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Biomedical subjects

D Webb

Publications and source records attributed to D Webb.

At least 37 records · Page 2Linked to original sources
PubMed2001

Potentiation of vincristine toxicity by itraconazole in children with lymphoid malignancies.

UNLABELLED: Eight consecutive paediatric patients with acute lymphoblastic leukaemia (ALL) (n = 7) and T-cell non-Hodgkin's lymphoma (NHL) (n = 1) presenting within a 5-wk interval were started on a standard induction protocol which included weekly treatment with vincristine for 4 wk. Itraconazole was commenced as antifungal prophylaxis, 1-21 d after the first injection of vincristine. Within 2 to 4 wk, enhanced vincristine neurotoxicity was noted in all patients, abdominal cramps and constipation occurred most frequently, and one patient developed a bowel perforation associated with paralytic ileus. Hyponatraemia associated with SIADH was observed in three patients and four patients developed seizures. An additional patient with B cell NHL developed seizures 5 d after an injection of vincristine. Recovery was complete in all patients and ranged from 2 d to 15 wk. CONCLUSION: The extent and consistency of adverse effects documented in this study support the recommendation that concurrent administration of vincristine and itraconazole should be avoided.

Adolescent↗
PubMed2001

Are selective endothelin A receptor antagonists better than mixed antagonists?

Pharmacological antagonism of the endothelin system presents a novel target for the treatment of a range of cardiovascular diseases. The antagonists developed so far differ in their endothelin receptor subtype specificity. Indeed, at present there is no consensus opinion as to what level of receptor selectivity defines a particular antagonist as 'selective' or 'mixed'. Antagonists that are highly selective for the endothelin A receptor (ETA) receptor subtype have a number of hypothetical advantages over non-selective antagonists. This theory is based on the analysis of the function of the endothelin B (ETB) receptor. Current evidence suggests that activation of the ETB receptor results in vasodilatation, diuresis and natriuresis, each of which are properties that might be advantageous to maintain in conditions such as cardiac failure and hypertension. However, definitive evidence to suggest a therapeutic advantage of selective ETA receptor antagonists requires long-term, head-to-head studies to be performed.

Amiloride↗
PubMed2001

Overexpression of the adenovirus type 12 (Ad12) pTP or E1A gene facilitates Ad12 DNA replication in nonpermissive BHK21 hamster cells.

In the adenovirus type 12 (Ad12) hamster cell system, abortive virus infection is one of the factors associated with the highly efficient oncogenesis in newborn Syrian hamsters. We have shown earlier that the replication and efficient late transcription of the Ad12 genome are blocked in Syrian hamster cells. Some of the early Ad12 functions are transcribed in these cells, although at a minimal rate. In the present study, we demonstrate that low expression levels of the E1A and precursor to terminal protein (pTP) genes of Ad12 seem to be responsible for the lack of Ad12 DNA replication in hamster cells. The Ad12 genes for the E1A functions or for pTP were tethered to the strong early promoter of the human cytomegalovirus and transfected into BHK21 cells. Subsequently, these cells were infected with Ad12 virions. In Ad12-infected BHK21 cells, which overexpressed pTP or E1A, full-length Ad12 DNA was de novo synthesized, as documented by metabolic labeling with [3H]thymidine and by zone velocity sedimentation in alkaline sucrose gradients followed by gel electrophoresis of the 3H-labeled DNA and Southern blot hybridization to 32P-labeled Ad12 DNA. Transfection of the cloned E1A region of Ad2 yielded similar results. The newly synthesized Ad12 DNA was covalently linked to pTP. The Ad12 DNA binding protein (DBP) and DNA polymerase (pol) genes were transcribed at levels similar to those in merely Ad12-infected cells. In pTP or E1A gene-transfected and Ad12-infected BHK21 cells, marginal levels of late Ad12 mRNA were detectable. Late Ad12 proteins were, however, not synthesized. Apparently, Ad12 DNA replication in hamster cells is rendered impossible due to insufficient threshold levels of the viral E1A and/or pTP.

Adenovirus E1A Proteins↗
PubMed2001

A comparison of elevated blood lead levels among children living in foster care, their siblings, and the general population.

