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Biomedical subjects

A J Smith

Publications and source records attributed to A J Smith.

At least 127 records · Page 7Linked to original sources
PubMed2000

The spectrum of skin disorders in abdominal stoma patients.

BACKGROUND: Skin integrity is essential for the normal usage of a stoma appliance. However, there is little published on the prevalence, nature or management of stoma-related skin disorders. Objectives To document stoma-related skin disorders in a large cohort of patients. METHODS: We sent a postal questionnaire to all surviving patients who had had abdominal stoma surgery at Hope Hospital, Salford, U.K. in the 10 years from 1 January 1989. Those reporting skin disease were invited to attend a clinic run by a dermatologist and a stoma-care specialist nurse. All lesions were categorized and swabs taken for microbiological examination. RESULTS: Of 525 surviving patients, 325 (62%) replied to the questionnaire. Of these, 73% reported a skin problem that had affected normal stoma bag use. Dermatoses included irritant reactions, particularly from leakage of urine or faeces (42%); pre-existing skin diseases, principally psoriasis, seborrhoeic dermatitis and eczema (20%); infections (6%); allergic contact dermatitis (0.7%) and pyoderma gangrenosum (0.6% annual incidence). A further 15% of patients with skin problems had persistent or recurrent dermatitis not explained by allergy, frank infection or faecal irritation. This responded to short-term treatment with topical corticosteroids. Further investigation is under way into its pathogenesis. CONCLUSIONS: Skin disorders are common in stoma patients, and various patterns can be recognized and effectively treated.

Abdomen↗
PubMed2000

Surgical management of intra-abdominal desmoid tumours.

BACKGROUND: Intra-abdominal desmoids are uncommon neoplasms. The aggressive nature of these tumours and the potential for major morbidity secondary to resection can present a difficult surgical dilemma. METHODS: Patients with histologically confirmed intra-abdominal desmoid tumours undergoing laparotomy were identified from a prospective database. Clinical features and outcomes in this group were evaluated. RESULTS: The study group comprised 24 patients. Sixteen patients underwent complete resection of the tumour while eight had biopsy only, with or without intestinal bypass. Small intestinal resection was performed in 12 patients, including three who had a near-total enterectomy. Median follow-up was 62 months, with an actuarial overall survival rate of 73 per cent at 10 years. There was no difference in survival rate between completely resected and unresected patients (P = 0.73). There were seven deaths in the entire group, of which four were in those undergoing complete resection. CONCLUSION: Operation can cure patients with intra-abdominal desmoid tumours, but may result in significant morbidity, especially from loss of small intestine. No other therapy is a predictably good alternative to operation but the natural history of desmoids is often characterized by prolonged periods of stability or even regression. A period of watchful waiting, until significant symptoms develop, may be the most appropriate course in patients who risk mesenteric vascular injury or substantial enterectomy with attempts at resection.

Abdominal Neoplasms↗
PubMed2000

Topical sucralfate in the management of peristomal skin disease: an open study.

Dermatoses affecting the skin around stoma sites are common and difficult to treat. We have investigated the effectiveness of topical sucralfate in the management of peristomal dermatoses in adults using an open study design. Apart from forming a physical barrier to further irritation, sucralfate binds to basic fibroblast growth factor preventing its degradation and thereby promotes healing. In eight out of nine patients with faecal or urine erosions, daily, topical sucralfate treatment was associated with healing within 4 weeks. There was limited or no response to treatment in a further nine patients with traumatic ulcers, excoriated dermatitis or pyoderma gangrenosum. Topical sucralfate represents a safe, inexpensive and effective therapeutic intervention, particularly for those patients with high output or short stomas where repeated stoma leakage may be unavoidable.

Abdomen↗
PubMed2000

Quality use of medicines: where does pharmacology 'end'? Invited ASCEPT Lecture. Australasian Society of Clinic and Experimental Pharmacologists and Toxicologists.

