Biomedical subjects
M Flanagan
Publications and source records attributed to M Flanagan.
Wound care: the healing process.
When caring for a patient with a wound, regardless of its aetiology, a thorough assessment of the patient, the wound and any other relevant factors must be undertaken before care can be planned, if a successful outcome is to be achieved and realistic time scales set. Accurate wound assessment and appropriate care planning is dependant upon an understanding of the physiology of healing and any factors that may potentially delay or prolong the healing process. To be accurate and meaningful the information recorded should be concise, objective and comprehensive.
Oral immunotherapy with short ragweed extract in a novel encapsulated preparation: a double-blind study.
BACKGROUND: In the past, oral immunotherapy with allergens has had limited clinical effectiveness, presumably because of gastrointestinal destruction of allergens. OBJECTIVE: We have developed a new technique for microencapsulating protein antigens that permits them, when given orally, to bypass the stomach and be delivered to the small intestine in a highly immunogenic form. This study's purpose was to confirm the immunologic potency of orally administered short ragweed pollen extracts (SRW) microencapsulated (mSRW) by this new technique and to study the effectiveness of mSRW in controlling the symptoms of ragweed-induced hay fever. METHODS: Twenty-one SRW-sensitive patients were treated with mSRW in a double-blind placebo-controlled study. Serum SRW IgG and IgE antibodies and nasal secretory IgA antibodies were determined. During the ragweed season, symptoms were quantified by symptom-medication scoring. RESULTS: The treated patients had high titers of serum SRW IgG antibodies (1.15 microg/ml at baseline, increasing to 21.21 microg/ml), experienced regulation of the seasonal increase in serum SRW IgE antibodies (+9% vs +59% in placebo-treated patients), and produced a small amount of nasal SRW IgA antibodies. Despite an insubstantial pollen count, the symptom-medication scores in the treated group were lower than those in the placebo group (4.28 vs 6.18, p = 0.059), but the differences were statistically significant only in the subgroup that tolerated high doses (>20 microg of Amb a 1 in 19 of 21 patients, p = 0.04). These effects were accomplished without inducing any systemic reactions with a dose of mSRW (mean, 23.8 microg of Amb a 1) only slightly higher than that used in high-dose subcutaneous immunotherapy. CONCLUSION: Oral mSRW seems a safe, easily administered, and immunologically potent treatment for ragweed-induced hay fever, but its ultimate utility requires further study.
Mesangial cell proliferation mediated by PDGF and bFGF is determined by levels of the cyclin kinase inhibitor p27Kip1.
Mesangial cell proliferation in vitro is regulated by many cytokines. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are potent mesangial cell mitogens, whereas transforming growth factor-beta1 (TGF-beta1) reduces their effects. We examined how these cytokines regulate rat mesangial cell proliferation at the level of the cell-cycle. Quiescent mesangial cells in vitro express the cyclin kinase inhibitor, p27Kip1 (p27), and PDGF- and bFGF-induced mesangial cell proliferation is associated with a substantial decrease in p27 levels. Consequently there is a marked increase in expression (Western blot analysis, immunostaining) of cyclin A and CDK2. The decline in p27 levels was prevented by TGF-beta1 during inhibition of PDGF- and bFGF-induced mesangial cell proliferation. To determine the functional role of p27 during cytokine-mediated mesangial cell proliferation, the expression of p27 was reduced with specific p27Kip1 antisense oligodeoxynucleotides. Reducing the levels of p27 resulted in an increased magnitude of mesangial cell proliferation (BrdU and 3H-thymidine incorporation) induced by PDGF and bFGF compared to non-transfected mesangial cells and mesangial cells transfected with control mismatch oligodeoxynucleotides. Furthermore, the onset of maximal proliferation occurred earlier in mesangial cells transfected with antisense compared to control. The reduction in proliferation by TGF-beta1 were not altered by decreased p27 expression. Reducing p27 expression in the absence of mitogens was not associated with entry into the cell-cycle. These results suggest cytokine mediated mesangial cell proliferation is associated with specific cell-cycle proteins, and that the levels of p27 may be important in determining the mesangial cell's proliferative response to PDGF and bFGF in vitro.
A profile of the nurse specialist in tissue viability in the UK.
A postal survey was conducted to develop a profile of practising tissue viability clinical nurse specialists in the UK. The aims of the study were to establish baseline data on the role and conditions of employment and identify any discrepancies. A sample of 110 practitioners were identified, of whom 87 replied. Prior to appointment, respondents had between 2-36 years (mean 13 years; SE 0.754) post-registration experience; the first appointment was in 1983 and there has been a steady increase; geographical distribution is uneven tending to cluster around metropolitan areas and on the south coast. The majority of practitioners are appointed in the area of general wound management; 36% have budget responsibility for tissue viability services, mostly for the provision and supply of pressure sore preventive equipment. The appointment was a new post for 90% of respondents, highlighting the lack of available role models and the potential isolation of the position. Most practitioners are working full-time (90%) and 62% are on Grade H; 28% are graduates with a further 19% studying for a first degree; 6% already hold a master's degree while 20% are undertaking courses at this level. However, 39% have no academic qualifications and only 34% had completed ENB courses in tissue viability.
