Magnetic resonance imaging for primary fistula in ano (Br J Surg 2003; 90: 877-881).
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Humans↗
Biomedical subjects
R Guy
Publications and source records attributed to R Guy.
A clinical evaluation of ophthalmic assessment in children with sensori-neural deafness.
BACKGROUND: Since 1991, children with sensori-neural deafness and their families within Southern Derbyshire have been supported by a multiagency approach to their diagnosis and management. RESULTS: One hundred and twenty-two children were seen at the Child Development Centre for an holistic assessment, and 110 of these children have had an ophthalmic assessment, of whom 48 (43.6%) were found to have ophthalmic abnormalities. These included 43 children (39.1%) with refractive errors, ranging from mild to severe. Of 82 children with uncomplicated deafness, 26 (31.7%) had refractive errors. The prevalence of ophthalmic problems was higher than the prevalence in hearing school children in the literature and in local pre-school children. There were six cases of Usher syndrome. Twenty-one children had more than one eye defect. The findings indicate that deaf and hearing impaired children are two to three times more likely to develop ophthalmic abnormalities than their hearing peers, which makes early detection of paramount importance. An important local outcome has been the establishment of guidelines for ophthalmic assessment to include assessment of vision and screening for Usher syndrome by electro-physiological testing at aged 7 years and above. Screening has been completed to date in 78 children with congenital sensori-neural deafness. CONCLUSIONS: Sensitive and efficient ophthalmic assessment and management are essential for all deaf and hearing impaired children and national guidelines need to be established for both assessment of vision and screening for Usher syndrome, based on further evaluated research.
Child↗
Co-existence of lysosomal storage diseases in a consanguineous family.
Lysosomal storage diseases are rare and coexistence of more than one in a family can present a diagnostic challenge as illustrated by this study. The index case born to consanguineous Asian parents presented with developmental delay. Investigations led to an incidental finding of Fabry disease. After numerous additional investigations over a year, a second diagnosis of aspartylglucosaminuria (AGU) was made. A family history of renal disease and developmental delay was disclosed. The sister and first cousin of the index case were diagnosed as homozygous for AGU, but do not have Fabry disease. The younger brother has since been diagnosed with both Fabry disease and AGU. Another cousin has learning difficulties and fits, but is heterozygous for AGU, and possibly has another uncharacterised autosomal recessive disorder. In a family with consanguinity when the clinical picture in an individual is not fully explained by the presence of one rare metabolic disease, it is essential to investigate further for the presence of others.
Acetylglucosamine↗
Updated audit database for breast imaging/histopathology correlation.
AIM: To develop, test and validate an audit database, evolved from a prior, peer-reviewed, audit tool for symptomatic multi-modality breast imaging services. MATERIALS AND METHODS: The database is to cover all aspects of non-invasive breast imaging and recognize subspeciality inputs. When more than one imaging investigation is used for diagnosis, an overall breast imaging audit grade is to be introduced. Data derived from clinical studies has been input into the new database. RESULTS: Results for mammography alone are virtually identical to those of the previous program. A slight increase in accuracy is suggested by using more investigations if the first investigation is not conclusive. More comprehensive reports can be issued. CONCLUSION: The audit program can be used in the same context as the old audit. If mammography is the sole investigation, there is no change from the previous standards of a minimum mammography (ultrasound)/histopathology agreement of 70%, an equivocal rate of less than 15%, a false-positive rate of less than 7.5% and a false-negative rate of less than 6.5%. Although there is no statistical difference when more than one imaging investigation is used, there is some marginal improvement. It is suggested that initial audit standards for multi-imaging should be 75% for minimum agreement, a 10% maximum for an equivocal rate, a 5% maximum for false negative and an unchanged false positive rate of 7.5% maximum. These standards will be refined with experience. Due to the nature of the database, complex queries can be made including those about histopathological data. If widely used, the database will be a useful tool to audit the accuracy of symptomatic breast imaging services and types and frequencies of symptomatic breast disease, as seen in routine settings.
Breast Neoplasms↗
p53 and thymic 'death by neglect': thymic epithelial cell-induced apoptosis of CD4+8+ thymocytes is p53-independent.
The involvement of the tumor suppressor protein, p53, in thymic epithelial cell-induced apoptosis of CD4+8+ (double positive) thymocytes, was studied in an in vitro model consisting of a thymic epithelial cell line (TEC) and thymocytes. p53 expression was not augmented in double positive (DP) thymocytes upon co-culturing with TEC, although extensive apoptosis was observed. In the same cells, p53 expression was upregulated in response to low ionizing irradiation, which was accompanied with massive apoptosis. Moreover, TEC induced apoptosis in two DP thymomas, derived from p53(-/-) mice, and in a double positive thymoma clone expressing mutant p53. The extent and kinetics of TEC-induced apoptosis was not affected by the status of p53 in the thymocytes tested. We conclude that thymic epithelial cell-induced apoptosis of immature DP thymocytes is p53-independent and apparently, involves a different apoptotic pathway than that triggered by DNA damage.
