20 research outputs found
Dupuytren’s Disease of the hand. The potential for reducing fibrosis using 5-Fluorouracil.
Get PDFDupuytren's disease is a progressive fibroproliferative disorder leading to reduced hand function. The main treatment is surgical correction but post-operative recurrence is high. Dupuytren's is characterised by palmar and digital nodules and cords with increased myofibroblast proliferation and excessive extracellular matrix production. Review of the literature establishes that transforming growth factor β-1 (TGFβ-1) has been shown to increase myofibroblast differentiation, fibroblast proliferation and extracellular matrix production acting via an autocrine loop. 5-fluorouracil (5-fu) has been reported to reduce fibroblast proliferation and differentiation in vitro and to reduce adhesion formation in a tendon injury animal model. The hypothesis tested in this project was that 5-fu would reduce the profibrotic characteristics of fibroblasts in culture. 5-fu could therefore reduce the postoperative recurrence rates in Dupuytren's disease. The investigation would require the establishment of the following cell cultures, tendon and Dupuytren's from nine and 12 subjects respectively. Total collagen synthesis was investigated by measuring the incorporated radioisotope, tritiated proline, in collagenase digestible samples. It was found that total collagen synthesis was specifically and selectively reduced by 5-fu compared with non-collagenous protein synthesis when fibroblasts were incubated with or without exogenous TGFβ-1. Gene expression for collagen types I and III was measured by RT-PCR. Basal collagen type III expression was found to be increased compared with collagen type I expression for both control and Dupuytren's fibroblasts. Basal collagen type III expression was increased for Dupuytren's compared with control fibroblasts. Pre-treatment with 5-fu did not induce a reduction in gene expression for collagen types I and III compared with vehicle control treated cells. TGFβ-1 secretion was assessed by a sandwich ELISA. TGFβ-1 secretion was found to be increased by fibroblasts from Dupuytren's compared with controls. Pre-treatment with 5-fu did not induce a reduction in TGFβ-1 secretion. Gene expression for collagen and TGFβ-1 was measured by reverse transcription-polymerase chain reaction. Basal TGFβ-1 gene expression was found to be increased in Dupuytren's fibroblasts compared with controls. A double blind prospective randomised clinical trial investigating the effect of 5-fu in reducing post-operative recurrence rates in Dupuytren's disease has been established by the author. Experience to date has shown that 5-fu has not caused a delay in wound healing. 5-fu treatment did not adversely affect the early (up to six months) surgical outcome when compared with control treated digits. The clinical picture regarding recurrence rates will become clearer with increased length of follow-up and number of patients. The transition has therefore been made from in vitro investigation to commencing a prospective randomised controlled clinical trial
‘Role and Ritual: Function and Performance in Domestic Spaces of Elite Eighteenth-Century English Houses, 1750-1800’
Get PDFThis thesis offers an, albeit necessary brief, historical analysis of the eighteenth-century incorporation of ritual practises and sociabilities enacted in a few elite interior environments of what I consider to be six of the most interesting English houses, either newly constructed or extended during the course of the eighteenth century. Two of which houses are now demolished in whole, as is the case with Bulstrode Park, situated in Gerrard’s Cross, Buckinghamshire, or part, as is the case with Norfolk House, located in St. James’s Square, central London.
It is useful to note that before the start of the research for this thesis began it was assumed on the part of the author that eighteenth-century domestic space were increasingly segmented for inflexible and separate activities. There follows a focused discussion of the varying types of display, ritual and sociable interaction made manifest in; the ground floor spaces of the Entrance Hall, Library, State Bedchamber and Etruscan Dressing Room at Osterley House and Great Hall and Long Gallery of Syon House; the Music and Ball Room of Norfolk House; and, finally, the first floor Dressing Rooms of Bulstrode Park, No. 23 Hill Street and Montagu House in Portman Square. Discussion has a concern to establish the ways in which such material display and sociabilities may have served their owners for a variety of ends. Such interior (and exterior) commissions of assimilated materiality and resulting sociabilities are found to serve their male householder, or as is discovered, female head of house, in a number of different, distinctive and often adaptable ways.
