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Biomedical subjects

C A Lee

Publications and source records attributed to C A Lee.

At least 55 records · Page 3Linked to original sources
PubMed2001

Multiple myeloma and human immunodeficiency virus-1 (HIV-1) infection.

Multiple myeloma (MM) in three human immunodeficiency virus (HIV)-infected patients is reported. HIV infection predisposes to the development of high-grade B-cell lymphomas, but few cases of plasma cell tumours in association with HIV have been reported. The coincidence of HIV infection and neoplasia highlights the distinct roles of immunodeficiency and infection with herpesviridae, including HIV itself, in the pathogenesis of HIV-related tumours. In addition, a number of cytokines (e.g., interleukin-6 [IL-6]) and angiogenic factors (e.g., vascular endothelial growth factor [VEGF] and basic fibroblastic growth factor [bFGF]) may play a role in the initiation, maintenance, and progression of multiple myeloma (MM). Infection was the first clinical consideration to the cause of the illness in two of our HIV-seropositive patients. The diagnosis of MM may be difficult in patients with advanced HIV infection as they often have renal failure, bone marrow plasmacytosis, repeated infections, and polyclonal hypergammaglobulinaemia, due to HIV infection itself, opportunistic pathogens, and/or medication.

Adult↗
PubMed2001

Retrospective review of the management of elective surgery with desmopressin and clotting factor concentrates in patients with von Willebrand disease.

Limited data are available regarding optimal treatment with desmopressin (DDAVP) or intermediate-purity FVIII concentrates rich in VWF (CFCs) in patients with von Willebrand disease (VWD) who undergo planned surgery. We undertook a retrospective review over 10 years (1988-1997) and identified 27 patients treated with DDAVP for 35 surgical events and 38 patients who received CFCs for 68 elective surgical events. Tranexamic acid was usually added for mucosal surgery. The FVIII:C levels and the severity of surgery were used to determine the frequency and the doses of postoperative treatment. For major surgery the median pre- and post-operative doses of CFCs were 54 and 43 IU/kg, respectively, and for minor surgery the median doses varied between 34 and 52 IU/kg preoperatively and between 23 and 37 IU/kg postoperatively. The effectiveness of haemostasis was excellent in 32 events (91%) treated with DDAVP and in 56 events (82%) treated with CFCs. It is concluded that patients with VWD do not carry an increased operative risk if appropriate therapy is given.

Anesthesia, Obstetrical↗
PubMed2001

Assessing the relationship between productivity levels and severity of haemophilia.

In this study, we assessed whether severity of haemophilia was associated with levels of productivity. Productivity levels were assessed by sending a 'time-use' questionnaire to 228 individuals with mild, moderate and severe haemophilia. The results showed that, after adjusting for differences in age and HIV serostatus, there were no differences between individuals with severe and mild/moderate haemophilia in terms of completed levels of education, employment status, absenteeism from work over the previous 2 weeks, the number of hours each week spent performing unpaid tasks and how efficiently individuals performed these tasks. The data did suggest, however, that a significantly larger proportion of individuals with severe haemophilia (32%) required help from family or friends to perform routine household tasks each week than individuals with mild/moderate haemophilia (13%). In conclusion, it is possible that individuals with severe haemophilia have similar levels of productivity compared to individuals with mild/moderate haemophilia or that treatment with secondary prophylaxis has helped to reduce differences between the two patient groups.

Activities of Daily Living↗
PubMed2001

AraC/XylS family members, HilC and HilD, directly bind and derepress the Salmonella typhimurium hilA promoter.

During infection, Salmonella enterica serovar Typhimurium colonizes the small intestine of its hosts. This process requires a type III secretion system encoded by several genes on Salmonella pathogenicity island 1 (SPI1), a 40 kb region of DNA near centisome 63 of the Salmonella chromosome. SPI1 gene expression is controlled by a complex regulatory cascade. HilA, a member of the OmpR/ToxR family of transcriptional regulators, directly activates the expression of two SPI1 operons encoding type III apparatus components. hilA transcription is repressed by many environmental conditions and regulatory mutations. This repression requires an upstream repressing sequence (URS) located between -314 and -68 relative to the hilA transcription start site. The repressing activity of the URS is counteracted by two AraC/XylS family members named HilC and HilD. We show that HilC and HilD bind directly to the hilA promoter region in vitro. We also provide evidence that HilC and HilD bind to the same or overlapping sites within the URS. Our data are consistent with a model in which HilC and HilD derepress hilA expression by binding directly to the URS and counteracting its repressing effect in vivo.

