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Biomedical subjects

C A Lee

Publications and source records attributed to C A Lee.

At least 127 records · Page 7Linked to original sources
PubMed1998

Retrospective neuropathological review of prion disease in UK haemophilic patients.

In 1996, the CJD surveillance unit in Edinburgh, UK described nvCJD which was thought to be the human equivalent of bovine spongiform encephalopathy (BSE). The identification of prion protein in the tonsil of an affected individual has raised the question of transmission of nvCJD via blood products. This study examines the post mortem brains of 33 patients who were treated with clotting factor concentrate of predominately UK donor source during the years 1962-1995. The brains were examined by conventional histological methods and also for the prion protein using monoclonal antibodies KG9 and 3F4. No evidence of spongiform encephalopathy was found and the immunocytochemistry was negative for PrP in all cases. It is concluded that, at present, there is no evidence for the transmission of nvCJD via clotting factor concentrate to patients with haemophilia.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Assessing the effectiveness and cost-effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrand's disease.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of prophylaxis with clotting factor against bleeding in patients with severe haemophilia and von Willebrand's disease (vWD). DESIGN: Treatment details that related to 179 patients with severe (< 1 u dL-1) haemophilia A, B and vWD were retrospectively examined for the period 1980-95. A subgroup of these patients, 25 adults and 22 children, who had previously received treatment on demand and who had switched to treating with prophylaxis, were studied in order to examine the effects of the change. The cost-effectiveness of prophylaxis was also analysed using another subgroup of 38 patients and by adjusting their treatment details by age and method of treatment. SETTING: Data were obtained on patients who were solely registered at the Royal Free Hospital Haemophilia Centre (RFHHC), London, UK. OUTCOME MEASURE: Bleeds. RESULTS: The median annual number of bleeds decreased from 23.5 (range 1-107) in 1980, to 14 (range 0-45) in 1995 (P < 0.0001). Switching from treating on demand to prophylaxis reduced bleeding frequency in 41 out of 47 patients within the period of 1 year. At the base scenario, switching to prophylaxis cost an additional pound547 per averted bleed; however, this figure was highly sensitive to certain variables. CONCLUSION: Prophylaxis can reduce bleeding frequency but requires more clotting factor than treatment on demand. More detailed proof of cost-effectiveness is likely to require the use of modelling techniques.

Adolescent↗
PubMed1997

Relation between soluble CD30 levels measured soon after HIV seroconversion and disease progression in men with hemophilia.

Soluble CD30 (sCD30) levels within 3 years of HIV seroconversion were studied in 85 hemophilic men infected with HIV. All men were coinfected with hepatitis C virus (HCV). Levels of sCD30 were elevated in these men when compared with controls. These elevated levels did not appear to be a result of treatment with intermediate-purity clotting factor concentrates and were unlikely to be due to HCV coinfection inasmuch as hemophilic patients infected with HCV alone showed only mildly elevated sCD30 levels when compared with those of hemophilic controls uninfected with HCV. Initial sCD30 levels were not significantly associated with progression to any endpoint, although a tendency was present for those with the highest initial levels to progress less rapidly than those with lower values. Despite elevated sCD30 levels in these men, we have not been able to confirm that high sCD30 levels are associated with more rapid HIV progression.

Disease Progression↗
PubMed1997

Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation.

BACKGROUND: Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. METHODS: We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. FINDINGS: Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. INTERPRETATION: There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.

Adult↗
PubMed1997

Survival after a very low (< 5 x 10(6)/l) CD4+ T-cell count in individuals infected with HIV.

OBJECTIVE: To describe survival after a CD4+ T-cell count of less than 5 x 10(6)/l and to identify possible baseline factors associated with outcome. DESIGN: A prospective cohort study. SETTING: A large teaching hospital in North London. PATIENTS AND PARTICIPANTS: Patients treated at the Royal Free Hospital, London, who had at least one reported CD4+ T-cell count of less than 5 x 10(6)/l and were being followed up for clinical care prior to the date of this cell count. MAIN OUTCOME MEASURE: Death. METHODS: Proportional hazards models, Kaplan-Meier analysis. RESULTS: One-hundred and sixty-nine patients were included in the study. The median survival after a very low CD4+ T-cell count was 0.95 years (95% confidence interval, 0.78-1.19), although 20% survived for over 2 years. Older age and a previous AIDS diagnosis were related to poorer outcome. A higher CD8+ T-cell count at baseline was also associated with a better prognosis. CONCLUSIONS: A CD4+ T-cell count of less than 5 x 10(6)/l did not necessarily mean imminent death, with a median survival after this count of just under 1 year. These results will enable clinicians to provide appropriate counselling for patients at this late stage and to plan terminal care.