Animals↗
Apoptosis of thymic lymphoma clones by thymic epithelial cells: a putative model for 'death by neglect'.
We have previously described an in vitro system in which thymic epithelial cells induce apoptosis in CD4+ 8+ thymocytes or thymic lymphoma cells, in the absence of an exogenous antigen. A thymic epithelial cell line (TEC) recapitulated the response, by inducing apoptosis in CD4+ 8+ thymocytes of the thymic lymphoma clone, PD1.6. The present study pursues the involvement of the T-cell receptor (TcR) in the response of PD1.6 to TEC. TcR cross-linking did not cause apoptosis of PD1.6, although it induced tyrosine phosphorylation of p95vav. In contrast, TEC did not induce phosphorylation of p95vav but induced apoptosis of PD1.6 cells. These results suggest that TcR-evoked signals are not involved in TEC-induced apoptosis of PD1.6. Intracellular calcium chelation, using BAPTA-loaded PD1.6 cells, diminished TEC-induced apoptosis. Protein kinase C depletion in PD1.6 cells augmented their apoptotic response to TEC. Thus, the response of PD1.6 to TEC is calcium-dependent and inhibited by PKC. Likewise, the apoptotic response of PD1.6 to A23187 was abrogated by PKC activation. PD1.6 cells may represent an immature double positive thymocyte population, which does not undergo negative selection. The interaction of PD1.6 with TEC may thus serve as a model for the TcR-independent 'Death by Neglect', which takes place in the thymus during thymocyte development.
Animals↗
The organ maintained human sebaceous gland.
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Cytokines↗
Blockage of skin invasion by schistosome cercariae by serine protease inhibitors.
Invasion of skin by schistosome cercariae is facilitated by a serine protease secreted from the acetabular cells of cercariae in response to skin lipid. Specific inhibitors of the protease, when applied to human skin in formulations designed to retain the inhibitor on and in the upper stratum corneum layers, block cercarial invasion of human skin. Both peptide-based, irreversible inhibitors and non-peptide, reversible inhibitors block cercarial invasion when applied in a propylene glycol:isopropyl alcohol (3:1) formulation in vitro. Arrest of cercarial invasion could be achieved even after immersion of treated skin in water for 2 hr. Peptide-based irreversible inhibitors in the presence of three different Topicare Delivery Compounds optimized arrest of cercarial invasion. The three Topicare Delivery Compounds applied alone prevented 80-100% of cercarial invasion. With inclusion of the inhibitor, there was 97-100% inhibition in vitro. The optimal formulation with inhibitor was then applied to the tails of BALB/c mice, and the mice were exposed to 120 cercariae by tail immersion. With the carrier lotion alone, there was a 50% reduction in worm burden and a 70% reduction in egg burden. When inhibitor was included, an 80% reduction in worm burden and a 92% reduction in egg burden was observed.
2-Propanol↗
A humanised therapeutic CD4 mAb inhibits TCR-induced IL-2, IL-4, and IL-10 secretion and expression of CD25, CD40L, and CD69.
The actions of a humanised therapeutic CD4 mAb YHB.46 on T cell activation were investigated in vitro. Soluble YHB.46 IgG or YHB.46-derived F(ab')2 fragments caused inhibitions of up to 100% of the proliferation of purified CD4+ T cells activated with immobilised CD3 mAb. The inhibitory effects of the CD4 mAb were equally potent in both CD45RA+ and CD45RO+ T cell subset proliferation assays. Inhibitory effects on DNA synthesis were nto explicable by increased T cell apoptosis. YHB.46 was inhibitory even when added 70 h after exposure of cells to immobilised CD3 mAb, but it had little effect on IL-2 receptor-driven proliferation signals. The CD4 mAb inhibited the CD3-induced expression of the CD25 and CD69 activation markers on the T cell surface and suppressed CD40 ligand expression, but not that of CD25 and CD69, when their expression was induced by phorbol ester plus ionomycin. YHB.46 also exerted a profound inhibitory effect on the production of IL-2, IL-4, and IL-10, irrespective of whether T cells were activated with CD3 mAb or with phorbol ester plus ionomycin. The inhibitory effects of YHB.46 on CD4+ T cell proliferation were partially prevented by the addition of exogenous IL-2 or autologous monocytes and were completely prevented by activating T cells with a novel CD3-CD28 bivalent F(ab')2 reagent. However, the inhibitory effects of YHB.46 on T cell proliferation were equipotent in the presence or the absence of CTLA-4Ig, showing that the CD4 mAb was not acting on CD28-induced activation signals per se. Our results show that the inhibitory effects of YHB.46 on T cell activation do not involve CD28 or IL-2 receptor signalling, but are directed at the TCR-mediated G0-G1 transition. These findings in vitro predict that YHB.46 may act as a potent immunosuppressant in the clinical context.