1. Pharmacology can be defined very narrowly (e.g. as solely a laboratory based specialty) or more broadly to include issues surrounding rational drug use in the community. 2. While the hypothetio-deductive approach is more clearly in evidence in laboratory and clinical pharmacological experimentation, it is no less important in the comparatively less-well charted area of drug use in the community. 3. Just as laboratory pharmacology has built new partnerships with molecular biology and genetics, the exploration of community drug use brings pharmacologists into partnership with other disciplines (epidemiology, economics, behavioural science) and other sectors (consumers, government, health professionals and industry). 4. Implementing Australia's Quality Use of Medicines Policy (1992) has led to vigorous exploration of issues and problems in medicinal drug use in the community and much scientific study of causes and potential interventions to improve the situation. 5. The Australian National Prescribing Service (1998) is attempting to bring an evidence-based approach to the many facets of prescribing and drug use, by prescribers and consumers alike. 6. Innovation commonly occurs at the interface between the boundaries of traditional disciplines.

Australia↗
PubMed2000

Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis.

BACKGROUND & AIMS: Patients with progressive familial intrahepatic cholestasis (PFIC) type 3 have a mutation in the MDR3 gene, encoding the hepatocanalicular phospholipid translocator. In general, liver failure develops within the first decade of life in these patients. Previous studies have shown that in the mdr2-knockout mouse, the animal model for this disease, the absence of phospholipids in bile causes chronic bile salt-induced damage to hepatocytes. We aimed to test the efficacy of hepatocyte transplantation and liver repopulation in this disease model. METHODS: Transgenic MDR3-expressing hepatocytes as well as normal mdr2(+/+) hepatocytes were transplanted in mdr2(-/-) mice, and liver repopulation was assessed by immunohistochemistry and measurement of biliary lipid secretion. RESULTS: Transplanted hepatocytes partially repopulated the liver, restored phospholipid secretion, and diminished liver pathology. Repopulation was stronger when hepatocellular damage was enhanced by a bile salt-supplemented diet. After 1 year, however, these animals developed multiple hepatic tumors, and biliary phospholipid secretion decreased. In transplanted animals receiving a control diet, repopulation was slower but eventually remained stable at 21%, while liver pathology was completely abrogated and tumor formation was prevented. CONCLUSIONS: These results suggest that moderate liver pathology is a safe condition for the induction of effective hepatocyte repopulation and that this therapy is potentially applicable to patients with PFIC type 3.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport.

The human multidrug transporter MDR1 P-glycoprotein and the multidrug resistance proteins MRP1 and MRP2 transport a range of cytotoxic drugs, resulting in multidrug resistance in tumour cells. To overcome this form of drug resistance in patients, several inhibitors (reversal agents) of these transporters have been isolated. Using polarized cell lines stably expressing human MDR1, MRP1 or MRP2cDNA, and 2008 ovarian carcinoma cells stably expressing MRP1 cDNA, we have investigated in this study the specificity of the reversal agents V-104 (a pipecolinate derivative), GF120918 (an acridone carboxamide derivative also known as GG918), and Pluronic L61 (a (poly)oxypropethylene and (poly)oxypropylene block copolymer). Transport experiments with cytotoxic drugs with polarized cell lines indicate that all three compounds efficiently inhibit MDR1 Pgp. Furthermore, V-104 partially inhibits daunorubicin transport by MRP1 but not vinblastine transport by MRP2. V-104 reverses etoposide resistance of 2008/MRP1 cells, whereas GF120918 does not reverse resistance due to MRP1. V-104 partially inhibits the export of the organic anion dinitrophenyl S-glutathione by MDCKII-MRP1 but not by MDCKII-MRP2 cells. Unexpectedly, export of the organic anion calcein by MDCKII-MRP1 and MDCKII-MRP2 cells is stimulated by Pluronic L61, probably because it relieves the block on entry of calcein AM into the cell by endogenous MDR1 Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Peristomal dermatoses: a novel indication for topical steroid lotions.