OBJECTIVES: To assess the prevalence of elevated blood lead levels (EBLLs) among children before and after foster care placement, and to compare the prevalence of EBLLs among children in foster care with that of their siblings and the general population. METHODS: We conducted a retrospective cohort study using administrative databases from the Philadelphia Department of Human Services and the Birth Certificate Registry and the Childhood Lead Poisoning Prevention Program at the Philadelphia Department of Public Health. Logistic regression analyses were performed to control for confounding variables, including age, race, gender, and the year, seasonal timing, and source (capillary vs venous) of test. RESULTS: From June 1992 to May 1997, there were 1824 children in foster care with available blood lead results in the Childhood Lead Poisoning Prevention Program database. Of these, 519 (28%) had initial lead screening before foster care placement and 654 (36%) after placement. There were 821 siblings and 73 608 children in the general population with available blood lead results. Before entering foster care, children were nearly twice as likely to have EBLLs as their siblings (adjusted odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.4, 2.0), those in placement (adjusted OR = 1.9; 95% CI = 1.6, 2.2), and the general population (adjusted OR = 1.7; 95% CI = 1.5, 2.0). At the highest point prevalence, 50% of children before placement had lead levels >/=20 microg/dL, and nearly 90% had levels >/=10 microg/dL. For all age categories, siblings of children in foster care placement had a higher prevalence of EBLLs than did the general population. After placement, children in foster care were nearly half as likely as the other groups to have EBLLs. CONCLUSIONS: Our findings suggest that children are at high risk for lead poisoning before entering foster care and that placement in foster care may have a beneficial effect on lead exposure. Children before foster care placement are nearly twice as likely to have EBLLs compared with children in foster care placement, the general population, and their siblings. Furthermore, siblings of children in foster care are at high risk for lead poisoning. Children receiving social services in their own homes and children suffering from abuse and neglect should be actively screened for lead poisoning. Greater efforts at preventing lead poisoning among these children must be made.

Child↗
PubMed2001

Pennsylvania's early discharge legislation: effect on maternity and infant lengths of stay and hospital charges in Philadelphia.

OBJECTIVE: To assess the effect of maternal length of stay (LOS) legislation on LOS and hospital charges associated with Philadelphia resident live births from 1994 through 1997. DATA SOURCE/STUDY SETTING: This was a descriptive epidemiological study involving secondary data analyses of linked birth record and hospital discharge data pertaining to all Philadelphia resident live births occurring between January 1, 1994 and December 31, 1997. STUDY DESIGN: Using these linked data, trends in median and mean maternal and infant LOS and hospital charges were described for three distinct time periods: (1) a "prelegislative" period (January 1, 1994 through June 30, 1995); (2) a one-year period during which LOS legislation was introduced, debated, modified, and eventually passed by Pennsylvania lawmakers (July 1, 1995 through June 30, 1996); and (3) a "post-LOS law" period immediately following enactment of Act 85 mandating minimum LOS for mothers and their newborns (July 1, 1996 through December 31, 1997). LOS variables for both mothers and infants were calculated based on the actual number of hours elapsing between birth and discharge; hospital charges were obtained directly from information available in the Hospital Discharge Survey data. PRINCIPAL FINDINGS: Maternal median charges and LOS per delivery for vaginal births rose from 5,270 dollars to 6,333 dollars and from 35 to 47 hours following the enactment of Pennsylvania maternal minimum LOS legislation. Median infant cost and LOS per delivery mirrored these trends. CONCLUSIONS: Pennsylvania LOS legislation had a profound effect on maternal and infant discharge practices in Philadelphia. As much as $20 million may have been added to annual health care costs associated with Philadelphia resident births.

Adult↗
PubMed2000

Recurrence of Langerhans cell histiocytosis in the graft after pediatric liver transplantation.

