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Biomedical subjects

Christine A Lee

Publications and source records attributed to Christine A Lee.

At least 19 recordsLinked to original sources
PubMed2006

Inhibitor development in hemophiliacs: the roles of genetic versus environmental factors.

Approximately 5 to 7% of patients with hemophilia A have inhibitory antibodies to factor (F) VIII, which increases to approximately 13% in patients with severe disease. The strongest determinant of the risk of inhibitor development identified is the type of mutation in the FVIII gene that gives rise to the disease. However, accumulating evidence clearly indicates that other genetic factors (e.g., major histocompatibility complex alleles and other immune-modulatory genes) and factors associated with treatment (e.g., type of FVIII concentrate, route of administration, and age of first exposure) may also influence the risk of inhibitor development. There is much interest in identifying such genetic and treatment-related factors to help minimize the risk of inhibitor development and improve treatment outcomes.

Age of Onset↗
PubMed2005

Factor XI deficiency database: an interactive web database of mutations, phenotypes, and structural analysis tools.

Factor XI (FXI) is the zymogen of a serine protease enzyme in the intrinsic pathway of blood coagulation and is an important factor in the creation of a stable fibrin clot. Deficiency of FXI leads to an injury-related bleeding disorder and is remarkable for the lack of correlation between bleeding symptoms and FXI coagulant activity (FXI:C). The FXI protein is composed of five domains: four tandem repeat domains of approximately 80 residues known as Apple (Ap) domains, and the catalytic serine protease (Sp) domain. A total of 65 mutations throughout the FXI gene (F11) have been reported in FXI deficient patients. An interactive web database of these mutations has been created (www.FactorXI.org) that integrates the phenotypic data with genetic data and structural homology models for the five FXI domains. The database provides a central repository for all reported genetic alterations within F11. With the use of recently developed visualization tools, each mutation can be highlighted on the structural models of the FXI domains together with an appropriate survey of patient data, such as FXI:C levels and FXI antigen levels. The database also enables new F11 mutations to be interpreted. The interactive design of this database will lead to a more comprehensive comparative understanding of the genetic factors that influence bleeding risk.

DNA Mutational Analysis↗
PubMed2005

Versatile peptide dendrimers for nucleic acid delivery.

Dendrimers are nonviral vectors that have attracted interest on account of a number of features. They are structurally versatile because their size, shape, and surface charge can be selectively altered. Here we examine the functions of a new family of composite dendrimers that were synthesized with lipidic amino acid cores. These dendrimers are bifunctional because they are characterized by positively charged (lysine) modules for interaction with nucleic acids and neutral lipidic moieties for membrane lipid-bilayer transit. We assessed their structure-function correlations by a combination of molecular and biophysical techniques. Our assessment revealed an unexpected pleitropy of functions subserved by these vectors that included plasmid and oligonucleotide delivery. We also generated a firefly luciferase cell line in which we could modulate luciferase activity by RNA interference. We found that these vectors could also mediate RNA suppression of luciferase expression by delivering double-stranded luciferase transcripts generated in vitro. The structural uniqueness of these lipidic peptide dendrimers coupled with their ease and specificity of assembly and the versatility in their choice of cargo, puts them in a new category of macromolecule carriers. These vectors, therefore, have potential applications as epigenetic modifiers of gene function.

Animals↗
PubMed2005

von Willebrand disease and women's health.

In 1926 von Willebrand described a bleeder family in Aland; this condition became known as von Willebrand disease (VWD). von Willebrand noted that "the trait seemed especially to be seen among the women." Today, the use of a pictorial bleeding assessment chart (PBAC) has enabled the prevalence of VWD to be established among women presenting with menorrhagia, as well as the documentation of this symptom in women with known VWD and the assessment of treatment response in menorrhagia. Treatments for menorrhagia include tranexamic acid, desmopressin (DDAVP) administered either intranasally or subcutaneously, the oral contraceptive pill, the "Mirena" coil (Schering Oy, Turku, Finland), and endometrial ablation. Von Willebrand factor (VWF) shows strong cyclical variation, with peak values occurring in the luteal phase. Although increased in pregnancy, levels of VWF decline postnatally and the incidence of both primary and secondary postpartum hemorrhage is high (20% to 25%). Baseline VWF levels less than 15 IU/dL are unlikely to reach greater than 50 IU/dL in the third trimester, and therefore prophylaxis with DDAVP or VWF-containing concentrate to cover delivery should be considered.

Female↗
PubMed2005

Transfusion-transmitted infection in hemophilia in developing countries.