Adolescent↗
PubMed1997

CD8+,CD38+ lymphocyte percent: a useful immunological marker for monitoring HIV-1-infected patients.

We investigated the relationship between three prognostic markers, CD4 lymphocyte count, serum beta2-microglobulin (beta2M) levels, and CD8+,CD38+ lymphocyte percent, and the association with the rate of development of AIDS. The markers were measured regularly throughout follow-up in 224 patients. The risk of developing AIDS during follow-up was investigated using Cox proportional hazards models. Time-updated values of the prognostic markers were used, which modelled the risk of AIDS according to the latest measurement of the marker rather than using a single value of the marker at baseline. During a median follow-up period of 13.6 months (range 0.5-31.9 months), 34 cases of AIDS occurred. In a univariate analysis, all three markers predicted the development of AIDS; a 10% increase in the percentage of CD8+ T cells expressing CD38+ resulted in an 88% increase in the risk of AIDS (95% confidence interval: 53-130%; p < 0.0001). After adjustment for the current CD4 count and beta2M, a 10% increase in the CD8+,CD38+ population was associated with a 37% increase in the risk of AIDS (95% confidence interval: 4-81%; p = 0.02). Thus, the percentage CD8+,CD38+ level predicts the development of AIDS independently of the latest CD4 count and beta2M. This assay is therefore potentially useful in conjunction with blood CD4 counts and serum beta2M levels in patient management and clinical trial design.

ADP-ribosyl Cyclase↗
PubMed1997

Type III secretion systems: machines to deliver bacterial proteins into eukaryotic cells?

Type III secretion systems in certain bacterial pathogens are induced upon contact with host cells and directly deliver virulence proteins into the host cell cytosol. The increasing number of Gram-negative bacterial pathogens discovered to encode type III secretion systems raises interesting questions. Are type III systems generic machines that deliver virulence proteins into host cells? Is contact with host cells a common regulatory cue for type III systems?

Bacterial Proteins↗
PubMed1997

The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophilic men.

Patients coinfected with both hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) have more rapid progression of HCV infection; however, little is known about the effect of coinfection with HCV on the progression of HIV disease. This study assessed the association between infection with different HCV genotypes on progression to AIDS and death in a cohort of men with hemophilia. Patients infected with HCV type 1 experienced a more rapid progression to both AIDS (P = .009) and death (P = .007) than did those infected with other types. This effect was largely independent of age at seroconversion, hemophilia diagnosis, and changes in CD4 cell count over the follow-up period. These results suggest an association between HCV genotype and progression of HIV disease, which, if confirmed, could have important implications for the treatment and care of patients coinfected with both HIV and HCV.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Aortic valve replacement in the elderly. Risk factors and long-term results.

OBJECTIVE: The current study was undertaken to determine long-term results of aortic valve replacement (AVR) in the elderly, to ascertain predictors of poor outcome, and to assess quality of life. SUMMARY BACKGROUND DATA: Aortic valve replacement is the procedure of choice for elderly patients with aortic valve disease. The number of patients aged 70 and older requiring AVR continues to increase. However, controversy exists as to whether surgery devoted to this subset reflect a cost-effective approach to attaining a meaningful quality of life. METHODS: This study reviews data on 247 patients aged 70 to 89 years who underwent isolated AVR between 1980 and 1995; there were 126 men (51%) and 121 women (49%). Follow-up was 97% complete (239/247 patients) for a total of 974.9 patient-years. Mean age was 76.2 +/- 4.8 years. Operative mortality and actuarial survival were determined. Patient age, gender, symptoms, associated diseases, prior conditions, New York Health Association class congestive heart failure, native valve disease, prosthetic valve type, preoperative catheterization data, and early postoperative conditions were analyzed as possible predictors of outcome. Functional recovery was evaluated using the SF-36 quality assessment tool. RESULTS: Operative mortality was 6.1% (15/247). Multivariate logistic regression showed that poor left ventricular function and preoperative pacemaker insertion were independent predictors of early mortality. After surgery, infection was predictive of early mortality. Overall actuarial survival at 1, 5, and 10 years was 89.5 +/- 2% (198 patients at risk), 69.3 +/- 3.4% (89 patients at risk), and 41.2 +/- 6% (13 patients at risk), respectively. Cox proportional hazards model showed that chronic obstructive pulmonary disease and urgency of operation were independent predictors of poor long-term survival. Postoperative renal failure also was predictive of poor outcome. Using the SF-36 quality assessment tool, elderly patients who underwent AVR scored comparably to their age-matched population norms in seven of eight dimensions of overall health. The exception is mental health. CONCLUSIONS: Aortic valve replacement in the elderly can be performed with acceptable mortality. Significant preoperative risk factors for early mortality include poor left ventricular function and preoperative pacemaker insertion. Predictors of late mortality include chronic obstructive pulmonary disease and urgency of operation. These results stress the importance of operating on the elderly with aortic valve disease; both long-term survival and functional recovery are excellent.