Guidelines and protocols in clinical decision-making.
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The role of p27kip1 in the in vitro differentiation of murine keratinocytes.
We have studied the regulation of cyclins and cyclin-dependent kinase activities during differentiation of primary mouse keratinocytes. Differentiation was induced by placing primary murine keratinocytes into suspension culture, under conditions which prevent cells from attaching to any surface. This treatment induces synthesis of keratin 1, one of the earliest known markers of keratinocyte differentiation, and also results in a profound change in the regulation of G1 and S-phase cyclins and their associated proteins as well as their activities. The placement of cells in suspension culture reduced cyclin A, D1, and E kinase activity within 6 h, accompanied by the cessation of DNA synthesis. K1 mRNA levels were observed to increase after this period, supporting the hypothesis that cell cycle withdrawal precedes the differentiation program. Our data further revealed that the p27kip1 protein level and associated cyclin-dependent kinase inhibitory activity increased when keratinocytes were induced to differentiate. Pretreatment of adherent keratinocytes with p27kip1 antisense oligonucleotides dramatically reduced the accumulation of p27kip1 protein upon subsequent suspension culturing and prevented the onset of differentiation independently of the loss of cyclin-dependent kinase activities. Although antisense oligonucleotide treatment inhibited differentiation, it did not prevent growth arrest. Therefore, the differentiation of primary mouse keratinocytes required a function of Kip other than the inhibition of cyclin-associated activities, and we suggest that this requirement may reflect a novel Rb kinase activity present in Kip immune complexes, which is dependent on the presence of cyclin D3. Thus, the placement of keratinocytes in suspension induces a program that includes loss of cyclin activity, which is linked to terminal growth arrest, and an induction of p27kip1, which is linked to the differentiation program.
Choosing pressure sore risk assessment tools.
The validity and reliability of many commonly used risk assessment scores is inconclusive. Some risk assessment scores appear to be more suitable for specific clinical settings, therefore selection requires careful consideration. Further research is required on the relationship between predictions of risk status and the selection of appropriate patient support surfaces.
Breaking of oral tolerance by an encapsulated antigen.
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Immunologic effects of encapsulated short ragweed extract: a potent new agent for oral immunotherapy.
BACKGROUND: Oral allergen immunotherapy with conventional allergens has not been a useful mode of treatment because of the lack of potency of allergens when administered by this route. OBJECTIVE: To study the immunologic potency of short ragweed pollen extracts microencapsulated by a new technique administered orally to short ragweed pollen-sensitive humans and to establish the dose of oral microencapsulated short ragweed pollen extract required for these effects. METHODS: Nine short ragweed pollen-sensitive patients were treated with a new oral agent for immunotherapy, microencapsulated short ragweed pollen extract, in an open study. The effectiveness of this treatment was determined by comparison to a group of nine matched short ragweed pollen-sensitive patients who received no treatment. Treated patients developed high titers of short ragweed-specific IgG and IgE antibodies and their expected seasonal increase in IgE antibodies was regulated. The dose of microencapsulated short ragweed pollen extract required to achieve these effects was only slightly higher than the dose of short ragweed pollen extract used in high dose subcutaneous immunotherapy. Furthermore, this dose was achieved in 7 weeks. There were no side effects other than mild gastrointestinal ones. The nine treated patients fared clinically better during the ragweed season than the untreated patients in this open study. CONCLUSION: This study suggests that allergens microencapsulated by this new technique may make oral immunotherapy a practical mode of treatment.
Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents.
A low proliferating fraction in solid tumors limits the effectiveness of cell cycle-dependent chemotherapeutic agents. To understand the molecular basis of such "kinetic" resistance we cultured tumor cells as multicellular spheroids and examined levels of p27Kip1, a cyclin-dependent kinase inhibitor known to be upregulated by intercellular contact in normal cells. When transferred from monolayer to three-dimensional culture, a consistent upregulation (up to 15-fold) of p27 protein was observed in a panel of mouse and human carcinoma cell lines. Antisense-oligonucleotide-mediated downregulation of p27 in EMT-6 mammary tumor cell spheroids reduced intercellular adhesion, increased cell proliferation, sensitized tumor cells to 4-hydroperoxycyclophosphamide, and restored drug- or radiation-induced cell-cycle perturbations repressed in spheroid culture. Our results implicate p27 as a regulator of drug resistance in solid tumors and suggest that tumor-targeted p27 antagonists may be useful chemosensitizers in conjunction with conventional anticancer therapy.
How can you accurately assess pressure damage on patients with darkly pigmented skins?
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Evaluation of an agar gel immunodiffusion test to detect infection of cattle with bluetongue viruses in Queensland, Australia.
