Biomedical subjects

S M Richards

Publications and source records attributed to S M Richards.

At least 55 records · Page 3Linked to original sources

PubMed1998

Prolactin is an antagonist of TGF-beta activity and promotes proliferation of murine B cell hybridomas.

Prolactin (PRL) is an immunomodulator that has been demonstrated to enhance immune responses both in vitro and in vivo. Prolactin enhances the proliferative response of lymphoid cells to both nonspecific mitogens and specific antigens and increases their production of IL-2 and interferon-gamma. Studies were performed to examine whether recombinant human prolactin (r-hPRL) also acts as a growth factor for B cell hybridomas. Prolactin was able to stimulate proliferation of murine B cell hybridomas in a dose-dependent manner and enhanced their proliferation in response to IL-4, IL-5, and IL-6. This increase in proliferation resulted in an overall increase in antibody production. Studies were also undertaken to examine the effect of PRL with transforming growth factor beta (TGF-beta), an immunosuppressive cytokine. Hybridoma cell lines incubated with TGF-beta demonstrated a dose-dependent decrease in proliferation. Variability in the degree of inhibition was observed among the various hybridomas in their responsiveness to TGF-beta. The addition of r-hPRL to the cultures reversed the antiproliferative effects of TGF-beta. The mechanism by which PRL can overcome the anti-proliferative effect of TGF-beta is under investigation. These findings provide an additional rationale for using r-hPRL clinically in immunosuppressed patients in certain disease settings such as AIDS and cancer, where overexpression of TGF-beta has been implicated in disease development and progression.

Adjuvants, Immunologic↗

PubMed1998

Continuous perfusion improves preservation of donor rat hearts: importance of the implantation phase.

BACKGROUND: Continuous hypothermic perfusion of donor hearts may provide extra protection for long ischemic times and suboptimal donors. The aim of three separate studies was to assess the effect of continuous hypothermic perfusion during simulated donor heart storage and implantation. METHODS: In study 1 twelve isolated rat hearts underwent 10 minutes of normothermic ischemia to simulate the effect of brain death on the heart and 5 hours of cardioplegic arrest, using University of Wisconsin solution. Six hearts were statically stored in University of Wisconsin solution at 2 degrees C, and six were perfused with University of Wisconsin solution. To assess the effect of simulated implantation, in study 2 an additional 12 hearts were statically stored for 5.5 hours in University of Wisconsin solution, six of which were rewarmed to a mean of 16 degrees C over the last 30 minutes of arrest. To assess the effect of simulated perfusion, in study 3 during implantation 12 hearts were rewarmed to a mean of 16 degrees C over the last 30 minutes of arrest, during which time six were perfused with 2 degrees C solution. RESULTS: Hearts perfused during storage demonstrated greater recovery of prearrest power, 85.8% +/- 1.8%, than hearts preserved by static storage, 72.7% +/- 3.0% (p < 0.01). The simulated warm implantation period reduced recovery of power from 68.3% +/- 5.1% to 40.2% +/- 2.0% (p < 0.001). Perfusion during warm implantation improved recovery to 61.8% +/- 3.9% (p < 0.01). In all experiments improved function was accompanied by improved metabolic energy status. CONCLUSIONS: During the implantation period of heart transplantation the donor heart sustains injury that could amount to 50% of total ischemic injury. Continuous perfusion during the cold storage phase and during simulated implantation improves recovery of the donor heart.

Adenine Nucleotides↗

PubMed1998

Aspartate improves recovery of the recently infarcted rat heart after cardioplegic arrest.

