A sharing, caring experience.
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Clinical Competence↗
Biomedical subjects
M Ferguson
Publications and source records attributed to M Ferguson.
Are our sportsmen and women getting a fair medical deal?
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Athletic Injuries↗
Myocardial infarction associated with physical exertion in a young man.
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Adult↗
Report of a collaborative study to establish the international standard for parvovirus B19 serum IgG.
With the introduction of commercial test kits and the wider availability of parvovirus B19 antibody testing, greater standardization is required. Moreover, with a B19 vaccine in the early stages of development, there will be long-term need of accurate measurement of parvovirus B19 antibody levels following natural infection and vaccination. A collaborative study was carried out to assess the suitability of a freeze-dried preparation designated 93/724 to serve as the International Standard for parvovirus B19 serum IgG. The proposed standard, which is a pool of sera from six U.K. blood donors, was assayed along with three coded samples. One was the proposed standard (Preparation A), one a pool of three donor sera (Preparation B) and the third an individual donor serum (Preparation C). These preparations were sent to nine laboratories in seven countries who tested them in 10 different enzyme immunoassays. There were no differences in the antibody content expressed relative to that of the proposed standard in assays using native or recombinant antigen. However, antibody was not detected in serum from an individual blood donor (Preparation C) in assays performed using kits which contained recombinant VP1 but not VP2. This highlights the differences which may be obtained in commercial kits which contain different antigens. The results of this study demonstrated that the proposed standard coded 93/724 is suitable to serve as the International Standard for parvovirus B19 serum IgG and this material has been established as the International Standard for parvovirus B19 IgG by the World Health Organization with an assigned unitage of 100 lU per ampoule. The standard, which is a pool of what can be assumed to be convalescent sera, will be suitable for standardizing diagnostic tests for use in seroprevalence studies and for assessing immunity. An additional standard will be required to standardise tests specifically for the detection of IgM and the diagnosis of acute infection.
Antibodies, Viral↗
Potency of wild-type or sabin trivalent inactivated poliovirus vaccine, by enzyme-linked immunosorbent assay using monoclonal antibiotics specific for each antigenic site.
Potency testing of inactivated poliovirus vaccine (IPV) is hampered by the absence of a standardized in vitro test, as well as the lack of a generally accepted quantitative animal test. In vitro tests must be able to measure selectively the content of the "D" antigen in the vaccine which includes virus neutralizing antibodies. We tested 12 poliovirus type 1, 12 type 2 and six type 3, D antigen-specific monoclonal mouse antibodies (mAb) for use in the enzyme-linked immunosorbent assay (ELISA). We characterized the site-specific reactivities of three mAbs, one for each poliovirus type. The reactivity of the complete mAb panel encompassed the important antigenic sites on the virus surface of each of the poliovirus serotypes. Some of the mAbs were cross-reactive between wild-type and Sabin strain IPV. At least one mAb of each poliovirus type that was D antigen-specific and reacted with both wild-type and Sabin IPV was directed against an antigenic site thought to be immunogenic in humans. These reagents may be useful for improved standardization of the ELISA for IPV.
Animals↗
Monocyte chemoattractant protein-1 mRNA expression in the human burn wound.
The inflammatory response following a thermal insult begins with the skin itself. Langerhan's cells, tissue macrophages, keratinocytes, fibroblasts, and endothelial cells contribute to the initial events of wound healing with active and passive release of cell mediators. One of the mediators potentially important to the repair process is monocyte chemoattractant protein-1 (MCP-1). Macrophages, fibroblasts, endothelial cells, and keratinocytes can produce MCP-1 in response to inflammatory stimuli. Therefore, we evaluated 10 human burn wound specimens for MCP-1 mRNA using in situ hybridization. Selected specimens of different ages were examined using combined in situ hybridization and immunocytochemistry to identify cell types that expressed MCP-1 mRNA. Antibodies to HAM56 for macrophages, CD45 for bone marrow-derived cells, Factor VIII for endothelial cells, and Factor XIIIa for dermal antigen-presenting cells were included in these experiments. By Postburn Day 2, basal layer keratinocytes at the edges of the wound had upregulated MCP-1 message; the increased signal persisted in the rate pegs deep in the dermal wound bed through 49 days postinjury. Occasional FXIIIa+ immunostained dermal cells expressed MCP-1 mRNA. Islands of granulation tissue throughout the wound bed were positive for increased expression of MCP-1; endothelial cells and inflammatory cells both contributed to this upregulated signal. Our data support the theory that the skin itself is a component of the immune system and that noninflammatory cells contribute to the initiation and maintenance of the inflammation at a wound site. Failure to produce MCP-1 or other related mediators by indigenous cutaneous cells may delay the inflammatory response to injury and potentially disrupt other essential phases of wound repair.