Analysis of the specific spatial environments in each elite household discussed reveals that different types of social rituals were often adopted depending upon the individual interests of a patron, their gender and nature of relationship to the head of household. Often divergent strands of cultural influence overlapping forms of ritual practise were incorporated in modernised, areas within a grand household, like that of Bulstrode Park’s Dressing Room, which could be tailored to a surprising number of functions and usages, according to the nature of the relationship with the householder. It also emerges, somewhat surprisingly, that strong and educated female patrons included in this thesis incorporated most successfully different cultural forms of practise and unusual methodologies of aesthetic display within the most private spatial areas in their residences. Again, illustrated most notably with the case of Bulstrode Park, that enabled these women to effectively, and creatively, portray a memorable image and identity individual to themselves
The Lady Markham Elegies
No full textThis project studies the contemporary manuscript transmission of three poems written on the 1609 death of Lady Bridget Markham. Lady Markham was the cousin of the influential courtier and patron Lucy, Countess of Bedford and her death prompted an outpouring of verses that were collected in manuscript verse miscellanies during the period. John Donne was in the process of establishing a patronage relationship with Lady Bedford at the time and wrote a respectful elegy on her cousin’s death. Francis Beaumont also wrote, for the same occasion, what has been called the most “repellent” work of the English Renaissance. That same year, Lady Bedford wrote an elegy on the death of another kinswoman, Cecilia Bulstrode, which several scribes redirected to Lady Markham. This project attends to the diverse ways contemporary verse collectors encountered, altered, and situated these poems, mediating the legacy of Markham’s death and Bedford’s patronage. The method for this project adapts elements of single-author critical editing to study the verses as a group. By organizing textual study around Lady Bedford and the death of Lady Markham, it reorients research away from the individual author towards the patron and her circle
Clostridium difficile colitis after aortic surgery
No full textObjective:To determine the incidence and outcome of Clostridium difficile colitis (CDC) following aortic surgery.Design:Retrospective clinical study, and case-note review.Patients:Of 180 patients undergoing aortic surgery for either aneurysmal or occlusive disease between 1 September 1994 and 31 August 1996 (24 months), 15 (8.4%) developed CDC. There were 12 male and three female patients of median age 65 (range 46–84).Results:Two patients died from multiple organ failure in association with CDC, one of whom underwent negative relaparotomy for suspected ischaemic bowel because the diagnosis of CDC had not been entertained. Previously identified risk factors for CDC comprised: age >65 (eight); renal impairment (four); chronic obstructive airways disease (seven); coexistent malignancy (three); admission from another hospital (four); H2 antagonist therapy (13); ITU (nine); and/or HDU care (14). Diarrhoea commenced a median of 9 (range 5–26) days, and CDC, was diagnosed a median of 14 (range 10–26) days after operation. All patients received intravenous Cefuroxime, originally prescribed as prophylaxis, for a median of 6 (range 3–16) days prior to onset of CDC. Two patients received 1 additional antibiotic; one received 2; two received 3; and one received 4 prior to onset of CDC.Conclusions:CDC is a common and potentially serious complication of vascular, and in particular, aortic surgery. Although such patients often possess several risk factors for CDC, colitis frequently follows prolonged ‘prophylactic’ cephalosporin administration, which should therefore be avoided
Repair of Ruptured Thoracoabdominal Aortic Aneurysm is Worthwhile in Selected Cases