Aged↗
PubMed1997

Recurrent venous thromboembolic disease and factor XI concentrate in a patient with severe factor XI deficiency, chronic myelomonocytic leukaemia, factor V Leiden and heterozygous plasminogen deficiency.

There are increasing concerns about the potential thrombogenic risks associated with the use of factor XI concentrates. We describe the case of a 49 year-old man with chronic myelomonocytic leukaemia and severe factor XI deficiency (< 1 u/dl), in whom the use of factor XI concentrate appeared to be associated with the development of venous thromboembolic disease. Subsequent investigations revealed the presence of both the factor V Leiden abnormality and heterozygous plasminogen deficiency. This case highlights the risks associated with the use of factor XI concentrates and suggests that these risks may be further increased in patients with an inherited or acquired prothrombotic abnormality or an underlying malignancy. Prothrombotic screening of patients with severe factor XI deficiency may be indicated particularly in younger patients in whom treatment with factor XI concentrates is a possibility.

Factor V↗
PubMed1997

Long-term evolution of the 5'UTR and a region of NS4 containing a CTL epitope of hepatitis C virus in two haemophilic patients.

Haemophilic patients exposed to unsterilized clotting factor concentrates prior to 1985 have become infected with hepatitis C virus (HCV). We have studied the sequence evolution of the 5'UTR and a region of NS4 over 12 years in one human immunodeficiency virus (HIV) positive haemophilic patient and 14 years for one HIV negative haemophilic patient. One sample each year from the date of HCV infection to 1994 was analysed for genotype, virus load and nucleotide sequence of the two genetic loci. Both patients were infected with HCV genotype 1 throughout the study period. The virus load profiles were similar except that the profile for the HIV infected patient was displaced 4 years earlier relative to the other patient. Mean divergence of the quasispecies at both the 5'UTR and NS4 loci was higher in the HIV coinfected patient. Phylogenetic analysis indicated that evolution of the 5'UTR was host independent, whereas the NS4 region containing a CD8 restricted CTL epitope evolved in a host specific fashion.

Amino Acid Sequence↗
PubMed1997

The obstetric experience of carriers of haemophilia.

OBJECTIVE: To review the obstetric problems, pregnancy outcome and management of carriers of haemophilia. DESIGN: Retrospective review of haemophilia and maternity unit records. SETTING: Haemophilia Comprehensive Care Centre. PARTICIPANTS: Thirty-two carriers of haemophilia (24 haemophilia A, eight haemophilia B) who had their obstetric care at the Royal Free Hospital over a 10-year period (1985-1995). MAIN OUTCOME MEASURES: Uptake and results of prenatal diagnosis, changes in factor levels during pregnancy, effect of knowledge of fetal gender on obstetric management and neonatal outcome, and maternal haemorrhagic complications. RESULTS: There were 82 pregnancies and 32 resulted in miscarriage or social abortion. The option of prenatal diagnosis was taken up in only 35% (17/48) of pregnancies. There were five affected male fetuses diagnosed prenatally but only three women opted for termination of the pregnancy. Knowledge of fetal gender was unavailable to the attending obstetrician in 46% (21/46) of pregnancies. A fetal scalp electrode was applied in eight, fetal blood sampling was performed in four, and ventouse delivery was conducted in one of these pregnancies. No adverse effects were reported from the first two procedures, but the ventouse delivery was associated with a huge cephalhaematoma requiring blood transfusion. On the other hand, in five cases fetal blood sampling was withheld because fetal gender was unknown. Four of the eight caesarean sections performed might have been avoided if the gender had been known. The incidence of primary and secondary postpartum haemorrhage was high, 22% (including two cases with massive haemorrhage) and 11%, respectively. CONCLUSION: Carriers of haemophilia A and B require special obstetric care with close liaison with the haemophilia centre, and management guidelines should be available and observed. Knowledge of fetal gender is very valuable for management in labour and should be determined antenatally even if the mother declines prenatal diagnosis.