Animals↗
The effects of inflammatory cytokines on the isolated human sebaceous infundibulum.
The human sebaceous pilosebaceous infundibulum was isolated and maintained in medium for up to 7 d. Freshly isolated infundibula were found to express keratins 1, 5, 6, 16, and 17, as determined by immunohistochemistry. In addition, freshly isolated infundibula expressed filaggrin, profilaggrin, involucrin, cornifin alpha, and loricrin. This pattern of expression was retained over 7 d. The addition of 100 U interferon (IFN)-gamma per ml over 3 d and 1 nM phorbol myristate acetate over 24 h resulted in the expression of intercellular adhesion molecule (ICAM)-1 and HLA-DR by infundibular keratinocytes, as determined by immunohistochemistry. Ten nanograms tumor necrosis factor-alpha per ml and 10 ng IL-6 per ml both caused expression of ICAM-1 alone. IL-1alpha had no effect on the expression of ICAM-1 or HLA-DR over 3 d, but addition of 1 ng IL-1alpha per ml over 7 d in culture resulted in hypercornification of the keratinocytes of the infundibulum, apparently brought about by early keratinocyte cornification. These data suggest that the isolated, maintained, infundibulum is a good model for studying the effects of inflammatory cytokines on the infundibulum, and that IL-1alpha acts on infundibular keratinocytes to promote cornification.
Cell Differentiation↗
The organ-maintained human sebaceous gland.
In the absence of epidermal growth factor (EGF) and phenol red in the maintenance medium, human sebaceous glands apparently retain in vivo rates of cell division and lipogenesis over 7 days and also retain in situ morphology. This is reversible on the re-addition of 10 ng/ml EGF and 10 mg/ml phenol red. The addition of 600 pM 17 beta-oestradiol results in a significant fall in the rate of lipogenesis over 7 days' maintenance, without affecting the rate of cell division. This effect is apparently due to abnormal differentiation of newly formed sebocytes. Neither 1 nM testosterone nor 1 nM dihydrotestosterone has any effect on rates of cell division or lipogenesis over 7 days. 1 microM 13-cis-retinoic acid causes a significant reduction in the rate of lipogenesis over 7 days.
Adult↗
Modelling the infundibulum in acne.
The human sebaceous-pilosebaceous infundibulum was isolated and maintained for 7 days. Infundibular viability was maintained over 7 days in this medium. The addition of 1 ng/ml interleukin 1 alpha (IL-1 alpha) caused hypercornification of the infundibulum similar to that seen in comedones which could be blocked by 1,000 ng/ml IL-1 receptor antagonist. However, in contrast to interferon gamma 1, IL-1 alpha had no effect on the expression of intercellular adhesion molecule or human leucocyte antigen type DR in infundibular keratinocytes. The addition of 5 ng/ml epidermal growth factor or 5 ng/ml transforming growth factor alpha to the medium caused a disorganization of the keratinocytes of the infundibulum. We are now, therefore, able to model histologically the major infundibular changes in acne. Furthermore, we suggest that IL-1 alpha causes the scaling seen in many inflammatory skin diseases.
Antigens, CD↗
Head movement in normal subjects during simulated brain imaging.
OBJECTIVE: Videotape images of 30 volunteers were used to classify and measure head movements that may occur during brain imaging. METHODS: A simple videotape setup was designed to record simultaneously the lateral and vertex views of the subject's head. Volunteer subjects were positioned for brain imaging and their heads were videotaped for 2 hr. Head movement was identified and measured. RESULTS: All subjects demonstrated angular movement within the transaxial plane (rotation of the head). There was angular movement in the sagittal plane and translation of the transaxial plane. There was no movement of the coronal plane, nor was there any translational movement of the sagittal plane. CONCLUSION: The most dominant head movement was rotation. The effects of other factors such as height, weight, age, smoking habits, and caffeine and alcohol intake could not be determined with this sample size.
Adolescent↗
Selective modification at the N-terminal region of human growth hormone that shows antagonistic activity.