Treatment of patients with bleeding disorders (especially those with hemophilia) with blood products has been associated with infections with blood-borne viruses. Of these, hepatitis B and C viruses (HBV and HCV, respectively) and the human immunodeficiency virus (HIV) have created major health problems. Although virus-inactivation procedures have virtually eliminated these viruses from newer factor concentrates since 1985, the risk remains in developing countries where there is no ready access to these concentrates. Although a few of these countries have established their own fractionation facilities and in others the respective governments make concentrates available, the large majority of countries still face the problems of blood-borne infections. HCV will invariably lead to liver damage and many hemophiliacs who were exposed to the HCV virus will succumb to cirrhosis. Only approximately 10% of hemophilic patients infected with HCV will clear the infection naturally. Coinfection with HIV shortens the life expectancy. The HIV epidemic in hemophiliacs began in the mid-1980s. Patients in developed countries were especially affected because they were predominantly treated with factor concentrates that were manufactured from thousands of blood donors. Hemophiliacs in developing countries have considerably less HIV infection, although it does exist and depends largely on the source of the plasma fractions. Progress has been made not only in the purification of factor concentrates, but also in the understanding of the HIV virus and in the development of antiretroviral treatment modalities. However, there are still several challenges in delivering antiretroviral treatment that must be addressed before the full impact of these transmitted infections is known.

Blood Coagulation Factors↗
PubMed2005

Detection of known haemophilia B mutations and carrier testing by microarray.

The molecular basis of haemophilia B is heterogeneous and many mutations of the Factor IX (FIX) gene have been characterised. Using the allele-specific arrayed primer extension (AS-APEX) technology, we have designed a FIX array to simultaneously analyse 69 mutations found in British, Thai and Chinese patients. This technology overcomes the problem of multiple reverse dot-blot analysis and has a 100% accuracy in the detection of both affected subjects and carriers in families with known mutations. In seven unknown mutations from Thailand, the array could detect the specific mutation in five and in the remainders the normal primer at specific spots failed to extend due to a mutation a few nucleotides upstream, thus allowing their identification. Hence this FIX array can detect 53% of the 2891 mutation entries in the FIX database. Each of the microarray slide can be used for three different test samples and would be useful for carrier testing for common mutations and prenatal diagnosis. It is simpler and more cost effective than genome sequencing and would be particularly useful in laboratories with limited technical capabilities.

Base Sequence↗
PubMed2004

The impact of HIV on mortality rates in the complete UK haemophilia population.

OBJECTIVE: To estimate the effect of HIV-1 infection on subsequent mortality in a complete population. DESIGN: Prospective cohort study. SUBJECTS: A total of 7250 haemophilic males were registered in the UK Haemophilia Centre Doctors' Organisation database, 1977-1998. Most were infected with hepatitis C virus. In the early 1980s, 1246 were infected with HIV-1 from contaminated clotting factor concentrate. The main outcome measure was the date of death. RESULTS: During 1977-1984 annual mortality in severely haemophilic males was 0.9%. For those with HIV, annual mortality increased progressively from 1985 reaching over 10% during 1993-1996 before falling to 5% in 1997-1999, whereas without HIV it remained approximately 0.9% throughout 1985-1999. For moderately/mildly haemophilic males the annual mortality was 0.4% during 1977-1984. Without HIV it remained approximately 0.4% throughout 1985-1999, but with HIV it was similar to that in severe haemophilia with HIV. Survival was strongly related to age at HIV infection. The large temporal changes in mortality with HIV were largely accounted for by HIV-related conditions. Without HIV annual liver disease mortality remained below 0.2% throughout 1985-1999, but with HIV it was 0.2% during 1985-1990, 0.8% during 1991-1996, and 0.8% during 1997-1999. CONCLUSION: These data provide a direct estimate of the effect of HIV-1 infection on subsequent mortality in a population with a high prevalence of hepatitis C. From approximately 3 years after HIV infection, large, progressive increases in mortality were seen. From 1997, after the introduction of effective treatment, substantial reductions occurred, although mortality from liver disease remained high.

Adolescent↗
PubMed2004

The effect of highly active antiretroviral therapy for HIV on the anti-HCV specific humoral immune response.

