVES: To test, in a variety of health settings, the ability of the Health Assessment Questionnaire (HAQ) disability index to predict the eligibility of patients with moderate or severe arthritis for disability living allowance or attendance allowance. METHODS: The study included patients from 20 general practices and four hospital out-patient departments across four areas in the southwest of England. Adults with an established diagnosis of rheumatoid arthritis, or osteoarthritis of the hip or knee, and who were not in receipt of Disability Living Allowance (DLA) or Attendance Allowance (AA) were sent an HAQ. Those who scored 1.5 or more were offered an appointment with a welfare advice worker at which they completed an application for DLA or AA. After 3 months they were contacted by the advice worker and asked about the outcome of their applications. RESULTS: Over half of those who completed an HAQ scored 1.5 or over (moderate to severe disability as measured by the HAQ) and were offered advice from experienced welfare benefits advisors. Of these, 87% applied for DLA or AA. Sixty-nine per cent of the applicants were successful. Those scoring 1.75 and over were more likely to be awarded benefit (73% success CLs 67, 79) than people scoring between 1.5 and 1.625 where 55% (CLs 41,69) of applicants were successful. CONCLUSION: The HAQ was shown to be a good predictor of eligibility for AA or DLA. It can be used, in a variety of health settings, to indicate patients who, with help from an experienced advisor, are likely to gain increased financial help.
The use of diffusion weighted imaging with apparent diffusion coefficient mapping in the diagnosis of cerebral fat embolism is shown here to demonstrate infarcts secondary to fat emboli more intensely than T2 weighted sequences 24 hours after the onset of symptoms. Embolic foci are hypointense on apparent diffusion coefficient mapping consistent with cytotoxic edema associated with cell death and restricted water diffusion. This technique increases the sensitivity for detecting cerebral fat embolism and offers a potentially important tool in its diagnosis.
OBJECTIVE: To determine the incidence and severity of tibial malrotation following reamed intramedullary nail fixation as measured by computerized tomography and to determine the repeatability of computed tomography measurement in the assessment of rotational malreduction. DESIGN: Prospective cohort. SETTINGS: Level 1 trauma center. PARTICIPANTS: Twenty-five consecutive patients with 25 tibial shaft fractures. INTERVENTION: All patients were treated with reamed intramedullary nailing. Appropriate radiographs and a postoperative lower extremity computed tomography scan were obtained for each patient who consented to the study. MAIN OUTCOME MEASURE: Rotational alignment of affected tibia as compared to a version of the normal contralateral limb. Malrotation was defined as an internal/external rotation deformity greater than 10degrees. RESULTS: Malrotation, comparing the fractured limb to normal limb, was determined using a similar measurement method previously described in the literature. Two patients declined inclusion, and in one case, the computed tomography was not acceptable for analysis. Malrotation, comparing the fractured limb to the normal limb, was determined using the measurements from axial computed tomography images. Results revealed a mean absolute rotational difference of 6.7degrees (SD +/-6.3degrees). Rotational malreduction ranged from 15degrees of internal rotation to 22degrees of external rotation. Five of the 22 tibia (22%) were malrotated greater than 10degrees. A larger degree of deformity was seen with certain injury patterns. The intraobserver and interobserver repeatability testing revealed a mean absolute difference between paired malrotation calculations of 3.4degrees and 3.9degrees, respectively, and a repeatability coefficient of 8degrees for both. CONCLUSION: Computed tomography measurement is a repeatable method of assessing tibial torsion and in this study revealed a significantly higher incidence of rotational malreduction than that previously reported in the literature.
OBJECTIVES: To evaluate functioning, 18 months after surgery, of 49 patients with good neurological recovery following aneurysmal subarachnoid haemorrhage (SAH), and to determine the extent of any improvements in disturbances of mood, cognitive functioning, and levels of activity and participation previously observed at 9 month follow up. METHODS: SAH patients, matched for age, gender, and occupation with healthy control participants, completely quantitative measures of mood (HADS, FIES, BDI) and activity/participation (BICRO-39 scales), and a brief cognitive assessment battery (verbal fluency, digit span, prose recall). Controls completed the HADS and the BICRO-39. RESULTS: Patients showed some recovery of cognitive functioning, though impairments of prose recall persisted. Anxiety and depression symptoms were higher in patients than in controls, but fewer than 20% scored in the clinical range on any questionnaires except for RIES-Intrusive thoughts (22%); only three showed signs of full blown post-traumatic stress disorder. Almost half showed elevated dependence on others for domestic activities and organisation and abnormally low levels of employment. Very little variance in outcome was predicted by demographic variables, neurological or cognitive impairment, prior life stress, or mood. However, levels of social activity and self-organisation were related to persisting fatigue. CONCLUSIONS: The observed decline in intrusive thoughts and avoidance over time is consistent with that seen after life threatening illness or trauma. The persistent reductions in independence and levels of employment may in some cases reflect considered lifestyle adjustments rather than adverse and unwanted changes but in others indicate a need for focused rehabilitation.