BACKGROUND: We have previously shown that aspartate improves the tolerance of normal hearts to cardioplegia. The aim of this study was to investigate whether aspartate is also beneficial in the recently infarcted heart. METHODS: Myocardial infarction was produced in rats by left coronary artery ligation. Twenty hours later their hearts were perfused on an isolated working rat heart apparatus and underwent cardioplegic arrest for 30 min at 37 degrees C with or without 20 mM aspartate in the cardioplegic solution (n = 11 per group). Functional recovery and myocardial high energy phosphate levels were measured at the end of arrest and after 30 min of reperfusion. RESULTS: There was no difference in pre-arrest pump function between the untreated and aspartate-treated groups. However, after reperfusion the aspartate group generated more power (3.4 +/- 0.2 mJ/s per g) than the untreated group (2.5 +/- 0.3 mJ/s per g; P < 0.05) such that the percentage recovery of pre-arrest power in the aspartate group (67.7 +/- 3.5%) was greater than in the untreated group (53.6 +/- 4.9%; P < 0.05). The aspartate group also showed increases in aortic flow and myocardial oxygen consumption compared to the untreated group (P < 0.05). There were no between-group differences in high energy phosphate levels at the end of arrest or after reperfusion. CONCLUSION: Aspartate improves functional recovery of the recently infarcted heart during cardioplegic arrest, and therefore has potential as a useful adjunct to myocardial protection in patients with recent myocardial infarction undergoing cardiac surgery.

Animals↗

PubMed1998

Mechanism of cardioprotective effect of orotic acid.

The pyrimidine base, orotic acid (OA), markedly improves the function of recently infarcted hearts subjected to global ischemia. The mechanism of cardiac action of OA is unclear, but it has been proposed that OA acts by correcting a relative deficiency of nucleotide precursors required for RNA synthesis in the stressed myocardium or by improving myocardial energy supply. The aim of this study was to investigate the mechanism of action of OA by (1) determining whether a high dose of OA can raise the concentration of pyrimidine metabolites in plasma, liver, and heart; (2) examining the effects of OA on adenine nucleotide (AN) concentrations in normal and infarcted hearts, before and after global ischemia; and (3) determining the effect of uridine, an important metabolite of OA, on myocardial energy metabolism. Three studies were performed: (1) The time course of changes in tissue and plasma concentrations of pyrimidine compounds was examined in unoperated rats after the administration of 100 mg/kg OA. (2) Rats were given OA (30 mg/kg/d) for 2 days after experimental infarction, and tissue and plasma pyrimidine concentrations were examined; the hearts were removed for perfusion in the isolated working rat heart model (37 degrees C), subjected to 30 minutes of global ischemia, and recovery of function was assessed. AN content was assessed in the noninfarcted myocardium before and after ischemia. Isolated hearts were subjected to 30 minutes of hypoxic perfusion and the effect of adding 17 microM uridine to the perfusate was examined. Study 1 showed that OA administration produced an increase in hepatic uridine and cytidine, followed by increased plasma uridine and cytidine (cytidine, +55%, P < 0.001; uridine, +124%, P = 0.011). Myocardial uracil nucleotides increased temporarily after 4 hours (+21%, P < 0.01). In infarcted hearts after 2 days of OA administration, there were no significant changes in myocardial uracil or cytosine nucleotides or total RNA. Infarction significantly reduced functional recovery after global ischemia (sham = 62%; infarct = 26% of preischemic level; P < 0.05). OA improved the recovery of preischemic function by 133% (P < 0.05) in infarcted, but not sham-operated, hearts. Preischemic ATP and total adenine nucleotides (TAN) were decreased in the surviving myocardium of infarcted hearts (ATP reduced from 21.7 +/- 0.8 to 14.7 +/- 0.7 mumol/g dry wt, P < 0.001; TAN decreased from 30.3 +/- 0.8 to 22.4 +/- 1.1 mumol/g dry wt, P < 0.001). OA treatment prevented these reductions. Study 3 showed that uridine improved myocardial ATP and TAN levels, and decreased purine loss in hypoxic hearts. The increased AN levels were accompanied by evidence of enhancement of anerobic glycolysis. We conclude: (1) That OA acts on the heart via the liver by increasing the availability of plasma uridine and cytidine. (2) Uridine is capable of increasing myocardial ATP production by stimulating anerobic glycolysis. (3) OA treatment improves tolerance to global ischemia in infarcted but not normal hearts by preventing depletion of AN in the surviving myocardium.