Two girls were diagnosed with Langerhans cell histiocytosis (LCH) at the age of 16 and 7 months and developed end stage chronic liver disease related to LCH-induced sclerosing cholangitis at 28 and 8 months, respectively. They received liver transplants at 34 and 14 months of age. Five months post-orthotopic liver transplantation (OLT) one of the patients developed posttransplant lymphoproliferative disease, successfully treated with a combination of surgery and reduction of immunosuppression. Fourteen months post-OLT she developed diabetes insipidus, bilateral ear discharge, and new osteolytic lesions. After transplantation both girls had mild skin reactivations of LCH, requiring minimal steroid increments. At 60 and 5 months post-OLT intrahepatic LCH recurrence was diagnosed on the basis of abnormal biliary enzymes and presence of Langerhans cells in the grafts. Initial cholangiography in both patients was unremarkable. LCH activity was controlled by maintenance chemotherapy with vinblastine, etoposide, and prednisolone. Ten months after reappearance of LCH in the liver graft a follow-up cholangiography in one of the girls demonstrated a low grade cholangiopathy. Residual elevation of liver enzymes probably represents an ongoing pathogenic process.

Cholangiography↗
PubMed2000

Nonmyeloablative stem cell transplantation for congenital immunodeficiencies.

The optimal approach for stem cell transplantation in children with immunodeficiency has yet to be determined. Conditioning therapy is necessary for reliable engraftment and full immune reconstitution; however, the beneficial effect of cytoreductive conditioning is counterbalanced by increased short- and long-term treatment-related toxicity. Whether bone marrow transplantation with a nonmyeloablative preparative regimen was sufficient for the establishment of donor immune reconstitution, with the resultant correction of disease phenotype, was investigated. Eight patients with severe immunodeficiency states underwent T-cell replete bone marrow transplantation from a human leukocyte antigen-matched unrelated (n = 6) or sibling (n = 2) donor with nonmyeloablative conditioning using a fludarabine-melphalan-anti-lymphocyte globulin-based regimen. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. All patients were engrafted with predominantly donor hematopoiesis, and the duration of neutropenia was brief. Significant acute graft-versus-host disease (GVHD) did not develop, but one patient had limited chronic GVHD. One patient died of disease recurrence, and 3 have stable, mixed chimerism. At a median follow-up of 1 year, all patients have had good recovery of CD3(+) T-cell numbers, and 6 of 7 evaluable patients have normal phytohemagglutinin stimulation indices. The rate of immune reconstitution is comparable with that of historical controls undergoing standard myeloablative protocols. Two patients with CD40 ligand deficiency now show significant expression, and a patient with adenosine deaminase deficiency has improved deoxy adenosine triphosphate metabolites. In summary, it has been demonstrated that nonmyeloablative stem cell transplantation permits rapid engraftment from both sibling and unrelated donors with minimal toxicity even in the presence of severe organ dysfunction. If long-term immune reconstitution of patients treated with this protocol is demonstrated, it is believed this approach might offer significant advantages compared with standard protocols by combining adequate immune reconstitution with reduced short- and long-term toxicity. (Blood. 2000;96:1239-1246)

Child↗
PubMed2000

Attitudes to 'Kaponya Mafumo': the terminators of pregnancy in urban Zambia.

As part of a larger study of adolescent sexual and reproductive health in urban Zambia, the issue of unwanted pregnancy and abortion was considered through the examination of the perceptions of both adolescents and adults. Young people rank sexual health as their primary health issue, and sexual behaviour is integrally linked into other aspects of their lives. Pregnancies were deemed to be a common occurrence amongst the adolescents, with an estimated two-thirds of unwanted pregnancies ending in unsafe abortion. The decision to abort is primarily determined by the reaction of the boyfriend and his willingness to accept paternity and the associated financial implications. Other crucial influences are the desire to stay in school and the stigma attached to unwanted pregnancy. The decision-making process regarding the abortion itself is related to the perceived advantages and disadvantages of various service providers. Around 40% of the respondents stated that in the event of an abortion being carried out, it would be performed either by the girl herself or with the assistance of other non-medical personnel. Less popular but still significant are traditional healers and private doctors. Formal health services tend to be rejected due to their poor perception by young people, centred on the lack of privacy and confidentiality, and the de facto illegal nature of abortion itself. The services of nurses are sought, but outside of the clinic setting. The most popular method of self-induced abortion is overdosing on chloroquine. Other methods involve the use of traditional medicines such as various types of roots, as well as more modern methods such as ingesting washing powder. Recommendations for policy-makers concentrate on the improvement of formal, 'youth friendly' health services and the development of appropriate outreach education methods which address specific concerns widely held by young people.

Abortifacient Agents↗
PubMed2000

A transgenic strategy for analysis of the function of the endothelin-B-receptor.

