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Biomedical subjects

D Talbot

Publications and source records attributed to D Talbot.

At least 91 records · Page 5Linked to original sources
PubMed1999

Spatiotemporal expression pattern of keratins in skin of AP-2alpha-deficient mice.

Transcription factor AP-2alpha has been implicated as being a cell-type-specific regulator of gene expression during vertebrate embryogenesis based on its expression pattern in neural crest cells, ectoderm, and the nervous system in mouse and frog embryos. In mice, AP-2alpha is expressed in surface ectoderm beginning at the single cell layer state around E8.75. AP-2alpha-deficient mice, derived by targeted mutagenesis, display a severe ventral closure defect resulting in cranio-abdominoschisis and a hypoplasia of the cranial ganglia. This study analyzed the effect of a targeted disruption of the AP-2alpha gene on the architecture and the expression of intermediate filaments in skin. We analyzed skin samples from newborn mice and found no difference in either the morphology of the skin or the amount of intermediate filaments expressed. This suggests that despite the results from other analyses, loss of transcription factor AP-2alpha does not affect the expression of intermediate filaments in the skin of newborn animals. We found an altered spatial distribution of intermediate filament expression in the single layered cranial ectoderm during days 9-12 of gestation leading to an evenly distributed expression of keratin 5 and 15 in the mutants. Furthermore, the mutants lack a ring of ectodermal cells highly positive for keratin 15 in the area where lens induction occurs, indicating a defect in the inductive interactions underlying eye formation.

Animals↗
PubMed1998

A short DNA methyltransferase isoform restores methylation in vivo.

Two murine DNA methyltransferase isoforms (MTases) have been observed, a longer form in somatic and embryonic stem (ES) cells and a shorter form in oocytes and preimplantation embryos. While the longer MTase is associated with maintenance methyltransferase activity in replicating cells, little is known about the shorter form. We present genetic and biochemical evidence that both isoforms are expressed from the same Dnmt1 gene by using different translation initiation sites in exons 1 and 4. We further demonstrate that the shorter isoform can functionally rescue Dnmt1 null ES cells that have a hypomethylated genome. These rescued ES cells differentiate in vivo into a variety of cell types, unlike the Dnmt1 null ES cells that die upon induction of differentiation. These results show that the shorter isoform can substitute for the longer maintenance MTase in ES and differentiated cells. Our data further indicate that the shorter MTase isoform found in oocytes is fully functional in vivo and may play an active role in the regulation of DNA methylation and the establishment of imprinting patterns.

Amino Acid Sequence↗
PubMed1998

Post-regraft supra-hepatic caval obstruction in liver transplantation: a successful outcome with expandable stents. A case report.

Supra-hepatic inferior vena cava (IVC) obstruction is an unusual complication following an orthotopic liver transplantation (OLT) and is seen more often in hepatic regrafts. Dilatation of these stenotic lesions and the use of endovascular stents has been described in the past. Although the results of this technique are unquestionably superior to surgical correction, their use in the very early post-operative period is not without danger. Herein we describe a case where this modality was used successfully within 24 h of an OLT.

Dilatation↗
PubMed1998

Conversion of renal transplant recipients from cyclosporin to low-dose tacrolimus for refractory rejection.

Twenty-five patients with refractory rejection following renal transplantation were converted from cyclosporin to tacrolimus in an attempt to salvage the allografts. All patients had received two or three pulses of methylprednisolone, 6 had OKT3, 14 had antithymocyte globulin (ATG) and 2 had both OKT3 and ATG prior to conversion. The median time from transplantation to conversion to tacrolimus was 32 days (range 12-322). Patients underwent a simple switch from cyclosporin- to tacrolimusbased therapy with tacrolimus administered at a median dose of 0.15 mg/kg per day. Doses were adjusted according to clinical response and trough blood levels. Twenty-one of the 25 patients (84%) with refractory rejection showed evidence of reversal of rejection as indicated by a significant reduction in serum creatinine (Student's paired t-test, P < 0.05) following conversion to tacrolimus. None of these patients had further episodes of rejection. Three patients had ongoing rejection and returned to dialysis, and 1 patient showed deteriorating renal function associated with a cytomegalovirus infection. Of 18 patients currently on tacrolimus, 15 have improved renal function and 3 have shown no further deterioration. We conclude that low-dose tacrolimus appears to be effective in salvaging renal allografts with resistant rejection.

Adult↗
PubMed1998

Conversion of renal transplant recipients from cyclosporin (neoral) to tacrolimus (prograf) for haemolytic uraemic syndrome.