Adenine Nucleotides↗

PubMed1998

The impact of age on outcome in lymphoblastic leukaemia; MRC UKALL X and XA compared: a report from the MRC Paediatric and Adult Working Parties.

The purpose of the study was to examine the influence of age on outcome in a large cohort of children and adults with lymphoblastic leukaemia who were treated on two similar trials. Factors influencing outcome were examined in 2204 patients aged over 1 year treated between 1985 and 1992 on the parallel Medical Research Council Trials UKALL X and XA, for children and adults, respectively. There was a progressive worsening in survival with increasing age from 85% (95% CI 83-87) at 5 years for children aged 1-9 to 24% (CI 17-31) for patients over 40. Induction failures, deaths in remission and bone marrow relapses increased significantly with age. Analysis of clinical and biological features showed dominance of early B-ALL in childhood and increasing incidence of the Ph' chromosome with age. Over 80% of eligible children, but a much lower proportion of adults especially those over 40, was entered. Compliance was stricter in the paediatric trial but most deviations in adults involved giving more treatment. Analysis of results in a proportional hazards model confirmed the overwhelming independent influence of age; with all other factors equal a 10 year old had half the risk of treatment failure of a 20 year old and a 44 year old double the risk. Selective entry to therapeutic trials and increased treatment-related toxicity are features of adult ALL but age itself remains a dominant prognostic factor. While improved supportive care and refinements of conventional therapy may have some effect on prognosis, new understandings and treatment approaches to adult ALL are needed.

Adolescent↗

PubMed1998

Analysis of the immunophenotype of children treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia Trial XI (MRC UKALLXI). Medical Research Council Childhood Leukaemia Working Party.

Despite many years of meticulous immunophenotyping of childhood acute lymphoblastic leukaemia (ALL) cases the prognostic significance of some subtypes remains unclear. The Medical Research Council UKALLXI trial (1990-1996) in which uniform treatment has been given to 2090 children with ALL below the age of 18 years and above the age of 1 year, has afforded the opportunity to review these issues. Children with ALL of mature B cell type were not entered into this trial. Immunophenotype analysis was performed in each individual trial centre, but results were centrally reviewed in all cases, and were both available and considered adequate in 1934 (93%) of the first 2090 patients entered. The main diagnostic categories were early pre-B or null reported in 60 cases (3.1%), common ALL in 1242 (64.2%), pre-B in 252 (13.0%), 'common' or pre-B in 172 (8.9%) and T cell in 207 (10.7%) cases. Children with T cell disease were significantly more likely to be over the age of 10 years, with central nervous system disease at diagnosis and to be CD34 negative. They also had a higher incidence of high white cell count and were more likely to be of the French-American-British (FAB) L2 morphological subtype. Patients with 'null' cell disease tended to be less than 2 years or greater than 10 years of age, and CD13 and CD33 positive. CD10 was associated with lower white cell count (WBC) at diagnosis, younger age and FAB L1 morphological subtype. The presence of cytoplasmic immunoglobulin in pre-B cells was not associated with any specific clinical or laboratory features. CD34 positivity was less common in T cell patients and was associated with low WBC. Disease-free survival (DFS) and 95% confidence intervals (CI) at 5 years from diagnosis was 52% (95% CI: 44-59%) for T cell disease, 58% (95% CI: 43-73%) for early pre-B (or null cell) disease and 65% (95% CI: 62-68%) for common or pre-B disease; there being no significant difference between common and pre-B disease with regard to disease outcome. Patients with T cell disease had a worse prognosis than any other immunophenotype group (P < 0.00005). However this worse outcome was no longer significant after allowing for the other principal prognostic factors of age, gender and white cell count at diagnosis except for the very small number with WBC <20 x 10(9)/l and T cell disease. Those with CD10-positive leukaemia did better than those who were CD10 negative (P < 0.00005), with DFS at 5 years 64% (95% CI: 62-67%) for positive vs 56% (95% CI: 49-62%) for CD10 negative. CD10 positivity did not have independent significance when white count, gender and age were taken into account. CD13, CD33, and cytoplasmic mu positivity carried no prognostic significance.