No full textAbstractIntroduction:the risks and benefits of operating on patients with ruptured thoracoabdominal aortic aneurysm (TAAA) have not been defined. The aim of the present study is to report this unit's experience with operations performed for ruptured TAAA over a 10-year period.Methods:interrogation of a prospectively gathered computerised database.Patients:between 1 January 1983 and 30 June 1996, 188 consecutive patients with TAAA were operated on, of whom 23 (12%) were operated for rupture.Results:there were nine survivors (40%). Patients whose preoperative systolic blood pressure remained above 100 mmHg were significantly more likely to survive (4/8 vs. 13/15,p=0.03 by Fisher's exact test). Survival was also related to Crawford type: type I (two of three survived); II (none of six); III (two of six); and IV (five of eight). All non-type II, non-shocked patients survived operation. Survivors spent a median of 28 (range 10–66) postoperative days in hospital, of which a median of 6 (range 2–24) days were spent in the intensive care unit. Survivor morbidity comprised prolonged ventilation (>5 days) (n=3); tracheostomy (n=1); and temporary haemofiltration (n=2). No survivor developed paraplegia or required permanent dialysis.Conclusions:patients in shock with a Crawford type II aneurysm have such a poor prognosis that intervention has to be questioned except in the most favourable of circumstances. However, patients with types I, III and IV who are not shocked on presentation can be salvaged and, where possible, should be transferred to a unit where appropriate expertise and facilities are available
Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development
Get PDFCongenital melanocytic nevi (CMN) are pigmented birthmarks that affect up to 80% of the skin surface area. The increased frequency of CMN in families of severely affected individuals is suggestive of a predisposing germline genotype. We noted a high prevalence of red hair in affected families, and considered a role for MC1R in this condition. A cohort of 166 CMN subjects underwent pigmentary phenotyping, with MC1R genotyping in 113. Results were compared with a local control group of 60 unrelated children and with 300 UK children without CMN. CMN subjects had higher prevalences of red hair and a red-haired parent than local controls and had a higher rate of compound heterozygosity and homozygosity for MC1R variants. The presence of a V92M or R allele (D84E, R151C, R160W, D294H) was associated with increasing size of the CMN, implying a growth-promoting effect of these alleles. Unexpectedly, the V92M and R151C alleles were also strongly associated with birth weight in the CMN cohort, a finding confirmed in the control group. The effect of germline MC1R genotype on development and severity of CMN led us to investigate potential broader effects on growth, revealing a role for MC1R in normal fetal development.Journal of Investigative Dermatology advance online publication, 10 May 2012; doi:10.1038/jid.2012.95
A matter of identity - Phenotype and differentiation potential of human somatic stem cells
Get PDFHuman somatic stem cells with neural differentiation potential can be valuable for developing cell-based therapies, including treatment of birth-related defects, while avoiding issues associated with cell reprogramming. Precisely defining the "identity" and differentiation potential of somatic stem cells from different sources, has proven difficult, given differences in sets of specific markers, protocols used and lack of side-by-side characterization of these cells in different studies. Therefore, we set to compare expression of mesenchymal and neural markers in human umbilical cord-derived mesenchymal stem cells (UC-MSCs), pediatric adipose-derived stem cells (p-ADSCs) in parallel with human neural stem cells (NSCs). We show that UC-MSCs at a basal level express mesenchymal and so-called "neural" markers, similar to that we previously reported for the p-ADSCs. All somatic stem cell populations studied, independently from tissue and patient of origin, displayed a remarkably similar expression of surface markers, with the main difference being the restricted expression of CD133 and CD34 to NSCs. Expression of certain surface and neural markers was affected by the expansion medium used. As predicted, UC-MSCs and p-ADSCs demonstrated tri-mesenchymal lineage differentiation potential, though p-ADSCs display superior chondrogenic differentiation capability. UC-MSCs and p-ADSCs responded also to neurogenic induction by up-regulating neuronal markers, but crucially they appeared morphologically immature when compared with differentiated NSCs. This highlights the need for further investigation into the use of these cells for neural therapies. Crucially, this study demonstrates the lack of simple means to distinguish between different cell types and the effect of culture conditions on their phenotype, and indicates that a more extensive set of markers should be used for somatic stem cell characterization, especially when developing therapeutic approaches