A new analogue of recombinant human growth hormone (hGH), hGH des(1-6,14) was expressed in Escherichia coli, refolded and purified to homogeneity. The mutation decreased the hormone's ability to bind lactogenic and somatogenic receptors through its site 1, and almost completely abolished its ability to bind these receptors through site 2, as evidenced by both binding and gel-filtration experiments. More specifically, the binding to prolactin receptors (PRLRs) from various species or their soluble recombinant extracellular domains (ECDs) was decreased 1.5-4-fold, whereas the binding to hGH receptor (hGHR) was decreased 10-85-fold. These changes caused an almost total loss of hormone agonistic activity in several in vitro bioassays and subsequently, the hGH des(1-6,14) analogue acquired antagonistic properties. This antagonistic activity was dependent upon modification of site 1. In those cases in which the binding was reduced only slightly, e.g. binding to rabbit PRLRs, hGH des(1-6,14) acted as a strong antagonist, whereas in others in which the binding of site 1 was reduced to a higher degree, such as other PRLRs and, in particular, hGHR, the antagonistic activity was correspondingly weaker. Circular dichroism spectra of the analogue suggested that these changes do not result from a decrease in overall alpha-helix content, but rather from minor local structural modifications at the N-terminus.
Animals↗
The regulatory biology of the human pilosebaceous unit.
The last few years have witnessed an acceleration in our understanding of the regulation of the human pilosebaceous unit. Recombination and histochemical experiments are beginning to elucidate the role of homeotic genes, transcription factors, growth factors and adhesion molecules in pilosebaceous embryology. Histochemical studies, experiments in gene-modified animals, and in vitro studies on growing human hairs, have identified a number of growth factors that are central to normal hair growth. Thus epidermal growth factor and transforming growth factor-alpha appear to be involved in the triggering of both anagen and catagen. Insulin-like growth factor-I appears to sustain normal anagen growth, transforming growth factor-beta will inhibit anagen growth, while interleukin-1-alpha and tumour necrosis factor-alpha will induce matrix cell death. These complex growth factor effects are beginning to be moulded into an integrated model of pilosebaceous regulation. The role of steroid hormones in modulating these growth factor effects is also beginning to be understood.
Cytokines↗
Human pilosebaceous culture.
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Cell Culture Techniques↗
T cell receptor-independent apoptosis of thymocyte clones induced by a thymic epithelial cell line is mediated by steroids.
We have studied the mechanisms involved in TcR-independent apoptosis of radiation leukemia virus (RadLV)-transformed thymocyte clones induced by a thymic epithelial cell line (TEC). TEC induced apoptosis of an immature CD4+8+3+ (PD1.6) but not of a CD4-8-3- (B10) thymocyte clone. TEC-derived conditioned medium did not mimic the signal induced by TEC in PD1.6 cells. However, the TEC-resistant clone B10 apoptosed in response to TEC, provided that PD1.6 cells were also present in the culture. This effect on bystander cells suggests that a secreted factor was involved. The involvement of glucocorticoid hormones as potential mediators was addressed. PD1.6 cells apoptosed in response to dexamethasone or a cell-permeating analog of cAMP, while BIO cells were relatively resistant to dexamethasone. TcR cross-linking inhibited both TEC- and dexamethasone- but not cAMP-induced apoptosis. Aminoglutethimide and Ru38486 inhibited TEC-induced apoptosis of PD1.6 cells, whereas Ru28318 had a negligible effect. The results suggest that steroid hormones are involved in TcR-independent apoptosis of immature double-positive thymocyte clones induced by TEC.
Aminoglutethimide↗
Fluorescent taxoids.
BACKGROUND: Taxol is a natural product produced by the Pacific Yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. Taxol's biochemical mode of action has been well studied: it binds to microtubules, stabilizing them and preventing their depolymerization to tubulin subunits. At lower dosage levels, taxol also interferes with the normal dynamics of the tubulin-microtubule equilibrium. This biochemical effect causes taxol's ultimate physiological effect, cell cycle arrest; taxol is thought to block anaphase A of mitosis. Taxol also causes a number of intriguing secondary effects on interphase cells that are poorly understood. We believed that a bio-active fluorescent taxol derivative could be a useful tool in the study of these cellular mechanisms, especially in interphase cells. RESULTS: We have synthesized and characterized a series of stable, fluorescently labeled derivatives of taxol that bind to microtubules and have cytotoxicities similar to that of taxol. Fluorescence microscopy experiments in interphase human foreskin fibroblast (HFF) cells indicate that one of these, a sulforhodamine taxoid, is particularly well suited for optical microscopy. The use of this taxoid in HFF cells revealed a previously undetected localization of taxoids to the nucleolus during interphase. CONCLUSIONS: The production of a new fluorescent derivative of taxol provides a useful tool, enabling cellular biologists to study taxol's mechanism of action. It is hoped that this material will prove particularly useful for the study of taxol's effects upon interphase cells. Although in common usage for the last 20 years, Taxol is now a registered trademark of Bristol-Myers Squibb. The copyright of Bristol-Myers Squibb is recognized when Taxol or taxol is used in this article.
Antineoplastic Agents↗