Adolescent↗

PubMed1998

Nitric oxide inhibits rhinovirus-induced cytokine production and viral replication in a human respiratory epithelial cell line.

To better understand the early biochemical events that occur in human rhinovirus (HRV) infections, we examined the kinetics and mechanisms of interleukin-8 (IL-8) and IL-6 production from infected epithelial cells. Several HRV strains caused IL-8 and IL-6 production, but HRV-16 induced maximal IL-8 and IL-6 mRNA expression and protein production more rapidly than did HRV-14, despite similar rates of replication of the two viral strains. Viral induction of cytokine mRNA does not require new protein synthesis, since it was unaffected by cycloheximide treatment. The potent glucocorticoid budesonide did not affect viral replication or cytokine mRNA induction but modestly inhibited cytokine protein production. Interestingly, the nitric oxide donor 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (NONOate) inhibited both rhinovirus replication and cytokine production in a dose-dependent fashion without reducing levels of cytokine mRNA. The NONOate effects were due to release of nitric oxide, because NONOate that had been depleted of its nitric oxide content had no effect. Thus, nitric oxide may play an important anti-inflammatory and antiviral role in colds and nitric oxide donors may represent a novel therapeutic approach.

Cell Line↗

PubMed1997

Cardioprotection by orotic acid: metabolism and mechanism of action.

The pyrimidine base, orotic acid (OA), improves the function of recently infarcted hearts subjected to global ischemia but its mechanism of action is unclear. Our aims were to examine (i) in normal rats, the effect of OA on pyrimidine levels in plasma, liver and heart; (ii) in rats with normal or infarcted hearts, the effect of OA on adenine nucleotide metabolism and mechanical function, before and after global ischemia. To investigate the metabolism of OA, normal rats received 100 mg/kg OA, and changes in plasma and tissue concentrations of pyrimidines were examined. The effects of OA were also studied in rats receiving OA for 2 days after coronary ligation or sham operations, and plasma and tissue pyrimidine concentrations examined. Their hearts were isolated and perfused, then subjected to 30 min of global ischemia. Mechanical function and adenine nucleotide content were assessed pre- and post-ischemia. In normal, unoperated rats, administration of 100 mg/kg OA significantly increased hepatic uracil and cytosine nucleotide concentrations, then increased plasma uridine (+124%) and cytidine (+55%), and transiently increased myocardial uracil nucleotides (+21%). Infarction significantly reduced recovery of cardiac work after global ischemia (sham=62%; infarct=26%; P<0.05), and OA treatment in infarcted hearts increased post-ischemic work by 192% (P<0.05), but not in shams. Pre-ischemic ATP was reduced in the surviving myocardium of infarcted hearts from 21.7+/-0.8 to 14.7+/-0. 7 micromol/g dry weight (P<0.001) and total adenine nucleotides (TAN) from 30.3+/-0.8 to 22.4+/-1.1 micromol/g dry weight (P<0.001). OA treatment prevented these reductions in infarcted hearts (ATP 20. 7+/-0.5; TAN, 29.1+/-0.6 micromol/g dry weight). We conclude that OA protects the infarcted heart against global ischemia by enhancing hepatic release of pyrimidine nucleosides into the plasma, which then prevent depletion of adenine nucleotides in the surviving myocardium.

Adenine Nucleotides↗

PubMed1997

Interferon-alpha: results from randomized trials.

Interferon alpha is effective in the treatment of chronic myeloid leukaemia in terms of disease control. However, it is an expensive treatment compared with conventional chemotherapy and is not without side-effects. Examination of all the available randomized evidence demonstrates an absolute improvement in survival at 5 years of 15% +/- 6% compared with conventional chemotherapy. There is no clear evidence that this benefit is different in any particular subgroup of patients. The size of benefit conferred by continuing interferon alpha in patients who show no cytogenetic response, the best dose to use, and whether it should be given in combination with chemotherapy all remain uncertain at present.