Knockout (KO) models have provided important insights into the function of many receptors and signalling molecules. However, analysis of endothelin (ET) receptor knockouts has been complicated by the development of lethal phenotypes. In this paper, we present our strategy for examining endothelin-B- (ET(B)) receptor function in the context of other strategies for rescuing the lethal phenotype of ET(B) knockout mice.

Animals↗
PubMed2000

Early onset of Friedreich's ataxia in a compound heterozygote.

Friedreich's ataxia (FA) is an autosomal recessive condition caused by a GAA trinucleotide repeat expansion in the X25 gene on chromosome 9. We describe an unusual form of "pseudodominant" inheritance to illustrate how a diagnosis of FA in a parent does not preclude the diagnosis in the child.

Age of Onset↗
PubMed2000

The Sixth International Conference on Endothelin. October 1999, Montreal, Canada.

Since its discovery in 1988, there has been an enormous amount of interest in endothelin-1 (ET-1) and its regulatory and growth-promoting role in cardiovascular physiology. Evidence from the Sixth International Conference on Endothelin, held in Montreal in October 1999, continued to demonstrate that the endothelin system is an important therapeutic target in cardiovascular disease, with promising results in animal studies now being confirmed by clinical trials in humans. In addition, many new and exciting roles for ET-1 were presented, suggesting that ET-1 antagonism may have a broader therapeutic potential than previously imagined.

Animals↗
PubMed2000

Effect of nonviable infants on the infant mortality rate in Philadelphia, 1992.

OBJECTIVES: This report measured the effect of births at 22 weeks' gestation or earlier on infant mortality in Philadelphia, Pa. METHODS: The proportion of live-born deliveries at 22 weeks or earlier was calculated. Overall and race-specific infant mortality was calculated after excluding live-born deliveries at 22 weeks' gestation or earlier. RESULTS: Of all deliveries, 1.5% were at 22 weeks or earlier. Of these, 68% were stillborn and 32% were live-born. Large hospital-to-hospital variation in the proportion of live-born deliveries at 22 weeks' gestation or earlier was noted. When nonviable births were excluded, overall infant mortality decreased 40%. CONCLUSIONS: The development of a standardized birth certificate policy is needed and will facilitate comparisons of infant mortality across spatial boundaries and racial/ethnic groups.

Birth Certificates↗
PubMed1999

Estrone potentiates myeloid cell differentiation: a role for 17 beta-hydroxysteroid dehydrogenase in modulating hemopoiesis.

Hormones such as 1 alpha, 25-dihydroxy vitamin D3 (D3), all-trans retinoic acid, and 9-cis retinoic acid stimulate differentiation of myeloid progenitor cells via their interaction with specific hormone receptors. However, the sensitivity of cells to these agents is not merely governed by the expression of their receptors and the availability of ligand to bind them. Recent studies from our group suggested that the actions of D3 and retinoids on myelopoiesis also are influenced by endogenous mechanisms involving other steroid hormones. In this study we examined the influence of local estrogen metabolism on the differentiation of HL60 cells and normal primitive myeloid progenitor cells. Quantitative thin-layer chromatography (TLC) analyses showed that HL60 and normal cells are able to generate estrone (E1) from estradiol (E2). Neither cell population generated significant amounts of E2 from E1. Reverse transcriptase polymerase chain reaction and Northern analyses confirmed that normal and leukemic myeloid progenitor cells expressed mRNA for the type I and IV isoforms of 17 beta-hydroxysteroid dehydrogenase. Conversion of E2 to E1 was upregulated within 24 hours when HL60 cells were treated with either all-trans retinoic acid or D3 at doses that induce their differentiation toward neutrophils or monocytes, respectively. Similarly, D3-induced monocyte differentiation of normal myeloid progenitor cells was associated with increased capacity to generate E1 from E2. When HL60 cells or normal myeloid progenitor cells were exposed to exogenous E1 they became more sensitive to the differentiation-inducing effects of D3. Data presented provide further evidence for the local modulation of myelopoiesis by intracrine mechanisms. In particular, our findings suggest that local metabolism of steroids by normal as well as leukemic myeloid cells influences their responsiveness to D3 and retinoids.

