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Biomedical subjects

S M Richards

Publications and source records attributed to S M Richards.

At least 91 records · Page 5Linked to original sources
PubMed1993

Remission death in acute lymphoblastic leukaemia: a changing pattern.

The pattern of remission deaths was examined in 842 children with acute lymphoblastic leukaemia (ALL) treated at a single centre over 18 years. The mortality rate from leukaemia fell significantly during three consecutive time periods during which treatment became progressively more intensive and that during remission induction fell from 3.5% to under 1%, but the rate of death in remission stayed constant at 5-6%. The factors associated with an increased risk of remission death were: young age, a higher leucocyte count, bone marrow transplantation, and Down's syndrome. The pattern of remission deaths changed over the years; measles and herpes viruses decreased while deaths associated with periods of intensification and gut toxicity increased. Four children developed second neoplasms. Treatment of ALL is still associated with a significant risk of death in remission but the pattern of infective deaths has changed. Many should be avoidable by provision of adequate supportive care, close supervision after periods of intensive treatment, and appropriate antibiotic, antifungal, and cytokine therapy.

Age Factors↗
PubMed1993

Role of extracellular UTP in the release of uracil from vasoconstricted hindlimb.

The source and function of elevated uracil release during vasoconstriction in the perfused rat hindlimb was investigated. The possibility that uracil release derived from the breakdown of released vasoactive uridine 5'-triphosphate (UTP) was examined. Exogenous UTP was found to be a potent vasodilator in the perfused rat hindlimb, opposing norepinephrine and angiotensin-induced increases in vasoconstriction and oxygen consumption. UTP was rapidly catabolized by the hindlimb to uridine 5'-monophosphate (UMP), uridine, and uracil, which were all devoid of vasoactivity. UTP was similarly catabolized by incubated rat aorta. Degradation of exogenous UTP by perfused hindlimb or aorta was inhibited by alpha, beta-methylene-adenosine 5'-diphosphate (AMP-CP), an inhibitor of ectonucleotidases. However, AMP-CP did not decrease uracil and uridine output by the hindlimb during angiotensin-mediated vasoconstriction and increased oxygen consumption. In particular, simultaneous infusion of AMP-CP with angiotensin did not increase efflux of UMP. Although exogenous UTP is a potent vasodilator in the perfused rat hindlimb, it appears not to be released intact during vasoconstriction. Hence, extracellular UTP is unlikely to be the precursor of the uracil release.

Adenosine Diphosphate↗
PubMed1992

Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X.

Bone marrow transplantation (BMT) has been recommended for children with high-risk acute lymphoblastic leukaemia (ALL) in first remission. The recent MRC UKALL X trial was designed to facilitate a non-randomised comparison between BMT and chemotherapy in children deemed to be at high risk of treatment failure. 198 children aged 1-15 had a presenting leucocyte count of more than 100 x 10(9)/l. All received induction and early intensification therapy. Children with an HLA-compatible sibling donor were eligible for BMT in first remission. All other children received cranial irradiation at 24Gy, late intensification, and two years of continuous treatment. 183 children achieved a stable remission of whom 111 were HLA typed; these tended to be older and to have T-cell ALL. A donor was identified in 41 cases, of whom 34 proceeded to BMT at a median time of 17 weeks; there was no difference in distribution of age, sex, or leucocyte count between the groups receiving BMT and chemotherapy. Comparison of the 144 children who were in remission at 17 weeks and received chemotherapy with the 34 proceeding to BMT showed no significant difference in event-free survival at five years (69% for BMT and 52% for chemotherapy). There were significantly more treatment-related deaths in the marrow transplant group (6 vs 4) and more relapses in the chemotherapy group (59 vs 4). There was no significant difference in event-free survival between children who were HLA typed and had a donor and those without a donor, although there were fewer relapses among the former. BMT can be evaluated in the context of a multicentre trial for paediatric ALL but the number of children with donors is too small to make a significant impact on overall survival. However, marrow transplantation was associated with a much lower relapse rate than that with the UK ALL protocol, and with better definition of higher risk patients BMT may be of benefit in some children with high-risk ALL in first remission.

Adolescent↗
PubMed1992

A close association between vasoconstrictor-mediated uracil and lactate release by the perfused rat hindlimb.