Antibodies↗
Comparison of Fy(b) status as determined serologically and genetically.
Comparison of the serologically determined phenotype and the genotype of samples as defined by PCR-RFLP indicated a significant percentage of discrepancies on analysis of serologically defined Fy(a + b-) samples. An investigation of these discrepancies has shown that the serologically determined phenotype of the samples varies with respect to the reagent used but that the PCR-RFLP assay gives reliable results for all the samples investigated. The samples which yielded the discrepant results were further investigated and the results indicated weakened expression of the Fyb antigen. This may arise by a method similar to the expression of Fyx although we found the incidence of these samples to be much higher than that reported for Fyx. These results may have important implications for the routine testing of blood donations, particularly in situations where the unit is to be transfused to a patient who has previously formed an anti-Fyb.
Duffy Blood-Group System↗
Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation.
Chronic wound healing states are often associated with aging, and despite the increased number of aged patients with nonhealing wounds, controversy still exists concerning the effects of age on wound repair. Our previous work showed that in both venous ulcers in humans and acute wounds in aged animals, fibronectin, an early component in granulation tissue, is deficient compared to normal skin and acute wounds in healthy young animals, respectively. In the present study, we have determined the protease responsible for fibronectin degradation by analyzing tissue taken from the margins of chronic venous ulcers and standardized acute cutaneous wounds collected from a large cohort of "Health status"-defined aged human subjects (screened as per the SENIEUR protocol). When tissue samples were subjected to fibronectin zymography, the main protease involved in the breakdown of fibronectin in both venous ulcers and acute wounds of elderly subjects was found to be a serine protease with a molecular weight of approximately 30 kd. This protease was identified as neutrophil elastase by immunoblotting. In tissue biopsies, elastase was localized to granulocytes by immunocytochemical techniques and shown to be present in greater quantities in venous ulcers and Day-7 and -14 healing acute wounds of healthy aged subjects relative to those of young subjects. The highest quantities were found in acute wounds of elderly women. Our results suggest that the process of aging in healthy human subjects is associated with an up-regulation of elastase during acute wound healing and that an abnormality in down-regulation of this protease could be partially responsible for the transition to chronic wound healing states in the aged.
Acute Disease↗
Testing plasma pools for markers of viral contamination: the UK experience.
The transmission of viral infections through the use of products derived from blood has emphasised the need for adequate validation of the production process, testing of materials used in production and quality control tests on the final product. Since the late 1980s, as part of its batch release procedures, NIBSC has tested for markers of viral infectivity plasma pools used in production of blood products used in the UK. As a result of testing over 9,000 pools, NIBSC has identified 9 pools contaminated with HBsAg and 2 pools containing antibodies to HIV-1. Since routine screening of plasma pools for anti-HCV was introduced in 1993, 8 pools out of the 4,000 tested have been found to contain antibodies to HCV. In addition, the release of 12 batches of blood products was withheld and it is known that further batches of material produced from the positive pools were not submitted for batch release. Studies involving assays of dilutions of known positive plasma samples indicated that there is considerable variation in the endpoint dilutions of antigen or antibody detected by test kits from different manufactures. The selection and validation of the kits used in such testing is therefore important. The usefulness of standardised low-level external controls in assays of plasma pools for markers of viral infection is discussed.
Antibodies, Viral↗
Use of pleural catheter for the management of simple pneumothorax.
STUDY OBJECTIVE: We assessed the use of a pleural catheter (Thoracic Vent) to determine its effectiveness in treating simple pneumothorax (PTX) and in preventing recurrent PTX. DESIGN: A retrospective review was conducted of 84 patients treated with a pleural catheter for iatrogenic (52) and spontaneous (11 primary, 21 secondary) PTX between 1989 and 1994. PATIENTS: There were 45 men and 39 women with a mean age of 50.4 years (range, 18 to 85 years). RESULTS: Mean time to lung reexpansion was 0.5 +/- 0.1 days. Forty-five (57%) patients manifested an air leak after catheter placement for 2.0 +/- 0.2 days. The duration of time to catheter removal was 3.3 +/- 0.2 days. Seventy-one (85%) patients had resolution of PTX with this therapy alone. Thirteen patients (15%) failed to resolve their PTXs and required subsequent tube thoracostomy alone (6) or surgical therapy (7). Four of 11 patients who required tube thoracostomy also failed to respond to this therapy. Treatment failure was more common among patients with spontaneous PTX than with iatrogenic PTX (34% vs 4%; p < 0.005). During a mean follow-up of 3.0 +/- 0.2 years, 6 (7%) patients suffered recurrent PTX an average of 23 days after initial therapy. CONCLUSION: This pleural catheter is effective in the management of simple iatrogenic and spontaneous PTX.