Five patients with cyclosporin-related haemolytic uraemic syndrome (HUS) following cadaveric renal transplantation were converted from cyclosporin- to tacrolimus-based immunosuppression. All patients had biochemical, haematological and biopsy evidence of HUS at the time of conversion. Four of the patients showed complete resolution of the syndrome within 1 week of conversion with normalisation of haemoglobin, platelets and lactate dehydrogenase levels. In the fifth patient renal function stabilised with slow resolution of the haematological and biochemical parameters. Four of the five patients are still taking tacrolimus, one having converted back to cyclosporin due to marked hair loss. We conclude that conversion to tacrolimus appears to be an effective treatment for cyclosporin-related HUS following renal transplantation.

Adult↗
PubMed1998

Long-term adult renal graft outcome after ureteric drainage into an augmented bladder or ileal conduit.

Patients with an augmented or diverted urinary system are considered higher risk recipients in view of increased technical problems and infective complications. We studied the long-term renal graft function and survival in patients with a pretransplant ileal conduit or ileal/caecocystoplasty. Between 1986 and 1997, 14 of 1253 (1.1%) renal transplant recipients had their transplant ureters anastomosed into an abnormal urinary tract. These consisted of ten ileal conduits and four ileal/caecocystoplasties. Median follow up was 42 months (range 1-156). All ten ileal conduits were discharged with a functioning graft. There was one graft loss chronic rejection and one cardiac death. The median creatinine level was 130 mmol/l and 50% have a urinary infection. All the patients with an ileal/caecocystoplasty were discharged with a functioning graft and these are still functioning; median creatinine of 132 mmol/l and 75% have a urinary infection. One- and 3-year graft survival was 93% and 86%. We conclude that the long-term outcome of renal transplantation in carefully assessed patients with an abnormal urinary tract is satisfactory despite a high incidence of urinary infection.

Adult↗
PubMed1998

Biliary reconstruction with or without an internal biliary stent in orthotopic liver transplantation: a prospective randomised trial.

Choledochocholedochostomy (CCD) with a 7 fr/8 fr Cotton Leung internal biliary stent removed at endoscopic retrograde cholangiography (ERC) 3 months following orthotopic liver transplantation (OLT) was the technique used on our unit for biliary reconstruction. From June 1995 to July 1996, we randomised 37 OLT patients with CCDs to receive either an internal stent (group I, nd = 18) or no stent (group II, n = 19). Patients in group I had an ERC at 3 months for stent removal whereas patients in group II had an ERC if indicated. The mean follow up was 19 (13-26) months. Biliary complications occurred in 9 out of 18 patients in group 1 compared to 1 out of 19 patients in group II (P = 0.007). In group I, ERC was required for complications in 8 patients and early surgery in 2, compared to 1 ERC for abnormal liver function tests in group II. Five of the early complications in group I were stent related. Late biliary stenosis occurred in 1 patient at 9 months. There was one stent-related death. The use of stents contributes to biliary complications and CCD without stenting is safe after OLT.

Adolescent↗
PubMed1998

Differential effects of cyclosporin A and tacrolimus on the production of TGF-beta: implications for the development of obliterative bronchiolitis after lung transplantation.

The development of obliterative bronchiolitis is a common cause for failure of lung allografts. Fibrinogenesis can occur for a number of different reasons but some groups have suggested that cyclosporin A (CsA) and tacrolimus (FK506) have different effects on the cytokines which induce fibrinogenesis. We investigated the effect of tacrolimus and CsA in tissue culture and found that there was indeed a negative effect on human lung small airway epithelial cell proliferation by recombinant transforming growth factor-beta (TGF-beta), which was reversed by anti-TGF-beta. The same effect was seen with CsA at immunosuppressive concentrations, which was also reversed by anti-TGF-beta, whereas no such inhibition was seen with tacrolimus at immunosuppressive doses unless high concentrations were used. Free TGF-beta was confirmed as being elevated in the supernatant of cell culture wells with standard dose CsA as opposed to low dose CsA or tacrolimus using an ELISA assay.

Bronchiolitis Obliterans↗
PubMed1998

Comparison of the efficacy of University of Wisconsin solution and Newcastle organ perfusion fluid in the preservation of livers for transplantation.

University of Wisconsin solution (UW) is now used widely for the preservation of livers for transplantation. However, the use of commercial solutions has added considerably to the cost. We were able to produce a local version of organ perfusion fluid (NOPF) incorporating all the constituents of UW except for the hydroxyethyl starch and adenosine. We compared graft outcome using NOPF with imported grafts perfused with commercial UW solution. The two recipient groups (15 patients each) were similar with respect to age and sex distribution, urgency of transplantation, regraft status and patient and graft survival. Postoperative duration of ventilation, dialysis requirements, peak bilirubin, peak ALT and lowest unsupported prothrombin time were also similar in both groups. In conclusion, local perfusion fluids based on UW can be produced without detriment to graft outcome with considerable financial savings. At our institution, this represents a reduction of 33% in the cost of perfusion fluids.

Adenosine↗
PubMed1998

Beta-chemokine expression and distribution in paraffin-embedded transplant renal biopsy sections: analysis by scanning laser confocal microscopy.