1. Angiotensin II (5 nM) increased perfusion pressure, O2 uptake and the release of lactate, uracil and uric acid from the perfused rat hindlimb. The release of all three substances was greatest 5 min after commencement of angiotensin II infusion and then decreased over the next 20 min to reach a plateau value that was approx. 2.5-fold basal values. Following removal of angiotensin, pressure, O2 uptake as well as lactate, uracil and uric acid release each returned to pre-infusion (basal) values. 2. Cyanide (1 mM) when added during angiotensin II (5 nM) infusion blocked the pressor effect and completely inhibited all O2 uptake. Cyanide (1 mM) also inhibited the angiotensin-induced increase in uric acid, uracil and lactate release, but the effects differed. Whereas uric acid release remained inhibited throughout the cyanide infusion, uracil and lactate release were only temporarily interrupted and a secondary release of both ensued. 3. Nitroprusside (0.5 mM) when added during angiotensin II (5 nM) infusion blocked pressure and O2 uptake. Lactate and uracil release were partly blocked and returned to pre-infusion (basal) values. However uric acid release was totally blocked and no release occurred when nitroprusside was present with angiotensin II. 4. Combined data showed a significant correlation (r = 0.831; P less than 0.001) between effluent lactate and effluent uracil. 5. It is concluded that lactate and uracil release which increase markedly during vasoconstriction of the hindlimb reflect an association between glycolysis and uracil nucleotide turnover within the same tissue, possibly vascular smooth muscle.

Angiotensin II↗
PubMed1992

Cytomorphology of childhood lymphoblastic leukaemia: a prospective study of 2000 patients. United Kingdom Medical Research Council's Working Party on Childhood Leukaemia.

Blast cell morphology of children with lymphoblastic leukaemia (ALL) entering two national multicentre trials was prospectively reviewed by three haematologists to define the clinical importance of (a) French-American-British (FAB) classification, (b) the presence of cytoplasmic vacuoles, and (c) the presence of 'hand-mirror' cells. Of 2135 evaluable children, 1907 (89%) had FAB L1 morphology and 228 (11%) L2. (L3 patients were not eligible for the trials in question). L2 patients more frequently had residual disease 14 d after starting treatment and had a significantly inferior disease-free survival, but not if the analysis was stratified for age, sex and diagnostic white cell count (WBC). 627 (29%) had blast cells with cytoplasmic vacuoles, and showed a significant survival advantage over the remainder. Vacuoles were positively associated with a low WBC, age range 1-6 years and blast cell positivity for CD10, but their benign influence was apparent even when these variables were taken into account. 'Hand-mirror' (HM) cells were only studied in UKALL X, and were noted in 316/1402 (23%) children. There appeared to be an inverse correlation between HM cells and cytoplasmic vacuoles and a weak association with T-cell immunophenotype, but no prognostic significance was evident. FAB classification appears to be of less prognostic importance than has previously been supposed, though L2 disease is more resistant to current remission induction regimens. Hand-mirror cells may be more common in T-ALL, but are seen in all types and are not related to prognosis. Cytoplasmic vacuoles are predictive of a good response to current therapeutic schedules even allowing for other prognostic variables, and are the single most important morphological feature relating to prognosis in childhood ALL.

Adolescent↗
PubMed1992

Serotonin and norepinephrine vasoconstriction in rat hindlimb have different oxygen requirements.

Serotonin (5-HT) and norepinephrine (NE) are potent vasoconstrictors in the non-erythrocyte constant-flow perfused hindlimb at 25 degrees C. Because 5-HT inhibits and NE stimulates oxygen uptake, these agonists may exert control at different sites in the vasculature that have different metabolic requirements. In this study, it was found that hypoxia, cyanide, or azide had no significant effect on 5-HT-mediated vasoconstriction; however, in the presence of cyanide and absence of glucose, vasoconstriction was transient. NE-mediated vasoconstriction displayed two prazosin-sensitive components. At low concentrations (less than 50 nM), NE-mediated vasoconstriction was totally blocked by hypoxia, cyanide, or azide. At concentrations of NE significantly greater than 50 nM, oxygen-independent vasoconstriction was observed. In conclusion, NE and 5-HT sites are biochemically distinguishable, with 5-HT sites probably located on larger vessels and supportable by anaerobic metabolism and oxygen-dependent NE sites probably located on smaller arteries or arterioles. Supraphysiological concentrations of NE may interact with a subgroup of vascular alpha 1-adrenoceptors on larger vessels giving results similar to 5-HT, thus highlighting problems with high levels of NE in the perfused rat hindlimb.