Adolescent↗

PubMed1997

Clearance of marrow infiltration after 1 week of therapy for childhood lymphoblastic leukaemia: clinical importance and the effect of daunorubicin. The Medical Research Council's Working Party on Childhood Leukaemia.

At the commencement of UKALL XI, a national MRC trial for childhood lymphoblastic leukaemia (ALL), the therapy included a bolus of daunorubicin (DR) on the first 2 d of the protocol. This component of treatment was subsequently withdrawn because of concern about long-term cardiotoxicity. All children both before and after this change of policy had their marrow status at the end of the first week assessed by central review as part of the trial to examine the clinical importance of the rate of disease clearance. This also afforded an opportunity to observe the effect of DR on gross residual disease at an early stage of therapy. 1419 children were studied: 342 received DR ('recipients'), 1077 did not. 44% of the recipients completely cleared their marrow of blast cells after 8 d compared with 13% of the non-recipients (chi2 = 158.2, P < 0.0001). The difference in the proportion with massive residual disease (>80% blasts) was less impressive but there was still a difference in favour of DR recipients (DR 9%, no DR 15%; chi2 = 7.7, P = 0.006). The rate of disease clearance correlated with disease-free survival for both recipients and non-recipients, but there was no significant difference in outcome when comparing the two groups with each other, either in terms of disease-free or relapse-free survival. DR accelerated the rate of blast cell disappearance from the marrow but the difference this made to disease free survival is small or non-existent. It appears to be the relative speed of response to a given therapeutic regimen that is prognostically important rather than the absolute rate of response when comparing one treatment with another.

Antibiotics, Antineoplastic↗

PubMed1997

Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia.

The relationship between the prescribed dose of drugs during continuing (maintenance) therapy, the degree of marrow suppression caused, and subsequent event-free survival was examined in a cohort of 740 children with lymphoblastic leukaemia treated on MRC UKALL X. Girls, younger children, and patients who had received intensification treatment, were prescribed lower doses of mercaptopurine, became neutropenic more readily, and had more interruptions of treatment. Children who had one or more episodes of neutropenia with a count of <0.5 x 10(9)/l had a better prognosis than those who never became neutropenic. We conclude that early intensification treatment influences the probability of neutropenia during continuing treatment and that patients exhibiting myelosuppression during this phase of treatment have a better chance of prolonged remission.

Adolescent↗

PubMed1997

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia.

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically-defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event-free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph-positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event-free survival of 87.5% at 5 years. A number of other non-random abnormalities were identified with no clear prognostic significance. We conclude that identification of certain genetic changes remains important in the management of acute lymphoblastic leukaemia, although whether molecular diagnosis of clinically relevant abnormalities can now supplant cytogenetics in the clinical trials context remains to be determined.

Child↗

PubMed1997

Intensification of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA. Medical Research Council Working Party on Leukaemia in Adults.

The MRC UKALL XA trial for patients aged 15 years and over with acute lymphoblastic leukaemia was designed to evaluate short blocks of intensive 'AML-style' treatment. Between 1985 and 1992, 618 eligible patients were entered into the trial. 450 patients were randomized to receive early intensification at 5 weeks, late intensification at 20 weeks, both, or neither. Unlike the concurrent children's trial, UKALL X, which was of similar design, UKALL XA does not demonstrate a clear benefit for intensification, although there was a significant reduction in the relapse risk due to the early block. The estimated increase in disease-free survival at 5 years was 2% with 95% confidence interval from 1% reduction to 5% increase. There may be a real difference between the effect of these treatments in adults and in children, but this result may be somewhat weakened by poorer compliance, with a greater proportion of adults not receiving the treatment arm to which they were randomized.