The effect of highly active antiretroviral therapy (HAART) on HCV replication is controversial, with some studies reporting no effect and others increases, reductions and even clearances of HCV RNA after treatment. In this study, the effect of HAART was investigated on the titre of anti-HCV specific antibodies and on the relationship between these antibodies and HCV RNA level in a cohort of 24 patients with inherited bleeding disorders. A significant inverse correlation between antibodies to both total HCV proteins and HCV RNA (R = -0.42, P = 0.05) and between antibodies to HCV envelope glycoproteins and HCV RNA (R = -0.54, P = 0.01) was observed pre-HAART. The relationship disappeared or was obscured after therapy (R = 0.24, P = 0.30 and R = 0.16, P = 0.50, respectively). Thus, we show that HAART affects the HCV specific humoral immune responses without affecting the HCV RNA level.

Animals↗
PubMed2004

von Willebrand disease in women with menorrhagia: a systematic review.

OBJECTIVE: To determine the prevalence of von Willebrand disease in women presenting with menorrhagia. DESIGN: Systematic review of studies evaluating the prevalence of von Willebrand disease in women with menorrhagia. SETTING: Hospital outpatient clinics (mainly gynaecological) and population surveys. POPULATION: Women presenting with menorrhagia. METHODS: Relevant studies were extracted from MEDLINE search, bibliographies of identified articles and published proceedings of meetings and conferences. MAIN OUTCOME MEASURES: Number of women with von Willebrand disease. RESULTS: Eleven studies were included, totalling 988 women with menorrhagia. One hundred and thirty-one women were diagnosed to have von Willebrand disease with prevalences in individual studies ranging from 5% to 24%. The overall prevalence was 13% (95% CI 11-15.6%). The prevalence was higher in the European studies-18% (95% CI 15-23%) compared with that in North American studies-10% (95% CI 7.5-13%). This difference (P= 0.007) is likely to be the result of differences in the studies, which include method of recruitment of study population, method of assessing menstrual blood loss ethnic composition of study population, criteria for diagnosis and use of race- and ABO blood group-specific values for von Willebrand factor. CONCLUSIONS: The prevalence of von Willebrand disease is increased in women with menorrhagia and is the underlying cause in a small but significant group of women with menorrhagia across the world. Testing for this disorder should be considered when investigating women with menorrhagia, especially those of Caucasian origin, those with no obvious pelvic pathology or with additional bleeding symptoms.

Europe↗
PubMed2003

Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study.

This study prospectively evaluated the rate of biologic response to desmopressin (DDAVP) in 66 patients with type 1 or 2 von Willebrand disease (VWD), each of whom had, on the basis of available records, a clinically significant bleeding history and at least one of the following laboratory abnormalities: bleeding time (BT) longer than 15 minutes, ristocetin cofactor activity (VWF:RCo) less than 10 IU/dL, factor VIII coagulant activity (FVIII:C) less than 20 IU/dL (severe VWD). Before the study, responsive patients were defined as those who, 2 hours after infusion of 0.3 microg/kg DDAVP, had increased baseline values of VWF:RCo and FVIII:C by at least 3-fold and achieved levels of at least 30 IU/dL for both and a BT of 12 minutes or less. The rate of biologic response varied according to VWD types and was higher in type 1 (7 of 26, 27%) than in type 2 (7 of 40, 18%) (type 2A [1 of 15, 7%], type 2M [3 of 21, 14%], type 2N [3 of 4, 75%]). Mutations in the VWF gene were previously known or newly identified in most patients with types 2A (n = 15 of 15), 2M (n = 15 of 21), and 2N (n = 4 of 4), but in none of those with type 1 VWD. Genotype provided more information than phenotype in predicting individual responses to DDAVP only in patients with 2A and 2N VWD. This prospective study showed that the rate of biologic response to DDAVP is relatively low not only in type 2 but also in type 1 VWD when uniform and stringent criteria for patient selection and responsiveness are applied.

Adolescent↗
PubMed2003

Prevalence, causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency.

Factor XI deficiency, an injury-related bleeding disorder, is rare worldwide but common in Jews in whom 2 mutations, Glu117Stop (type II) and Phe283Leu (type III), prevail. Mean factor XI activities in homozygotes for Glu117Stop and for Phe283Leu are 1 and 10 U/dL, respectively. Inhibitors to factor XI in patients with severe factor XI deficiency have been reported in a small number of instances. This study was undertaken to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discern whether these inhibitors are related to specific mutations, and characterize their activity. Clinical information was obtained from unrelated patients with severe factor XI deficiency, and blood was analyzed for factor XI activity, inhibitor to factor XI, and causative mutations. Immunoglobulin G purified from patients with an inhibitory activity was tested for binding to factor XI, effects on activation of factor XI by factor XIIa and thrombin, and activation of factor IX by exogenous factor XIa. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for Glu117Stop who had a history of plasma replacement therapy. Three additional patients with inhibitors from the United Kingdom and the United States also had this genotype and were exposed to plasma. The inhibitors affected factor XI activation by thrombin or factor XIIa, and activation of factor IX by factor XIa. The results imply that patients with a very low factor XI level are susceptible to development of an inhibitor following plasma replacement.