Bacterial Proteins↗
PubMed2001

The HilA box and sequences outside it determine the magnitude of HilA-dependent activation of P(prgH) from Salmonella pathogenicity island 1.

Salmonella requires genes on the Salmonella pathogenicity island 1 (SPI1) for the intestinal phase of infection in several models of pathogenesis. In Salmonella enterica serovar Typhimurium, most SPI1 genes are arranged in operons that are coordinately regulated by the SPI1-encoded protein HilA. In the past, it has been shown that HilA directly activates two promoters on SPI1, P(invF-1) and P(prgH). P(invF-1) contains a HilA binding site, termed a HilA box, that is necessary and sufficient for activation by HilA. The HilA box is 17 nucleotides long and contains a direct repeat comprised of two hexamers separated by 5 nucleotides, centered at -45 relative to the start site of transcription. P(prgH) also contains a HilA box, and here we investigate its role at P(prgH). We have found that the HilA box is necessary, but not sufficient, for HilA-dependent activation of P(prgH). Instead, half-site-like hexamers outside the HilA box appear to be required for HilA-dependent activation of P(prgH), even though HilA binds to the HilA box in the absence of these hexamers. Thus, although HilA-dependent activation of P(invF-1) and P(prgH) coordinates the expression of the structural genes for a type III secretion apparatus and the effectors secreted by that apparatus, it is also possible that mechanisms not apparent under in vitro inducing conditions could separate the expression of invFGEABC-spaMNOPQRS-sicA-sipBCDA-iacP-sicP-sptP and prgHIJK-orgABC.

Arabinose↗
PubMed2001

Roles of hilC and hilD in regulation of hilA expression in Salmonella enterica serovar Typhimurium.

Sequences between -332 and -39 upstream of the hilA promoter are required for repression of hilA. An unidentified repressor is thought to bind these upstream repressing sequences (URS) to inhibit hilA expression. Two AraC-like transcriptional regulators encoded on Salmonella pathogenicity island 1 (SPI1), HilC and HilD, bind to the URS to counteract the repression of hilA. The URS is required for regulation of hilA by osmolarity, oxygen, PhoP/PhoQ, and SirA/BarA. Here, we show that FadD, FliZ, PhoB, and EnvZ/OmpR also require the URS to regulate hilA. These environmental and regulatory factors may affect hilA expression by altering the expression or activity of HilC, HilD, or the unknown repressor. To begin investigating these possibilities, we tested the effects of environmental and regulatory factors on hilC and hilD expression. We also examined hilA regulation when hilC or hilD was disrupted or expressed to a high level. Although hilC is regulated by all environmental conditions and regulatory factors that modulate hilA expression, hilC is not required for the regulation of hilA by any conditions or factors except EnvZ/OmpR. In contrast, hilD is absolutely required for hilA expression, but environmental conditions and regulatory factors have little or no effect on hilD expression. We speculate that EnvZ/OmpR regulates hilA by altering the expression and/or activity of hilC, while all other regulatory conditions and mutations regulate hilA by modulating hilD posttranscriptionally. We also discuss models in which the regulation of hilA expression is mediated by modulation of the expression or activity of one or more repressors.

Bacterial Outer Membrane Proteins↗
PubMed2001

Liquid chromatography-mass spectrometry and liquid chromatography-NMR characterization of in vitro metabolites of a potent and irreversible peptidomimetic inhibitor of rhinovirus 3C protease.