Abortion, Induced↗
PubMed1997

Identification of CYP1A5 as the CYP1A enzyme mainly responsible for uroporphyrinogen oxidation induced by AH receptor ligands in chicken liver and kidney.

Uroporphyrinogen is an intermediate of the heme biosynthetic pathway. The oxidation of uroporphyrinogen to uroporphyrin (UROX) has been demonstrated to be catalyzed by mammalian CYP1A2. This reaction has an important role in uroporphyria caused by halogenated aromatic compounds. Two CYP enzymes induced by Ah receptor ligands were purified recently from chick embryo liver. One, designated CYP1A5, was preferentially active in arachidonic acid epoxygenation and the other, designated CYP1A4, in 7-ethoxyresorufin deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH), reactions mainly catalyzed by CYP1A1 in rodents. The amino acid sequences of both CYP1A5 and CYP1A4 are more similar to CYP1A1 than to 1A2, and neither can be classified as an ortholog of mammalian CYP1A1 or 1A2. Here we report that reconstituted purified CYP1A5 was eight times more active than CYP1A4 in catalyzing UROX. The stimulation of UROX by 3,4,3',4'-tetrachlorobiphenyl that has been observed in microsomes was also observed with the reconstituted enzymes. Similar dose response relationships were found for induction of UROX and EROD in both chick embryo liver microsomes and in cultured chick hepatocytes, indicating coinduction of CYP1A5 and CYP1A4. UROX was induced by the Ah receptor ligand, 3-methylcholanthrene, in chicken kidney as well as liver. The findings reported here and other evidence that CYP1A4 and CYP1A5 tend to exhibit CYP1A1 and 1A2-like enzyme activites, respectively, indicate that the division of some enzyme activities among CYP1A enzymes applies to different vertebrate classes.

Animals↗
PubMed1997

Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product.

Use of high purity and recombinant factor VIII (FVIII) concentrates has been thought to be associated with an increased incidence of FVIII inhibitors in patients with severe haemophilia A. Comparison with comparable historical control groups has suggested that the true incidence of inhibitors in patients with severe haemophilia A was approximately 20-25%, similar to the incidence seen with new high purity and recombinant FVIII products. We have conducted a study of inhibitor development in a cohort of 37 boys with severe haemophilia A (VIII:C <2 u/dl) exposed only to a single FVIII concentrate (BPL 8Y) with no previous blood or blood product exposure. This factor VIII concentrate is an intermediate purity product with a specific activity of approximately 2 IU/mg protein and contains well preserved von Willebrand factor multimers. It is manufactured by conventional fractionation technologies and terminally dry heat treated at 80 degrees C for 72 h.

Antibodies↗
PubMed1997

Mechanism of cytochrome P450 activation by caffeine and 7,8-benzoflavone in rat liver microsomes.

Caffeine and 7,8-benzoflavone activate CYP3A2 in rat liver microsomes. Both activators appear to enhance enzyme activity by an increase in Vmax and to a lesser extent a decrease in Km. Additive effect studies demonstrated that the two activators oppose one another's effect. Electron transfer steps in the cytochrome P450 cycle are involved in the mechanism of cytochrome P450 activation, as indicated by the lack of effect of caffeine or 7,8-benzoflavone on cumene hydroperoxide-supported oxidation of acetaminophen by cytochrome P450. The involvement of cytochrome b5 in the formation of N-acetyl-p-benzoquinone imine (NAPQI) was implicated through a synergistic effect of NADH on the NADPH-supported reaction. Anti-cytochrome b5, but not anti-cytochrome P450 reductase IgG, diminished the activation effect of caffeine on NAPQI formation. Neither antibody altered the effect of 7,8-benzoflavone on NAPQI formation. The impairment of NAPQI formation by cytochrome b5 antibody suggests that cytochrome P450 activation by caffeine but not 7,8-benzoflavone is mediated in part through enhancement of the transfer of the second electron to cytochrome P450 from cytochrome b5.

Animals↗