BACKGROUND: Dermatoses that interfere with the normal use of a stoma appliance are common. When preventable causes, such as infection or allergy, are not identified, barrier preparations or topical steroids have been used. However, topical medicaments formulated in a cream or ointment base will cause stoma bags to detach, resulting in leaks. OBJECTIVE: Our purpose was to investigate the efficacy and suitability of corticosteroids in aqueous/alcohol lotions in the management of peristomal dermatoses. METHODS: A clinic run by a dermatologist and 2 stoma nurses was created. Patients with a variety of noninfective, inflammatory dermatoses were treated with topical corticosteroid lotions up to a maximum of 4 weeks, with occasional use thereafter in some cases. RESULTS: Topical, aqueous/alcohol, corticosteroid lotions have been used in 60 patients and have proved particularly useful for the treatment of irritant dermatitis, pyoderma gangrenosum, psoriasis, and constitutional eczema. After the initial treatment course, occasional applications, approximately every 2 weeks, may be necessary to control the skin disorder. This low frequency of application minimizes the risk of side effects so that we have not identified local or systemic side effects in any of the patients treated so far. CONCLUSION: Topical corticosteroids formulated in aqueous alcohol lotion are effective and acceptable treatments for peristomal dermatoses. If used appropriately, the risk of side effects is low.

Administration, Topical↗
PubMed2000

Colorectal cancer vaccines: antiidiotypic antibody, recombinant protein, and viral vector.

The colorectal cancer antigen GA733 (also termed CO17-1A, KSI-4, Ep-CAM, KSA) has proved to be a useful target in passive immunotherapy with monoclonal antibody and in active immunotherapy with antiidiotypic antibodies in cancer patients. The GA733 antigen was molecularly cloned and expressed in baculovirus (BV), adenovirus (AV), and vaccinia virus (VV). Recombinant BV-, VV-, and AV-GA733 induced antigen-specific cytotoxic antibodies and proliferative and delayed-type hypersensitive lymphocytes. However, only the AV recombinant induced antigen-specific cytolytic T lymphocytes and regression of established tumors. Cured mice were protected against challenge with antigen-negative tumors, indicating antigen spreading of immune responses. In a model of active immunotherapy against the murine homologue of the human GA733 antigen, murine epithelial glycoprotein (mEGP), BV-derived mEGP protein in various adjuvants did not protect mice against a challenge with mEGP-positive tumors. AV mEGP, only when combined with interleukin-2, significantly inhibited growth of established mEGP-positive tumors. This is in contrast to the same vaccine expressing the human antigen that was effective without interleukin-2. AV GA733, in combination with interleukin-2, is a candidate vaccine for colorectal cancer patients.

Animals↗
PubMed2000

Methods of positioning fish for surgery or other procedures out of water.

Several methods are available for positioning fish and other aquatic species during surgery or other experimental procedures out of water. This paper reviews current methods in the light of criteria for humane handling, and suggests the implementation of a novel method, currently used for positioning mammals during surgery, that gives optimal support and a minimum of damage.

Animals↗
PubMed2000

Guidelines for reporting the results of experiments on fish.

A detailed account of experimental design, including an accurate description of the animals used, is an essential part of good research practice. Without these details, the reader will be unable not only to form an opinion on the significance of the findings but also to repeat the experiment in another laboratory. This paper presents suggested guidelines for reporting experimental studies using fish.

Animal Husbandry↗
PubMed2000

Postoperative pulpal and repair responses.

BACKGROUND: Each year in the United States, the success of 10 million surgically restored carious lesions depends on a favorable tertiary dentin repair response to preparation, restoration and patient factor variables. The authors investigated the relationship between these variables and dentinal response. METHODS: Standardized rectangular Class V restoration preparations were cut into the buccal dentin of intact first or second premolars of 27 patients without exposing the pulp and were restored. The patients were between 9 and 17 years of age. The treated teeth were scheduled for extraction for orthodontic reasons. After tooth extraction, the tertiary dentin was analyzed histomorphometrically. RESULTS: The area of tertiary reactionary dentin was found to be correlated using linear regression analysis of variance with restoration residual dentin thickness (P = .0024), age of the patient (P = .0045), restoration floor surface area (P = .0266) and restoration width (P = .0415). The authors did not find a correlation with the premolar position (P = .0594), sex of the patient (P = .650), pulpal inflammatory reaction (P = .613) or the time elapsed since surgery (P = .531). Restoration with zinc oxide eugenol was found to negatively influence tertiary dentin matrix secretion (post hoc analysis of variance, P = .030). CONCLUSIONS: The age of a patient at treatment, the choice of restorative material and the size of the restoration preparation are all factors that can positively or negatively affect the pulpal repair response. CLINICAL IMPLICATIONS: Age of the patient affects dentin repair capacity and may be a factor in treatment planning decisions. Minimizing the cutting of dentin, especially the width and base of the preparation, reduces the probability of recurrent pulpal complications.