Adolescent↗

PubMed1996

Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis.

Cystic fibrosis (CF) is a common autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator gene. Recombinant adenoviruses have shown promise as vectors for transfer of CF transmembrane conductance regulator cDNA to airway epithelia and correction of the Cl- transport defect. However, because adenovirus-mediated gene transfer is transient, use of adenovirus as a vector for treatment of CF would require repeated administration. Therefore, we evaluated repeat administration of an adenovirus vector to the nasal epithelium of patients with CF with five escalating doses of up to 10(10) infectious units. There were no detectable adverse affects. All subjects were initially seropositive but developed additional humoral immune responses. The vector partially corrected the defect in airway epithelial Cl- transport in some subjects, although there was variability between subjects and there was less correction with subsequent administration, perhaps because the immune response limited gene transfer. Future work must focus on vectors with increased efficiency and with the ability to evade host defenses.

Adenoviridae↗

PubMed1996

Comparison of UW solution and St. Thomas' solution in the rat: importance of potassium concentration.

BACKGROUND: University of Wisconsin solution (UW) is in limited clinical use for heart transplantation, but there are doubts about its efficacy and concerns about the effect of its high K+ concentration on endothelium. St. Thomas' solution with or without aspartate is widely used and is of proven efficacy. METHODS: Using a modified (starch-free) variant of UW (MUW) we studied: (1) recovery of function with UW compared with aspartate-containing St. Thomas' solution; (2) effect of elevation of K+ in St. Thomas' solution to the level in UW; and (3) effect of reduction of K+ in UW and addition of Ca2+ or aspartate. Isolated rat hearts underwent 7 hours of arrest at 1 degrees C using MUW with or without 20 mmol/L aspartate or using aspartate-containing St. Thomas' solution. RESULTS: Functional recovery with MUW (51.8% +/- 2.5%) was superior to that with aspartate-containing St. Thomas' solution (37.1% +/- 4.3%; p < 0.01). Addition of aspartate to MUW had no effect. During 6 hours of arrest, lowering the K+ in MUW from 125 mmol/L to 20 mmol/L reduced functional recovery from 59.9% +/- 4.2% to 42.3% +/- 4.3% (p < 0.01). The addition of 1 mmol/L Ca2+ had no effect. Elevation of K+ in St. Thomas' solution produced more rapid arrest but no improvement in recovery. CONCLUSIONS: The protective effect of starch-free UW is greater (+13%) than that of aspartate-enriched St. Thomas' solution. Reduction of K+ in UW to lessen possible deleterious effects would decrease its protective effect by about 30% to a level comparable with that of St. Thomas' solution.

Animals↗

PubMed1996

Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X.

The benefits of achieving a long term event free survival of 60-70% by using increasingly intense treatment regimens must be weighed against the increased risk of treatment toxicity. From 1985 to 1990, 1612 children with childhood acute lymphoblastic leukaemia (ALL) in the UK were treated on MRC UKALL X with intensive induction therapy, central nervous system directed therapy (cranial irradiation and intrathecal methotrexate), and continuing treatment for two years. There was a randomisation to receive blocks of additional intensification treatment at five weeks, 20 weeks, not at all, or both. The five year disease free survival was 71% for children randomised to two blocks of intensification, a 14% improvement on children randomised to no intensification treatment. Treatment related mortality in this national multicentre study has been analysed for induction and first remission (including those after intensification treatment). There were 38 induction deaths, 2.3% and 53 deaths in first remission, 3.3% (including those from a second malignancy). Thirty one (84%) of the induction deaths followed an infection: bacterial in 22 and fungal in nine. Thirty seven infective remission deaths occurred: bacterial in 11, viral in 16, fungal in seven, and three caused by Pneumocystis carinii pneumonia. Ten of these deaths followed a block of intensification treatment. The majority of noninfective remission deaths followed the development of a second tumour. Risk analysis for an induction death showed girls and children with Down's syndrome to be at greater risk. For deaths in first remission analysis showed an increased risk for bone marrow transplant (BMT) patients and children with Down's syndrome. There was no effect of age and leucocyte count for either group. Most significantly when BMT patients were excluded from the analysis, intensification treatment did not increase the risk of remission death.