An agar gel immunodiffusion (AGID) test to detect group-specific antibodies to infection of cattle by bluetongue viruses was evaluated using field collected sera in Queensland, Australia. The AGID test was compared to the serum neutralisation (SN) test used to detect serotype-specific bluetongue virus antibodies. The AGID test was found to be highly sensitive (95% confidence interval, 80.7-100%) but to have moderate specificity (95% confidence interval, 59.3-79.6%), relative to the SN test. The correlation between AGID and SN test results was 0.41 (P < 0.001). Using likelihood ratio estimates the chance (posttest probability) of an AGID test positive serum sample being positive (titre > or = 1:20) in the SN test was estimated to be 87% and 90% for 2+ and 3+ AGID test reactions, respectively. A serum sample was estimated to have a probability of 40% of being positive in the SN test if it gave a 1+ reaction in the AGID test. Results suggest that the AGID test should ideally be used as a screening test in serological surveys and surveillance programs. If the test is to be used for identification of individually infected cattle, a cutoff point of > or = 2+ should be employed.
Infection of cattle with bluetongue viruses in Queensland, Australia: results of a sentinel herd study, 1990-1992.
Between 1990 and 1992, 47 sentinel herds of 10-20 cattle each were established throughout Queensland, Australia to monitor bluetongue virus infection. Sixteen herds at 12 locations seroconverted to bluetongue viruses during the study. Herd incidence rates ranged from 0.0 to 3.45 seroconversions per cattle-year at risk. The mean incidence rate was 0.29 seroconversions per cattle-year at risk (95% confidence interval 0.23-0.36), and the median incidence rate was 0.32 seroconversions per cattle-year at risk (95% CI 0.0-0.54). Only seroconversions to bluetongue virus serotypes 1 and/or 21 were detected in the study; no evidence was found of infection with other serotyped previously isolated in Australia (3, 9, 15, 16, 20, 23). Seroconversion to serotype 1 occurred more frequently than seroconversion to serotype 21. Seroconversion generally occurred between April and July, being most common in May, but varied considerably within each of the 3 years of the study. This study confirmed the presence of only serotypes 1 and 21 in Queensland and demonstrated the sporadic and restricted nature of bluetongue virus infection in the Queensland cattle herd.
Antibodies to bluetongue and related orbiviruses in sheep and goats in bluetongue virus-endemic areas of northern and central Queensland.
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The effects of vaccination of Merino ewes with an attenuated Australian bluetongue virus serotype 23 at different stages of gestation.
A cell culture attenuated Australian bluetongue virus serotype 23 (BLU23) prototype vaccine was assessed for its effects on pregnant Merino sheep. Seventy-six ewes were vaccinated at 5 different stages of gestation, and the failure to lamb at term was as follows: 35 to 43 days of gestation, 20/36 (56%); 57 to 64 days of gestation, 3/10 (30%); 81 to 88 days of gestation, 3/10 (30%); 109 to 116 days of gestation, 0/10 (0%); 130 to 137 days of gestation, 0/10 (0%). Of 30 ewes vaccinated with a cell culture supernatant fluid control between 35 and 43 days of gestation, 6.7% (2/30) failed to lamb at term. Two ewes vaccinated with BLU23 vaccine between 35 and 43 days of gestation had lambs with hydranencephaly. All other lambs born were clinically normal. Three ewes vaccinated with BLU23 aborted. Two of these were vaccinated between 35 and 43 days of gestation, the 3rd between 81 and 88 days of gestation. Five lambs were born with BLU group antibody. Four of these were from ewes vaccinated between 35 and 43 days of gestation, and 2 of these had hydranencephaly. The fifth was from a ewe vaccinated between 57 and 64 days of gestation. The vaccine did not produce disease in adult sheep, but was a potent cause of early foetal death and to a much lesser extent foetal malformation.
Infection of cattle in Queensland with bluetongue viruses: 1. Prevalence of antibodies.
A survey of nearly 20,000 cattle in Queensland was conducted to describe the prevalence and distribution of infection by serotypes of bluetongue virus. The overall prevalence of serum antibodies to one or more bluetongue viruses was 8.7% (95% confidence interval 8.3 to 9.1). Sera from cattle contained neutralising activity against 2 serotypes, 1 and 21. No evidence was found of infection with other serotypes previously isolated in Australia. The overall prevalence of serotype 1 antibodies was 7.7% (95% CI 7.3 to 8.0) and the prevalence of serotype 21 antibodies was 3.3% (95% CI 3.1 to 3.6). The prevalence of serotype 1 antibodies was significantly (P < 0.05) higher than that of serotype 21 in every region of the State, except in the central highlands and south-west Queensland. Overall, 3 significantly (P < 0.05) different zones of prevalence were found: high prevalence (> 20%) in far north Queensland, moderate (5 to 20%) in north-west, northern and southern coastal Queensland, and low (< 5%) in the central highlands, Darling Downs and south-west Queensland.
The efficacy of a hydrogel in the treatment of wounds with non-viable tissue.
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