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Biomedical subjects

C A Lee

Publications and source records attributed to C A Lee.

At least 73 records · Page 4Linked to original sources
PubMed2000

A survey of patients with acquired haemophilia in a haemophilia centre over a 28-year period.

Data of patients with acquired inhibitors to clotting factors seen in a haemophilia centre from 1970-98 was collected. Twenty-four patients with anti-factor VIII antibodies and four with acquired von Willebrand disease case records were evaluable. Two-thirds of the patients were females and their age ranged from 2 to 92 years (median 69). There was no correlation between the inhibitor titres and the severity or the pattern of bleeding. Porcine factor VIII and activated prothrombin complex were both effective for acute bleeds. Prednisolone and cyclophosphamide proved valuable for suppression of the antibodies without adverse effects even in the elderly group of patients. Three deaths were directly related to bleeding. This review has shown the life-threatening nature of this acquired bleeding disorder, its variable clinical presentation and the importance of early referral to a specialist centre for appropriate therapy.

Adolescent↗
PubMed2000

Reproductive choices of women in families with haemophilia.

To assess women's experiences in pregnancy and attitudes towards their reproductive choices, a structured questionnaire was sent to all obligate and potential carriers of haemophilia (A and B), aged 14-60 years, registered with our haemophilia centre. One hundred and ninety-seven of 545 (36%) returned completed questionnaires. Clinical details, including type and severity of the disease in the family and results of DNA analysis for carrier detection, were obtained from patient notes. One hundred and sixty women had been pregnant at least once, of whom 36 (23%) had received a prenatal diagnostic test. Of the 41 women who had pregnancy terminations, haemophilia was the main reason in only 11 (27%) women. This decision was affected by the woman's religion and results of DNA studies. Living close to a haemophilia centre, proper counselling at the centre and awareness of the availability of prenatal diagnostic tests influenced the women's decision to become pregnant in 14% and 10% of first and subsequent pregnancies, respectively. These factors were considered more frequently in women with severe haemophilia in the family (P = 0.002) and in confirmed carriers of haemophilia (P = 0.04). When women made a conscious decision not to have children, the reasons were fear of passing haemophilia onto their child (44%), previous experience with haemophilia (6%) and the stress of going through prenatal tests (7%). Severity of the disease in the family, haemophilia diagnosis, results of DNA studies, religion and year of birth had no effect on this decision. Our data indicate that haemophilia and related factors in the family have an influence on women's reproductive choices.

Abortion, Induced↗
PubMed2000

Primary prophylaxis for individuals with severe haemophilia: how many hospital visits could treatment prevent?

OBJECTIVES: To assess how many hospital visits primary prophylaxis with clotting factor could prevent. DESIGN: The potential for reducing hospital visits was assessed by comparing rates of in-patient, Out-patient and day-case visits per patient-year for individuals with severe (< 1 IU dL-1) haemophilia who had never received primary prophylaxis with attendance rates for individuals with mild/moderate (1-50 IU dL-1) haemophilia. Hospital attendance data were collected retrospectively for the period 1988-97 inclusive for individuals who were aged 18 years or over. SETTING: Data were obtained on patients who were registered at the Katharine Dormandy Haemophilia Centre (KDHC), London, UK. OUTCOME MEASURES: In-patient stays, Out-patient and day-case visits. RESULTS: Individuals with mild/moderate haemophilia were 45% (31-56), 36% (30-41) and 70% (68-73) less likely to have required in-patient, Out-patient and day-case visits than were individuals with severe haemophilia. HIV serostatus and age were also shown to be significant and independent predictors of the rate of Out-patient and day-case visits, but not the rate of in-patient stays. CONCLUSION: These results suggest that primary prophylaxis for individuals with severe haemophilia could significantly reduce the demand for in-patient stays, and Out-patient and day-case visits.

Adolescent↗
PubMed2000

Unravelling the mysteries of virulence gene regulation in Salmonella typhimurium.