Aged↗
PubMed2003

NKT cell subsets in infection and inflammation.

We recently identified two stably expressed cell surface markers, IL-18R and ST2L, which are selectively expressed on T1/NK1 and T2/NK2 cells, respectively. Here we use these molecules in direct ex vivo analysis of PBMCs from patients with AIDS, psoriasis (PS) atherosclerosis and to show the importance of these markers as determinants of the functional dichotomy of lymphocyte subsets, in particular NKT. In a cohort of 22 HIV patients made up of a mixture of long term non-progressors, seroconvertors, progressors and asymptomatics, we found a clear NKT1 to NKT2 shift (P=0.001) in the HIV-infected individuals. We also show a predominance of NKT2 cells over NKT1 cells in the PBMCs of patients with mild to moderate PS (N=13, P=0.005) but not in atopic dermatitis or healthy controls. However, in patients (N=6) requiring surgery for aneurysm, a predominance of Type 1 (IL-18R(+)) NKT lymphocytes over NKT2 was detected among infiltrating lymphocytes isolated from atherosclerotic plaques. Our data therefore demonstrate that ST2L and IL-18R could serve as important determinants of the immune status of human diseases.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Markers of HIV-1 disease progression in individuals with haemophilia coinfected with hepatitis C virus: a longitudinal study.

BACKGROUND: Low serum albumin concentration is associated with short-term survival in individuals with HIV-1. However, few investigators have assessed whether individuals with a low serum albumin concentration have delayed progression to AIDS, or survive in the long term. We aimed to assess the relation between markers of liver function and progression to AIDS and death in individuals with haemophilia infected with HIV-1 and hepatitis C virus. METHODS: We measured markers of liver function and took CD4 counts every 3 months in 111 patients registered at the Royal Free Hospital Haemophilia Centre, London, UK. HIV RNA concentrations were measured yearly and then every 3-6 months from 1996. We used Cox's regression models to assess the independent prognostic value of these markers for AIDS and death. FINDINGS: As a fixed covariate, albumin concentrations measured shortly after HIV-1 seroconversion were associated with risk of AIDS (relative hazard 0.91 [95% CI 0.84-1.00], p=0.04) and death (0.89 [0.82-0.96], p=0.004) over a 15-year period. These findings were independent of the CD4 count and HIV-1 RNA concentration. As a time-updated covariate, after adjustment for CD4 count and HIV-1 RNA concentrations, albumin was not associated with progression to AIDS (0.96 [0.90-1.01], p=0.13), but was strongly associated with death (0.88 [0.84-0.93], p<0.0001) in the short term. INTERPRETATION: Low concentrations of albumin in individuals infected with HIV-1 could indicate a poor outlook and should therefore prompt concern at any stage of infection.

Acquired Immunodeficiency Syndrome↗
PubMed2002

The incidence of lymphoma in the UK haemophilia population between 1978 and 1999.

OBJECTIVE: To determine the incidence of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) in the UK haemophilia population during the 22 year period 1978-1999. DESIGN AND METHODS: An analysis of patient data included on the UK Haemophilia Centre Doctors' Organisation lymphoma register. The number of cases of NHL and HD occurring in HIV-positive and negative patients in each 3-year period were compared with the expected incidence in the general male population. RESULTS: Eighty-nine cases of lymphoma were identified. Seventy-two cases (81%) occurred in HIV-positive patients (67 NHL, five HD), and 17 cases (19%) in HIV-negative patients (nine NHL, eight HD). The incidence of NHL in the HIV-positive cohort was significantly increased, with a ratio of observed to expected cases of 83.92 (P < 0.001) in the period 1985-1996. The ratio reduced to 42.15 during the period 1997-1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART). There was a significant excess of HD in HIV-positive patients, with an observed to expected ratio of 10.50 between 1985 and 1999 (based on five cases, P < 0.001). During the whole observation period, there was a significant excess of HD in HIV-negative patients, with an observed to expected ratio of 2.66 (based on eight cases, P < 0.05). CONCLUSION: The incidence of lymphoma is significantly higher in HIV-positive UK haemophilia patients compared with HIV-negative individuals. Since the introduction of HAART, the incidence of lymphoma has tended to fall in the HIV-positive group.

HIV Infections↗