Animals↗
PubMed1992

Vasoconstrictor-mediated release of lactate from the perfused rat hindlimb.

The effects of different vasomodulators on lactate release by the constant-flow-perfused rat hindlimb were examined and compared with that by perfused mesenteric artery, incubated preparations of aortas, soleus and epitrochlearis muscles, and perifused soleus muscles. Infusion of vasopressin (0.5 nM), angiotensin II (5 nM), norepinephrine (50 nM), and methoxamine (10 microM) into the hindlimbs of 180- to 200-g rats increased the perfusion pressure by 112-167% from 30.4 +/- 0.8 mmHg, O2 consumption by 26-68% from 6.4 +/- 0.2 mumol.g-1 x h-1, and lactate efflux by 148-380% from 5.41 +/- 0.25 mumol.g-1 x h-1. Hindlimbs of 100- to 120-g rats responded similarly to angiotensin II. Isoproterenol (1 microM) had no effect on O2 uptake or perfusion pressure but increased lactate release by 118%. Nitroprusside (0.5 mM) markedly inhibited the vasoconstrictor-mediated increases in lactate release, perfusion pressure, and O2 consumption by the hindlimb but had no effect on isoproterenol-mediated lactate efflux. Serotonin (6.7 microM) increased lactate release from the perfused mesenteric artery by 120% from 5.48 mol.g-1 x h-1. Lactate release by incubated aorta was increased by angiotensin II (50 nM), isoproterenol (1 microM), and mechanical stretch. The increase mediated by angiotensin II was blocked by glycerol trinitrate (2.2 microM), which had no effect on lactate release by isoproterenol. Neither angiotensin II (5 nM) nor vasopressin (0.5 nM) increased lactate release from incubated soleus and epitrochlearis muscles; however, lactate release was increased by isoproterenol, and this increase was unaffected by glycerol trinitrate (2.2 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Gaucher's disease: lack of antibody response in 12 patients following repeated intravenous infusions of mannose terminal glucocerebrosidase.

An amplified ELISA has been employed for monitoring the safety of repeated intravenous infusions of modified human placental glucocerebrosidase. The enzyme infusions consisted of biweekly injections of macrophage targeted glucocerebrosidase over a 6 month duration. Serum samples collected throughout the study were assayed by use of an ELISA using alkaline phosphatase coupled to alcohol dehydrogenase for amplification. Using this protocol, 0.2-5 ng affinity purified immunoglobulin specific for glucocerebrosidase can be detected. Occasional false positives necessitate multiple repeat assays over time to accurately assess immunogenic response. Blinded ELISAs were performed on sera from both infused patients with Gaucher's disease and uninfused control patients and compared with apparent immunoglobulin concentration in 54 normal control sera. Although several samples showed apparently elevated immunoglobulin levels, repeat analyses failed to demonstrate high levels reproducibly. Furthermore, these sera were unable to neutralize enzyme or to precipitate radiolabelled enzyme, confirming the absence of antibody. Problems with high sensitivity ELISA formats are discussed.

Animals↗
PubMed1990

Release of purine and pyrimidine nucleosides and their catabolites from the perfused rat hindlimb in response to noradrenaline, vasopressin, angiotensin II and sciatic-nerve stimulation.

Uric acid and uracil were released at constant rates (0.95 and 0.4 nmol/min per g respectively) by the perfused rat hindlimb. Noradrenaline, vasopressin or angiotensin II further increased the release of these substances 2-5-fold, coinciding with increases in both perfusion pressure (vasoconstriction) and O2 uptake. The hindlimb also released, but in lesser amounts, uridine, hypoxanthine, xanthine, inosine and guanosine, and all but hypoxanthine and guanosine were increased during intense vasoconstriction. Uric acid and uracil releases were increased by noradrenaline in a dose-dependent manner. However, the release of these substances did not fully correspond with the dose-dependent increase in O2 uptake and perfusion pressure, where changes in the latter occurred at lower doses of noradrenaline. Sciatic-nerve stimulation (skeletal-muscle contraction) did not increase the release of uracil, uric acid or uridine, but instead increased the release of inosine (7-fold) and hypoxanthine (2-fold). Since the UTP content as well as the UTP/ATP ratio are higher in smooth muscle than in skeletal muscle, it is proposed that release of uric acid and uracil arises from increased metabolism of the respective adenosine and uridine nucleotides during intense constriction of smooth muscle.