Adolescent↗
PubMed2000

Stent-based gene therapy.

Delivery of gene therapy to inhibit intimal hyperplasia has been proposed to prevent postangioplasty restenosis. We sought to apply gene therapy by using a stent-based technique. There are several hurdles that must be overcome before gene-stent therapy can be applied successfully in clinical trials. These include increasing the efficiency of gene delivery through atherosclerotic plaque; increasing intramural retention times; preventing the inflammatory reaction that stents coated with biodegradable polymers can elicit; overcoming the risk of systemic gene delivery; and accessing the adventitia via percutaneous approach. We evaluated a gene-stent delivery mechanism based on microporous metal microneedles developed with nanotechnology in an attempt to overcome some of these problems. A novel approach to the transfection of genes by microfabricated technology was evaluated in smooth muscle cells in culture. We demonstrated that microneedles can deliver gene therapy to smooth muscle cells in culture and can produce controlled penetration of the IEL and intima. We conclude that taller microneedles need to be developed to reach the media in diseased human arteries and that this technology has the potential to be incorporated in a stent to deliver gene therapy in atherosclerotic plaque.

Angioplasty, Balloon, Coronary↗
PubMed2000

Parastomal pyoderma gangrenosum: clinical features and management.

BACKGROUND: The importance of pyoderma gangrenosum (PG) as a cause of ulceration around abdominal stomas is not well recognized. OBJECTIVE: Our purpose was to describe the incidence, clinical and histologic features, disease associations, and possible risk factors for parastomal PG. METHODS: A clinic, run by a dermatologist and two stoma nurses, was created. Five hundred patients approached by postal questionnaire were invited to attend if they had skin problems. In addition, local surgical, dermatologic, and nursing services were invited to refer patients with parastomal skin problems. Cases of parastomal PG were identified, investigated, and treated. RESULTS: The annual incidence of parastomal PG in the questionnaire-based cohort of patients was 0.6% (3 patients). An additional 23 patients with the condition were seen. No consistent hematologic, biochemical, immunologic, microbiological or histologic abnormalities were identified. Local skin damage did not appear to be an important trigger for parastomal PG. The condition is recurrent in one third of cases. Topical tacrolimus (0.3% in carmellose sodium paste) has been effective in 4 patients. CONCLUSION: Parastomal PG is far more common than previous reports would suggest, and it may be associated with diseases other than inflammatory bowel disease.

Abdomen↗
PubMed1999

The fatty acid transport protein (FATP1) is a very long chain acyl-CoA synthetase.

The primary sequence of the murine fatty acid transport protein (FATP1) is very similar to the multigene family of very long chain (C20-C26) acyl-CoA synthetases. To determine if FATP1 is a long chain acyl coenzyme A synthetase, FATP1-Myc/His fusion protein was expressed in COS1 cells, and its enzymatic activity was analyzed. In addition, mutations were generated in two domains conserved in acyl-CoA synthetases: a 6- amino acid substitution into the putative active site (amino acids 249-254) generating mutant M1 and a 59-amino acid deletion into a conserved C-terminal domain (amino acids 464-523) generating mutant M2. Immunolocalization revealed that the FATP1-Myc/His forms were distributed between the COS1 cell plasma membrane and intracellular membranes. COS1 cells expressing wild type FATP1-Myc/His exhibited a 3-fold increase in the ratio of lignoceroyl-CoA synthetase activity (C24:0) to palmitoyl-CoA synthetase activity (C16:0), characteristic of very long chain acyl-CoA synthetases, whereas both mutant M1 and M2 were catalytically inactive. Detergent-solubilized FATP1-Myc/His was partially purified using nickel-based affinity chromatography and demonstrated a 10-fold increase in very long chain acyl-CoA specific activity (C24:0/C16:0). These results indicate that FATP1 is a very long chain acyl-CoA synthetase and suggest that a potential mechanism for facilitating mammalian fatty acid uptake is via esterification coupled influx.