Salmonella typhimurium, which causes gastroenteritis in calves and humans as well as a typhoid-like disease in mice, uses numerous virulence factors to infect its hosts. Genes encoding these factors are regulated by many environmental conditions and regulatory pathways in vitro. Many virulence genes are specifically induced at particular sites during infection or in cultured host cells. The complex regulation of virulence genes observed in vitro may be necessary to restrict their expression to specific locations within the host. In vitro and in vivo studies provide clues about how virulence genes might be regulated in vivo. Future studies must assess the actual environmental signals and regulators that modulate each virulence gene in vivo and determine how multiple regulatory pathways are integrated to co-ordinate the appropriate expression of virulence factors at specific sites in vivo.

Animals↗
PubMed2000

The cis requirements for transcriptional activation by HilA, a virulence determinant encoded on SPI-1.

In several models of pathogenesis, Salmonella requires genes encoded on Salmonella pathogenicity island 1 (SPI-1) for virulence. In Salmonella enterica serovar Typhimurium (S. typhimurium), most SPI-1 genes are arranged in operons and are co-ordinately regulated in response to environmental signals via the SPI-1-encoded protein HilA. In order to understand how HilA controls the transcription of SPI-1 genes, we have analysed the invF and prgH promoters. We have reconstituted HilA-dependent activation of both promoters in Escherichia coli by supplying hilA on a plasmid, strongly suggesting that HilA acts directly on the promoters. By analysing the HilA-dependent activity of deletions and mutations in PinvF, we identified cis elements necessary for HilA-dependent activation. Through biochemical studies, we have defined a probable HilA-binding sequence in the invF promoter. This 'HilA box' is intact in the minimal promoter identified through deletion analysis, and it is disrupted in one class of PinvF mutants that has reduced activation by HilA. The prgH promoter also contains a HilA box in the same position relative to the +1 of transcription. This work is the first to connect HilA-dependent environmental regulation with a specific sequence in a SPI-1 virulence gene promoter.

Bacterial Proteins↗
PubMed2000

LDL of Taiwanese vegetarians are less oxidizable than those of omnivores.

The vegetarians in Taiwan consume diets high in polyunsaturated fatty acids. To investigate whether this dietary pattern results in high susceptibility of LDL to oxidation, 109 long-term (8 +/- 5 y) male and female vegans and lactovegetarians (ages 31-45 y) from Taipei and females from Hualien and matched omnivores were recruited to have 24-h-recall dietary assessments and blood lipid analysis. Body mass index and blood pressure were significantly lower in all vegetarian groups than in the matched omnivore groups (P < 0.05). Vegetarians consumed less energy except in the males and less protein, fat and cholesterol (P < 0.05). The mean polyunsaturated/saturated fatty acid (P/S) ratio of 2.4 in vegetarian diet was about two times that in omnivore diet (P < 0. 001). The concentrations of plasma total- and LDL-cholesterol (LDL-C) but not HDL-cholesterol (HDL-C) were significantly lower (P < 0.001) and resulting HDL-C/LDL-C ratio was 38, 46 and 30% higher (P < 0.01) in Taipei female, male and Hualien female vegetarians, respectively, than in the matched omnivores. Plasma triglyceride concentration was significantly lower only in the Hualien women vegetarians (31%, P < 0.001) than in the matched omnivores. The lag time of conjugated diene formation in LDL oxidized in vitro induced by copper was longer in Taipei female (62%, P < 0.001), male (29%, P < 0.05) and Hualien female (38%, P < 0.01), and the production of thiobarbituric acid reactive substances (TBARS) in LDL after 2-4 h of oxidation was 22-32% less (P < 0.005) in Taipei male and Hualien female vegetarians than the matched omnivores. Lag time of LDL oxidation was negatively related to LDL arachidonic (r = -0.55, P = 0.0003) and eicosapentaenoic (r = -0.47, P = 0.003) acid contents. LDL-TBARS production was negatively related to LDL linoleic acid content (r = -0.36, P = 0.023), but positively related to LDL arachidonic (r = 0.56, P = 0.0002) and eicosapentaenoic (r = 0.45, P = 0.004) acids. No significant differences were found in dietary vitamins C and E intakes and plasma LDL alpha-tocopherol concentrations between vegetarians and omnivores. Our results suggest that vegetarian diets decrease the susceptibility of LDL to oxidation despite their higher dietary P/S ratio.