17-Hydroxysteroid Dehydrogenases↗
PubMed1999

Cholesterol reduction using manufactured foods high in monounsaturated fatty acids: a randomized crossover study.

In two separate studies, the cholesterol-lowering efficacy of a diet high in monounsaturated fatty acids (MUFA) was evaluated by means of a randomized crossover trial. In both studies subjects were randomized to receive either a high-MUFA diet or the control diet first, which they followed for a period of 8 weeks; following a washout period of 4-6 weeks they were transferred onto the opposing diet for a further period of 8 weeks. In one study subjects were healthy middle-aged men (n 30), and in the other they were young men (n 23) with a family history of CHD recruited from two centres (Guildford and Dublin). The two studies were conducted over the same time period using identical foods and study designs. Subjects consumed 38% energy as fat, with 18% energy as MUFA and 10% as saturated fatty acids (MUFA diet), or 13% energy as MUFA and 16% as saturated fatty acids (control diet). The polyunsaturated fatty acid content of each diet was 7%. The diets were achieved by providing subjects with manufactured foods such as spreads, 'ready meals', biscuits, puddings and breads, which, apart from their fatty acid compositions, were identical for both diets. Subjects were blind to which of the diets they were following on both arms of the study. Weight changes on the diets were less than 1 kg. In the groups combined (n 53) mean total and LDL-cholesterol levels were significantly lower at the end of the MUFA diet than the control diet by 0.29 (SD 0.61) mmol/l (P < 0.001) and 0.38 (SD 0.64) mmol/l (P < 0.0001) respectively. In middle-aged men these differences were due to a mean reduction in LDL-cholesterol of -11 (SD 12)% on the MUFA diet with no change on the control diet (-1.1 (SD 10)%). In young men the differences were due to an increase in LDL-cholesterol concentration on the control diet of +6.2 (SD 13)% and a decrease on the MUFA diet of -7.8 (SD 20)%. Differences in the responses of middle-aged and young men to the two diets did not appear to be due to differences in their habitual baseline diets which were generally similar, but appeared to reflect the lower baseline cholesterol concentrations in the younger men. There was a moderately strong and statistically significant inverse correlation between the change in LDL-cholesterol concentration on each diet and the baseline fasting LDL-cholesterol concentration (r -0.49; P < 0.0005). In conclusion, diets in which saturated fat is partially replaced by MUFA can achieve significant reductions in total and LDL-cholesterol concentrations, even when total fat and energy intakes are maintained. The dietary approach used to alter fatty acid intakes would be appropriate for achieving reductions in saturated fat intakes in whole populations.

Adult↗
PubMed1998

Effect of long-term olive oil dietary intervention on postprandial triacylglycerol and factor VII metabolism.

Although the beneficial effects of Mediterranean-type diets, which are rich in olive oil, a good source of monounsaturated fatty acids (MUFAs), are generally accepted, little is known about the effects of long-term dietary MUFA intake on postprandial lipoprotein metabolism and hemostasis. This study used a single-blind, randomized, crossover design to investigate the relative effects of a long-term dietary olive oil intervention and a control [saturated fatty acid (SFA)-enriched] diet on postprandial triacylglycerol metabolism and factor VII activity. The postprandial response to a standard test meal was investigated in 23 healthy men who adhered to both diets for 8 wk. cis-MUFAs were successfully substituted for SFAs in the MUFA diet without affecting total dietary fat or energy intakes. The long-term dietary MUFA intervention significantly reduced plasma and LDL-cholesterol concentrations (P = 0.01). Postprandial triacylglycerol concentrations were significantly greater in the early postprandial period after the MUFA diet (P = 0.003). Postprandial factor VII activation and the concentration of the factor VII antigen were significantly lower after the MUFA diet (P = 0.04 and P = 0.006, respectively). This study showed that isoenergetic substitution of MUFAs for SFAs reduces plasma cholesterol and reduces the degree of postprandial factor VII activation. The alterations in the postprandial triacylglycerol response suggest a greater rate of dietary fat absorption and postprandial triacylglycerol metabolism after a diet rich in MUFAs. This study presents new insights into the biochemical basis of the beneficial effects associated with long-term dietary MUFA consumption, which may explain the lower rates of coronary mortality in Mediterranean regions.

Adult↗