Angiotensin II↗
PubMed1990

Pharmacokinetics in chimpanzees of recombinant human tissue-type plasminogen activator produced in mouse C127 and Chinese hamster ovary cells.

Pharmacokinetics of recombinant tissue-type plasminogen activator (rt-PA) produced in mouse C127 cells (t-PA(C127] and Chinese hamster ovary cells (t-PA(CHO] was investigated in chimpanzees. rt-PA was administered via a constant rate i.v. infusion for 60 min, and t-PA concentration and activity in plasma were measured during and after infusion. The noncompartmental parameters were calculated according to the moment analysis method, and a population pharmacokinetic analysis was performed to obtain the mean and interindividual variability of the pharmacokinetic parameters. The mean residence time of t-PA(C127) was significantly longer and the total body clearance was significantly less than that of t-PA(CHO). t-PA(C127) has an alpha-galactosyl moiety in its carbohydrate chains, whereas such a structure is not found in t-PA(CHO). These results demonstrate that two preparations of rt-PA's with different carbohydrate structures show different pharmacokinetics, and suggest that the carbohydrate structure can affect the efficiency of hepatic uptake of t-PA. A possible mechanism is an interaction of t-PA(C127) with the natural anti-alpha-galactosyl antibody. The anti-alpha-galactosyl antibody level in plasma decreased in association with the plasma levels of t-PA(C127) but was unaffected by t-PA(CHO) levels.

Animals↗
PubMed1990

Quantitative and functional assays compared for determination of zymogen and activated human protein C.

We evaluated quantitative and functional assays for protein C, using either purified protein C samples or pooled normal plasma as assay standards. The purified protein C samples were examined as the zymogen form and after activation by thrombin. Mass concentrations of protein C were determined by amino acid analysis and confirmed by enzyme-linked immunosorbent assay (ELISA). Functional activity was assessed in both standard clot inhibition and amidolytic assays. The accuracy and precision of the ELISA was acceptable, with all three preparations of protein C having similar linear curves. The clot inhibition assay demonstrated marked variability when used according to the manufacturer's instructions; however, modifications to the protocol significantly decreased the CV, to less than 10%. Both activated protein C and the zymogen gave linear standard curves. Pooled normal human plasma gave a nonlinear curve, which contributed to inaccurate sample recoveries. We obtained the most nearly accurate recoveries when we used activated protein C as the assay standard. Amidolytic assays provided no insights into the appropriateness of the preparations for that assay format. A uniform, consistent source of protein C, e.g., recombinant activated protein C, would be useful for standardizing all assays of protein C.

Enzyme Precursors↗
PubMed1989

Prognostic importance of myelosuppression during maintenance treatment of lymphoblastic leukaemia. Leukaemia in Childhood Working Party of the Medical Research Council.

Children from the UKALL V trial were studied to assess the clinical importance of myelosuppression during uninterrupted 'maintenance' treatment of 'standard risk' lymphoblastic leukaemia. Those receiving daily 6-mercaptopurine and weekly methotrexate who were in first remission 20 months from diagnosis were divided into two groups on the basis of whether or not they had ever had an absolute neutrophil count of less than 0.5 x 10(9)/l recorded during maintenance treatment up to that time. Of 105 evaluable children, 45 (43%) became neutropenic at least once, and 60 (57%) did not. Seven (16%) of the neutropenic group subsequently relapsed compared with 27 (45%) of the remainder. This difference was still significant if the analysis was stratified by total treatment time (two or three years), age, sex, or diagnostic white cell count. Seven (16%) neutropenic children died in remission, compared with one (2%) of the non-neutropenic children. Therapeutic myelosuppression during standard maintenance treatment of 'standard risk' lymphoblastic leukaemia is associated with increased toxicity but a reduced risk of relapse. The unexplained improvement in long term survival in the United Kingdom in recent years may in large part be due to this.

Adolescent↗
PubMed1988

Blast cell vacuoles in childhood lymphoblastic leukaemia.