Animals↗
PubMed1999

Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice.

IL-18, formerly designated IFN-inducing factor, is a novel cytokine produced by activated macrophages. It synergizes with IL-12 in the induction of the development of Th1 cells and NK cells. To define the biological role of IL-18 in vivo, we have constructed a strain of mice lacking IL-18. Homozygous IL-18 knockout (-/-) mice are viable, fertile, and without evident histopathologic abnormalities. However, in contrast to the heterozygous (+/-) or wild-type (+/+) mice, which are highly resistant to the infection of the protozoan parasite Leishmania major, the IL-18-/- mice are uniformly susceptible. The infected IL-18-/- mice produced significantly lower levels of IFN-gamma and larger amounts of IL-4 compared with similarly infected +/- and +/+ mice. In contrast, when infected with the extracellular Gram-positive bacteria Staphylococcus aureus, the IL-18-/- mice developed markedly less septicemia than similarly infected wild-type (+/+) mice. However, the mutant mice developed significantly more severe septic arthritis than the control wild-type mice. This was accompanied by a reduction in the levels of Ag-induced splenic T cell proliferation, decreased IFN-gamma and TNF-alpha synthesis, but increased IL-4 production by the mutant mice compared with the wild-type mice. These results therefore provide direct evidence that IL-18 is not only essential for the host defense against intracellular infection, but it also plays a critical role in regulating the synthesis of inflammatory cytokines, and therefore could be an important target for therapeutic intervention.

Animals↗
PubMed1999

The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis.

The MLL gene from human chromosome 11q23 is involved in >30 different chromosomal translocations resulting in a plethora of different MLL fusion proteins. Each of these tends to associate with a specific leukaemia type, for example, MLL-AF9 is found mainly in acute myeloid leukaemia. We have studied the role of the Mll-AF9 gene fusion made in mouse embryonic stem cells by an homologous recombination knock-in. Acute leukaemias developed in heterozygous mice carrying this fusion as well as in chimeric mice. As with human chromosomal translocation t(9;11), the majority of cases were acute myeloid leukaemias (AMLs) involving immature myeloblasts, but a minority were acute lymphoblastic leukaemia. The AMLs were preceded by effects on haematopoietic differentiation involving a myeloproliferation resulting in accumulation of Mac-1/Gr-1 double-positive mature myeloid cells in bone marrow as early as 6 days after birth. Therefore, non-malignant expansion of myeloid precursors is the first stage of Mll-AF9-mediated leukaemia followed by accumulation of malignant cells in bone marrow and other tissues. Thus, the late onset of overt tumours suggests that secondary tumorigenic mutations are necessary for malignancy associated with MLL-AF9 gene fusion and that myeloproliferation provides the pool of cells in which such events can occur.

Animals↗
PubMed1999

MRP3, an organic anion transporter able to transport anti-cancer drugs.

The human multidrug-resistance protein (MRP) gene family contains at least six members: MRP1, encoding the multidrug-resistance protein; MRP2 or cMOAT, encoding the canalicular multispecific organic anion transporter; and four homologs, called MRP3, MRP4, MRP5, and MRP6. In this report, we characterize MRP3, the closest homolog of MRP1. Cell lines were retrovirally transduced with MRP3 cDNA, and new monoclonal antibodies specific for MRP3 were generated. We show that MRP3 is an organic anion and multidrug transporter, like the GS-X pumps MRP1 and MRP2. In Madin-Darby canine kidney II cells, MRP3 routes to the basolateral membrane and mediates transport of the organic anion S-(2,4-dinitrophenyl-)glutathione toward the basolateral side of the monolayer. In ovarian carcinoma cells (2008), expression of MRP3 results in low-level resistance to the epipodophyllotoxins etoposide and teniposide. In short-term drug exposure experiments, MRP3 also confers high-level resistance to methotrexate. Neither 2008 cells nor Madin-Darby canine kidney II cells overexpressing MRP3 showed an increase in glutathione export or a decrease in the level of intracellular glutathione, in contrast to cells overexpressing MRP1 or MRP2. We discuss the possible function of MRP3 in (hepatic) physiology and its potential contribution to drug resistance of cancer cells.

ATP-Binding Cassette Transporters↗