Previous immunohistochemical and in situ hybridisation studies have shown that, in tubulitis associated with acute cellular rejection of human renal allografts, intratubular T cells proliferate and are fully activated in situ. In the immunohistochemical study reported here we have attempted to establish some understanding of the involvement of the beta-chemokines RANTES, MCP-1, MIP-1alpha and MIP-1beta in recruiting T cells to the intratubular site. Paraffin-embedded routine biopsy sections were treated for conventional indirect immunofluorescence to detect the selected chemokines. Scanning laser confocal microscopy was used to provide a measure of fluorescence intensity resulting from binding of FITC-labelled secondary antibody. Cells expressing chemokines could be identified and, within the limits of the staining method, it was possible to obtain a semi-quantitative assessment of individual chemokine activity at different points in biopsy sections by constructing a profile of fluorescence intensity. High concentrations of chemokines (especially RANTES, MIP-1beta and/or MIP-1alpha) were localised to the basolateral surface of tubular epithelial cells (TEC). MCP-1 was also consistently present but at a lower level than RANTES except in one case identified as BANFF category 3. There was diffuse distribution of chemokines in the interstitial matrix and low intensity fluorescence outlined some endothelial cells of peritubular venules and interstitial fibroblast-like cells. Our results suggest a mechanism for specific chemotactic recruitment of inflammatory cells by TEC-produced chemokines.

Biopsy↗
PubMed1998

Early risk factors in pediatric renal transplantation at a single center.

BACKGROUND/PURPOSE: Renal transplantation is the preferred treatment for renal failure in childhood, but the incidence of graft failure is generally higher than that in adult recipients. A single center was studied to determine if there were any correctable factors that could contribute to graft failure. METHODS: Recipient, donor, and perioperative factors were analyzed using standard statistical tests in 59 pediatric renal transplants performed between 1992 and 1995 using standard cyclosporin-based immunosuppression. RESULTS: Three factors were found to be significantly different between those recipients with good graft function and those who either died or were returned to dialysis. Any history of donor hypotension was a detrimental factor (P < .05, chi(2) test). In addition, those with failed grafts were more likely to have received their grafts from younger donors (P = .025, Mann Whitney U test). A third risk factor was a low postoperative central venous pressure in those whose graft ultimately failed (P = .0012, Mann Whitney U test). CONCLUSIONS: With a pediatric recipient who is stable and has a low priority for a renal graft, small donors, particularly those who have experienced hypotension, should be considered not suitable for transplantation. The chances of a successful graft can be improved by good communication between surgeon, pediatrician, and anesthetist. The importance of maintaining a positive central venous pressure is emphasised.

Age Factors↗
PubMed1998

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer.

PURPOSE: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 micrograms/ml for five days (5d) or 1 microgram/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. PATIENTS AND METHODS: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. RESULTS: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%-42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 10(9)/1 after 5d and 5.0 x 10(9)/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. CONCLUSIONS: Although the number of patients entered into this trial was small, the low activity seen at 1 microgram/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration-controlled studies with prolonged EP infusions are required.

Adult↗
PubMed1997

Baculovirus-mediated expression and characterization of the full-length murine DNA methyltransferase.

The original cDNA sequence reported for the murine DNA methyltransferase (MTase) was not full length. Recently, additional cDNA sequences have been reported that lie upstream of the original and contain an extended open reading frame with three additional ATGs in frame with the coding region [Tucker et al . (1996) Proc. Natl. Acad. Sci. USA , 93, 12920-12925; Yoder et al . (1996) J. Biol. Chem . 271, 31092-31097]. Genomic DNA upstream of this ATG contains two more ATGs in frame and no obvious splice site. We have constructed, and expressed in baculovirus, MTase clones that begin at each of these four ATGs and examined their properties. Constructs beginning with any of the first three ATGs as their initiator methionines give a predominant DNA MTase band of approximately 185 kDa on SDS-PAGE corresponding to translational initiation at the third ATG. The fourth ATG construct gives a much smaller protein band of 173 kDa. The 185 kDa protein was purified by HPLC, characterized by mass spectrometry and has a measured molecular mass of 184 +/- 0.5 kDa. All of these MTases were functional in vitro and steady state kinetic analysis showed that the recombinant proteins exhibit similar kinetic properties irrespective of their length. The homogeneous recombinant enzyme from the fourth ATG construct shows a 2.5-fold preference for a hemi-methylated DNA substrate as compared to an unmethylated substrate, whereas the 185 kDa protein is equally active on both substrates. The kinetic properties of the recombinant enzyme are similar to those reported for the native MTase derived from murine erythroleukemia cells. The new clones are capable of yielding large quantities of intact MTases for further structural and functional studies.

Amino Acid Sequence↗
PubMed1997

Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group.

BACKGROUND: To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection. METHODS: A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids. RESULTS: At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment. CONCLUSIONS: The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.

Adolescent↗