As part of a central review of cell morphology in childhood lymphoblastic leukaemia (ALL), marrow smears from entrants to the Medical Research Council trial UKALL VIII, other than those from children with B-ALL, were studied prospectively for the presence or absence of blast cell vacuoles and for any clinical or biological relevance this feature might have. Adequate slides were available from 733 patients (88% of the trial entrants) after five with B ALL were excluded. Vacuolated blast cells (greater than 10%) were present in 204 (28%). The presence of vacuoles was associated with PAS positivity (chi 2 = 27.8; P less than 0.0001), a diagnostic white cell count (WBC) less than 50 x 10(9)/l (chi 2 = 13.1; P less than 0.0001), and the immunophenotype of 'common' ALL (CD10 positive) (chi 2 = 9.1; P less than 0.01). There was no clear association with French-American-British (FAB) type L1 or L2. The 204 patients with vacuoles had a significantly superior disease free survival compared to the remainder (2P = 0.01), a difference which remained significant when the analysis was stratified by FAB type (2P = 0.01), age (2P = 0.02) or sex (2P = 0.02), but which was lost when stratified by WBC (2P = 0.06). These findings provide further evidence that, outside the context of B-ALL, vacuoles are indicative of a relatively benign disease which responds well to therapy. The French-American-British (FAB) classification should be modified to take this into account.

Adolescent↗
PubMed1986

Does ovarian sex cord tumour with annular tubules produce progesterone?

Probable progesterone production was identified by an immunoperoxidase assay in a case of an ovarian sex cord tumour with annular tubules. The tumour was associated with a serous cystadenofibroma in the opposite ovary and with adenoma malignum (adenocarcinoma) of the cervix.

Adenocarcinoma↗
PubMed1986

French American British (FAB) morphological classification of childhood lymphoblastic leukaemia and its clinical importance.

As part of the Medical Research Council Leukaemia Trial UKALL VIII, 738 unselected children with acute lymphoblastic leukaemia (ALL) had the morphology of their marrow blast cells reviewed by a panel of three haematologists. Ninety four (13%) showed appearances classifiable as type L2 by the French American and British (FAB) cooperative group's criteria, five (0.7%) were typed L3, and the remaining 639 (86%) as L1. Disregarding the patients classified as L3, those with the L2 variant showed an inferior disease free survival to that of the remainder (p less than 0.01), and more of them failed to remit after receiving "standard" remission induction treatment (p less than 0.01). They included an excess of older children (p less than 0.01) with less profound marrow failure at diagnosis, and fewer of them expressed the common ALL antigen (p = 0.05). There was no association between L2 morphology and the diagnostic white cell count, sex, or the presence of a mediastinal mass. These findings confirm earlier reports that FAB L2 ALL is associated with a poor prognosis and that it occurs more commonly in older children. The high remission failure rate is a recent observation and indicates that alternative early treatment may be appropriate for such patients.

Actuarial Analysis↗
PubMed1983

Incidence of self poisoning in patients prescribed psychotropic drugs.

The drugs most commonly used in self poisoning are the psychotropics, but the proportion of patients given these drugs who take overdoses is unknown. In a prospective study of 43117 people in Oxfordshire, prescriptions issued by general practitioners were linked with records of hospital admissions and deaths. During two years there were 79 episodes of deliberate self poisoning leading to hospital admission or death. The number of patients who took overdoses of psychotropic drugs was small in relation to the total number prescribed such drugs. Of 5600 people aged 10 or older who received psychotropic drugs during one year, 17 (3.0 per 1000) poisoned themselves with these drugs within 12 months. The rate of self poisoning with psychotropic drugs declined significantly with increasing age (p less than 0.001). Almost three quarters of the patients who took overdoses of prescribed psychotropics received further psychotropic drugs during the three months after their admission to hospital.

Adolescent↗
PubMed1983

The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease. Results from 20 years of prospective observation.

From 1954 to 1961, pulmonary function was assessed in 2,718 British men by forced expiratory maneuvers, and mucus hypersecretion and smoking habits were assessed by questionnaires. In 20 to 25 yr of follow-up, 104 men (all of whom had smoked) died of chronic obstructive pulmonary disease (COPD). The risk of death from COPD was strongly correlated with the initial degree of air-flow obstruction. Among men with similar initial air-flow obstruction, however, age-specific COPD death rates were not significantly related to initial mucus hypersecretion, supporting the concept that air-flow obstruction and mucus hypersecretion are largely independent disease processes. A moderate relationship existed between initial mucus hypersecretion and subsequent lung cancer mortality, but it is not known whether this was due solely to a common correlation of both conditions with the effective degree of exposure of the large bronchi to causative factors such as tobacco smoke.

Adult↗