Adolescent↗

PubMed1996

Progress with interferon in CML--results of the MRC UK CML III study.

527 patients with CML were entered into the multicentre randomised MRC CML III study comparing IFN-alpha n1 to standard chemotherapy, either busulphan or hydroxyurea. Haematologic response to IFN as assessed by the level of control of the WCC predicted cytogenetic response to IFN. Cytogenetic response (< 80% Ph + ve) was seen in 22% of all patients randomised, 11% showing major or complete responses. Major cytogenetic response rate was 18% in Sokal low risk patients, 15% in intermediate risk patients but only 4% in high risk patients. Mantel Byar analyses allowing for time to response showed a survival advantage for cytogenetic responders compared to non-responders. In addition, cytogenetic non-responders to IFN did significantly better than chemotherapy-treated patients. Median survival for all patients was 61 months in the IFN treated groups and 41 months in the no-IFN group. For Ph + ve patients only, the median survival was 63 months compared to 43 months. Sub-group analysis comparing busulphan or hydroxyurea treatment in the IFN and no-IFN treatment arms showed a significant advantage for IFN-compared to busulphan, but no significant difference between IFN and hydroxyurea treated patients, although there was a trend favouring IFN. A proposed overview of all randomised trials comparing IFN to hydroxyurea should, by virture of larger numbers, enable a more accurate assessment of the probable benefit of IFN compared to hydroxyurea therapy.

Adult↗

PubMed1995

Improved preservation of saphenous vein grafts by the use of glyceryl trinitrate-verapamil solution during harvesting.

BACKGROUND: High-pressure distension during harvesting damages the saphenous vein (SV) and may contribute to subsequent coronary artery bypass graft (CABG) occlusion. Application of vasodilator agents to the SV during harvesting may reduce the need for high-pressure distension and improve graft quality. We tested the effects of a vasodilator solution containing glyceryl trinitrate and verapamil (GV) or the conventional agent papaverine (Pap) on the pressure necessary to overcome SV spasm and on the structure and biochemistry of the SV graft. METHODS AND RESULTS: Thirty-six patients undergoing CABG were randomly allocated to receive an application of either topical and intraluminal GV solution, topical Pap, or topical and intraluminal Ringer's solution (untreated) to the SV during harvesting. The peak and mean pressures required to distend the vein were recorded. Samples of SV were taken for microscopy and biochemical analysis just before we performed the anastomosis. The percentage of endothelial coverage was calculated by area measurements of stained en face preparations of the vein intima. The results for peak pressures (mmHg) were: untreated, 479.2 +/- 27.5; Pap, 384.8 +/- 29.0; and GV, 309.5 +/- 28.3 (P < .001, GV plus Pap versus untreated); and the results for mean pressures (mm Hg) were untreated, 136.2 +/- 9.6; Pap, 102.2 +/- 10.8; and GV, 98.0 +/- 8.3 (P < .01, GV plus Pap versus untreated). The results for endothelial cover (%) were: untreated, 43.7 +/- 7.0; Pap, 44.1 +/- 9.2; and GV, 68.7 +/- 7.0 (P < .05, GV versus Pap); and the results for ATP (nmol/g wet wt) were: untreated, 67.3 +/- 12.7; Pap, 112.0 +/- 19.4; and GV, 132.5 +/- 22.7 (P < .05, GV plus Pap versus untreated). CONCLUSIONS: First, pharmacological treatment of SV during harvesting, especially with GV solution, allows the use of a lower distension pressure and reduces the breakdown of high-energy phosphates in the vein wall. Second, topical and intraluminal use of GV solution during vein harvesting improves endothelial coverage compared with the topical use of Pap or no pharmacological treatment.

Aged↗