Adolescent↗
Another case of virologically confirmed zoster sine herpete, with electrophysiologic correlation.
A third virologically-confirmed case of thoracic-distribution zoster sine herpete is reported. Electromyography (EMG) of paraspinal muscles demonstrated frequent fibrillation potentials restricted to chronically painful thoracic root segments. Treatment with intravenous acyclovir and oral famciclovir were ineffective. These findings suggest the usefulness of EMG of muscles corresponding to painful dermatomes, combined with virologic studies, to support the diagnosis of zoster sine herpete.
Aged↗
Vinorelbine (Navelbine), cisplatin, and concomitant radiation therapy for advanced malignancies of the chest: a Phase I study.
Most patients with advanced solid tumors of the chest will have local and/or distant disease progression despite standard therapy. Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France) is a new semisynthetic vinca alkaloid with single-agent activity in lung cancer that recently also has been shown to act as a radiosensitizer in vitro. This study aims to define the maximum tolerated dose and dose-limiting toxicity when vinorelbine is given with cisplatin and concomitant radiation therapy. To date, 25 patients with advanced malignancies of the chest have been treated in a dose-escalation trial of vinorelbine administered once weekly with cisplatin (100 mg/m2 every 21 days) and concomitant thoracic radiation therapy (2 Gy/d x 30 fractions for 60 Gy). Vinorelbine was initially given at 20 and 25 mg/m2/wk. Acute dose-limiting toxicity was myelosuppression, which was seen at a vinorelbine dose of 25/mg/m2/wk, with grade 4 neutropenia in two of three patients and one treatment-related death from neutropenic sepsis. At vinorelbine 20/mg/m2/wk, no acute dose-limiting toxicity was seen, but grade 3 or 4 esophagitis developed in three of six patients near the end or after completion of radiation therapy. We subsequently decreased the administration of vinorelbine to weeks 1, 2, 4, and 5. Tolerance appears to be greater with this schedule; however, severe or life-threatening esophagitis at the completion of therapy continues to be observed. Given these preliminary results, it appears feasible to treat patients with advanced chest malignancies with concomitant cisplatin, vinorelbine, and radiation therapy. The significant dose reduction of vinorelbine that is necessary with concomitant radiation therapy provides the first in vivo evidence of a strong radiosensitizing effect of vinorelbine. The schedule is currently being modified to reduce the incidence of esophagitis.
Adult↗
Expression of collagen, interstitial collagenase, and tissue inhibitor of metalloproteinases-1 in restenosis after carotid endarterectomy.
Extracellular matrix is the principal component of the fibrous caps of atherosclerotic plaques and intimal hyperplastic lesions of reconstructed arteries. Interstitial collagen form an important part of the matrix, and the balance between collagen synthesis and degradation by interstitial collagenase (matrix metalloproteinase-1, MMP-1) may determine whether plaques rupture or vessels develop stenosis. We examined type I procollagen gene expression in human atherosclerotic and restenotic carotid arteries using in situ messenger RNA (mRNA) hybridization and the expression of MMP-1 and its endogenous inhibitor (tissue inhibitor of metalloproteinases-1, TIMP-1) by immunohistochemistry. Compared with normal arteries, atherosclerotic plaques bed increased expression of immunoreactive MMP-1 and TIMP-1 with modest increase of type 1 procollagen mRNA. Early restenotic lesions (< 1.5 years) contained abundant type I procollagen mRNA but little immunoreactive MMP-1 and TIMP-1. Late restenotic lesions (> 4 years) resembled atheroma and exhibited increased immunoreactive MMP-1 and TIMP-1 as well as abundant type I procollagen mRNA. Compared with atherosclerotic plaques, type I procollagen is increased and MMP-1 is decreased in early restenotic lesions. MMP-1 and TIMP-1 expressions are upregulated in lesions with a clear atheroma. These findings suggest that the balance between proteolysis and matrix synthesis may influence both the stability of atheromatous plaques and the development of restenotic lesions.
Arteriosclerosis↗
Management of blunt chest injury.
The development of regional techniques of analgesia has revolutionized the management of blunt thoracic trauma. The standard of care has evolved from intubation and mechanical ventilation for all patients to optimization of pain control combined with chest physiotherapy. Although many methods have been used, it appears that in appropriately selected patients, epidural analgesia is the preferred technique for pain control in severe thoracic trauma. Epidural catheters for continuous narcotic or local anesthetic administration are both the most reliable and the most effective, and once in place they can be managed by nursing outside of the intensive care setting. It still remains for improvement in outcome to be demonstrated when epidural analgesia is used, but it is clear that subjective patient comfort is increased and that pulmonary parameters can be improved. In appropriately selected patients, those without head injury or who have been adequately evaluated for intra-abdominal injury, epidural analgesia is currently the preferred method for pain control following severe thoracic trauma.