Adult↗
PubMed2000

Invasion genes are not required for Salmonella enterica serovar typhimurium to breach the intestinal epithelium: evidence that salmonella pathogenicity island 1 has alternative functions during infection.

Salmonella enterica serovar Typhimurium invasion genes are necessary for bacterial invasion of intestinal epithelial cells and are thought to allow salmonellae to enter and cross the intestinal epithelium during infection. Many invasion genes are encoded on Salmonella pathogenicity island 1 (SPI1), and their expression is activated by HilA, a transcription factor also encoded on SPI1. We have studied the role of Salmonella invasion genes during infection of mice following intragastric inoculation. We have found that strains containing a mutation in hilA or invG were recovered from the intestinal contents, intestinal tissues, and systemic tissues at a lower frequency than their parental wild-type strain. In contrast, a strain in which SPI1 is deleted was recovered from infected mice at a frequency similar to that of its parental wild-type strain. The DeltaSPI1 phenotype indicates that S. enterica does not require invasion genes to cross the intestinal epithelium and infect systemic tissues. This result has forced us to reconsider the long-held belief that invasion genes directly mediate bacterial infection of the intestinal mucosa and traversion of the intestinal barrier during infection. Instead, our results suggest that hilA is required for bacterial colonization of the host intestine. The seemingly contradictory phenotype of the DeltaSPI1 mutant suggests that deletion of another gene(s) encoded on SPI1 suppresses the hilA mutant defect. We propose a model for S. enterica pathogenesis in which hilA and invasion genes are required for salmonellae to overcome a host clearance response elicited by another SPI1 gene product(s).

Animals↗
PubMed2000

Multiple factors independently regulate hilA and invasion gene expression in Salmonella enterica serovar typhimurium.

HilA activates the expression of Salmonella enterica serovar Typhimurium invasion genes. To learn more about regulation of hilA, we isolated Tn5 mutants exhibiting reduced hilA and/or invasion gene expression. In addition to expected mutations, we identified Tn5 insertions in pstS, fadD, flhD, flhC, and fliA. Analysis of the pstS mutant indicates that hilA and invasion genes are repressed by the response regulator PhoB in the absence of the Pst high-affinity inorganic phosphate uptake system. This system is required for negative control of the PhoR-PhoB two-component regulatory system, suggesting that hilA expression may be repressed by PhoR-PhoB under low extracellular inorganic phosphate conditions. FadD is required for uptake and degradation of long-chain fatty acids, and our analysis of the fadD mutant indicates that hilA is regulated by a FadD-dependent, FadR-independent mechanism. Thus, fatty acid derivatives may act as intracellular signals to regulate hilA expression. flhDC and fliA encode transcription factors required for flagellum production, motility, and chemotaxis. Complementation studies with flhC and fliA mutants indicate that FliZ, which is encoded in an operon with fliA, activates expression of hilA, linking regulation of hilA with motility. Finally, epistasis tests showed that PhoB, FadD, FliZ, SirA, and EnvZ act independently to regulate hilA expression and invasion. In summary, our screen has identified several distinct pathways that can modulate S. enterica serovar Typhimurium's ability to express hilA and invade host cells. Integration of signals from these different pathways may help restrict invasion gene expression during infection.

Bacterial Proteins↗
PubMed2000

The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985.