Analgesia, Epidural↗
Anencephalic infants as organ donors.
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Adult↗
Osteopontin is expressed in human aortic valvular lesions.
BACKGROUND: Nonrheumatic stenosis of trileaflet aortic valves, in which calcification is a prominent feature, has been termed a "degenerative" condition, but it has been demonstrated recently that chronic inflammation is a characteristic feature of the developing lesion of aortic stenosis. This observation raised the possibility that calcification in the aortic valve might be actively regulated. Thus, the present study investigated whether osteopontin, a protein implicated in the regulation of both normal and dystrophic calcification, could be detected in lesions of valvular aortic stenosis. METHODS AND RESULTS: Morphological and immunohistochemical studies were performed on 14 human aortic valves, representing a range of pathology from normal to clinically stenotic. The extent of calcification and macrophage accumulation and their relation to the presence of osteopontin protein were characterized. Highly statistically significant associations were found between the degree of osteopontin expression and the degrees of both calcification and macrophage accumulation in early through late lesions of aortic stenosis. Further, in situ hybridization localized osteopontin mRNA to a subset of lesion macrophages. CONCLUSIONS: These results suggest that, rather than representing a degenerative and unmodifiable process, calcification in aortic stenosis may be, in part, an actively regulated process with the potential for control either through modification of inflammation or synthesis of proteins such as osteopontin, which may modulate calcification in this tissue.
Aortic Valve↗
Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis.
BACKGROUND: In human atherosclerosis, most clinical events occur when plaque integrity is compromised and hemorrhage and thrombosis result. One mechanism for this might be the release by plaque cells of matrix-degrading proteases, such as interstitial collagenase (matrix metalloproteinase-1, MMP-1), which degrades two major plaque structural proteins, types I and III collagen. This study was undertaken to determine whether MMP-1 is expressed in human atherosclerotic plaques. METHODS AND RESULTS: To determine the cellular source and location of MMP-1 in human carotid atherosclerotic lesions, in situ hybridization and immunohistochemistry were performed on 20 endarterectomy specimens. Six nonatherosclerotic carotid arteries also were studied. Intense MMP-1 expression (mRNA and protein) was detected in a subset of plaque macrophages located at the borders of the lipid cores adjacent to fibrous caps and shoulder regions. Subsets of plaque smooth muscle cells and endothelial cells also expressed MMP-1. There was a strong correlation between the percentage of the lipid core occupied by hemorrhage and the percentage of the lipid core perimeter positive for MMP-1 (r = .823, P = .0001). MMP-1 was not detected in any cell type in nonatherosclerotic carotid arteries. CONCLUSIONS: This study demonstrates that MMP-1 is expressed by several cell types in human carotid atherosclerosis and that there is a correlation between the expression of the protease and histopathological evidence of plaque instability. Since MMP-1 may degrade the major structural collagens of the plaque, expression of the protease by macrophages in regions critical to plaque integrity could contribute to plaque expansion, rupture, and hemorrhage.
Aged↗
Platelet-derived growth factor A-chain expression in developing and mature human kidneys and in Wilms' tumor.
Regulated expression of PDGF A-chain may be important in kidney development. We employed two polyclonal antisera to detect expression of PDGF A-chain in fetal and normal adult kidneys by immunohistochemistry. Specificity of the antisera was demonstrated by Western blots of fetal and adult kidneys, demonstrating monospecific bands at 10 to 15 kD, and by absorption studies with PDGF-A peptide. PDGF A-chain is uniformly expressed by visceral glomerular epithelial cells and the epithelial cells of the distal nephron, including collecting ducts and contiguous urothelium lining the renal pelvis, in both fetal and adult kidneys. Fetal kidneys also demonstrate expression of PDGF A-chain at the earliest stages of vesicle formation from the metanephric blastema; this expression is then only intermittently detectable in developing glomeruli until differentiation of visceral epithelial cells occurs. Fetal and mature arterial smooth muscle cells, and some express PDGF A-chain. In situ hybridization with a riboprobe made from PDGF A-chain cDNA showed close correlation of mRNA expression with protein immunohistochemistry. PDGF A-chain expression was also identified in epithelial elements of 5/6 Wilms' tumors studied. These are the first studies to localize PDGF A-chain expression in human kidney and suggest sites of activity for PDGF A-chain in development, neoplasia, and in the renal arterial sclerosis of aging.
Aging↗