AIM: This study describes the long term follow up of haemophilic patients infected with hepatitis C virus (HCV) between 1961 and 1985. METHODS: Clinical and treatment records from 310 patients with inherited coagulation disorders treated with blood product before 1985 were reviewed. Standard survival analysis methods were used to model progression to liver failure and death. RESULTS: A total of 298/305 (98%) patients tested were anti-HCV positive. Twenty seven (9%) individuals consistently HCV polymerase chain reaction negative were considered to have cleared the virus. By 1 September 1999, 223/310 (72%) were alive, 26 (8%) had died a liver related death, and 61 (20%) had died from other, predominantly human immunodeficiency virus (HIV) related, causes. Kaplan-Meier progression rates to death from any cause and liver related deaths 25 years after exposure to HCV were 47% (95% confidence intervals (CI) 34-60) and 19% (95% CI 10-27), respectively. After 13.3 years from 1985, by which time all patients had seroconverted to HIV, progression rates to death from any cause and liver related deaths were, respectively, 8% (95% CI 4-13) and 3% (95% CI 0.4-6) for those HIV negative, and 57% (95% CI 48-66) and 21% (95% CI 13-31) for those HIV positive (p=0.0001). Using Cox proportional hazard models, the adjusted relative hazard of death for individuals coinfected with HIV compared with those infected with HCV alone was 19.47 (95% CI 9.22-41.10), 0.99 (95% CI 0.39-2.53), 3.47 (95% CI 1.40-8.63), and 9.74 (95% CI 3.91-24.26) for the age groups at infection 10-19 years, 20-29 years, and >30 years, respectively, compared with the age group <10 years. The adjusted relative hazard for genotype 1 compared with other genotypes was 2.7 (95% CI 1.36-5.15). CONCLUSIONS: While 25 year follow up of 310 haemophilic patients has shown the potentially lethal combination of HIV and HCV coinfection, HCV singly infected individuals show slow progression of liver disease.

Adolescent↗
PubMed2000

Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling.

In order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

Amino Acid Substitution↗
PubMed1999

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements.

The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 approximately 0.10 microM, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.

3C Viral Proteases↗
PubMed1999

Factor XI deficiency in women.

Factor XI (FXI) deficiency is an uncommon autosomally transmitted coagulopathy found predominantly in Jewish kindreds. It is associated with variable bleeding tendency that usually manifests after trauma, surgery, or other challenges to hemostasis. Therefore, women with FXI deficiency are at risk of excessive bleeding during their menstrual periods, childbirth, and after surgery. Increased awareness and close collaboration among hematologists, obstetricians, and gynecologists and availability of management guidelines is essential to minimize these risks. This review provides data from current research in FXI deficiency and pregnancy care, menstrual problems, and the role of screening for this disorder in women referred with menorrhagia.

Factor XI Deficiency↗
PubMed1999

Shorter survival in HIV-positive patients with diarrhoea who excrete adenovirus from the GI tract.

Adenoviruses have been described as a cause of diarrhoea in patients infected with the human immunodeficiency virus (HIV). The prevalence of adenoviruses was studied in all HIV-positive patients presenting with diarrhoea at the Royal Free Hospital in London between 1991 and 1995. In addition, all postmortems carried out in HIV-positive individuals registered at the same centre between 1990 and 1997 were reviewed for evidence of adenovirus infection. Adenovirus was detected in 16.1% of patients presenting with diarrhoea. These individuals had a significantly lower CD4 count and were more likely to have had a diagnosis of acquired immunodeficiency syndrome (AIDS) than patients with diarrhoea in whom adenovirus was not detected. The median survival was 1 year compared with 2.4 years for those without adenoviruses; this difference remained significant (P = .008) after controlling for differences in CD4 counts between the groups. Gastrointestinal adenovirus excretion occurs at an advanced stage of HIV disease, and is associated with a poor prognosis. We suggest that adenoviruses may contribute to mortality in this population.

Adenoviridae↗