In vitro metabolism of AG7088 [trans-(4S,2'R,5'S,3"'S)-4-[2'-4-(4-fluorobenzyl)-6'-methyl-5'-[(5"-methylisoxazole-3"-carbonylamino]-4-oxoheptanoylamino]-5-(2"'-oxopyrrolidin-3-"'-yl)pent-2-enoic acid ethyl ester] was studied in liver microsomes isolated from mice, rats, rabbits, dogs, monkeys, and humans. The structures of the metabolites were characterized by liquid chromatography (LC)-tandem mass spectrometry and LC-NMR methods. Hydrolysis of the ethyl ester to produce metabolite M4 (AG7185) is the predominant pathway in all species, with the greatest activity observed in rodents and rabbits, followed by monkeys, dogs, and humans. Several hydroxylation products were identified as minor metabolites, including diastereomers M1 and M2, with a hydroxy group at the P1-lactam moiety, and M3, with a hydroxy group at the methyl position of the methylisoxazole ring. Rodent and rabbit liver microsomes formed almost exclusively the acid metabolite M4 (AG7185), with very little hydroxylated metabolites, whereas monkey liver microsomes formed more secondary metabolites (i.e., acid analogs of the hydroxylated metabolites). The overall metabolic profile of AG7088 formed in dog liver microsomes closely resembled that of human liver microsomes; therefore, this species may be the most appropriate animal model relative to humans for exposure to AG7088 and its metabolites.

3C Viral Proteases↗
PubMed2000

A secreted Salmonella protein induces a proinflammatory response in epithelial cells, which promotes neutrophil migration.

In response to Salmonella typhimurium, the intestinal epithelium generates an intense inflammatory response consisting largely of polymorphonuclear leukocytes (neutrophils, PMN) migrating toward and ultimately across the epithelial monolayer into the intestinal lumen. It has been shown that bacterial-epithelial cell interactions elicit the production of inflammatory regulators that promote transepithelial PMN migration. Although S. typhimurium can enter intestinal epithelial cells, bacterial internalization is not required for the signaling mechanisms that induce PMN movement. Here, we sought to determine which S. typhimurium factors and intestinal epithelial signaling pathways elicit the production of PMN chemoattractants by enterocytes. Our results suggest that S. typhimurium activates a protein kinase C-dependent signal transduction pathway that orchestrates transepithelial PMN movement. We show that the type III effector protein, SipA, is not only necessary but is sufficient to induce this proinflammatory response in epithelial cells. Our results force us to reconsider the long-held view that Salmonella effector proteins must be directly delivered into host cells from bacterial cells.

Actins↗
PubMed2000

Pre-AIDS mortality and its association with HIV disease progression in haemophilic men, injecting drug users and homosexual men.

OBJECTIVE: To study pre-AIDS mortality and its association with HIV disease progression in different exposure groups with known intervals of HIV seroconversion. DESIGN AND METHODS: The type and rate of pre-AIDS deaths were assessed in 111 HIV-infected haemophilic men followed in London, and 118 injecting drug users and 158 homosexual men followed in Amsterdam. In each group, the association between CD4+ T-cell count, HIV RNA and pre-AIDS mortality was studied using proportional hazards analysis. RESULTS: By 10 years after seroconversion 7.3% of the haemophilic men had died without AIDS and 38.2% had developed AIDS. These figures were 20.2 and 30.5% for injecting drug users, and 8.0 and 55.0% for homosexual men. The major causes of pre-AIDS mortality appear to differ in the three exposure groups. The risk of pre-AIDS death tended to increase with decreasing CD4 cell count and increasing HIV RNA levels in injecting drug users and homosexual men. In men with haemophilia the associations were less obvious, although the log-transformed CD4 cell count was predictive for pre-AIDS death. CONCLUSIONS: Pre-AIDS deaths occur and are at least partially related to HIV disease progression irrespective of how individuals became infected. Because of the longer life expectancy due to highly active antiretroviral therapy (HAART), pre-AIDS deaths are likely to show a further increase. Methods to incorporate these intermediate outcomes should be considered in the estimation of the size of the HIV epidemic and in the survival analysis of HIV-infected individuals. Prevention and treatment of non-AIDS infections, especially hepatitis C virus infection, and cancers will become increasingly important in HIV-infected individuals. The interaction between these therapies and HAART should be closely monitored.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Two decades of HIV infection in a cohort of haemophilic individuals: clinical outcomes and response to highly active antiretroviral therapy.

OBJECTIVES: Many haemophilic individuals infected with HIV died before receiving antiretroviral therapy (ART). Most who remain alive are chronically infected with hepatitis C virus (HCV), which has implications for their prognosis and choice of ART. The clinical status of a cohort of HIV-positive haemophilic men is reported together with their response to highly active antiretroviral therapy (HAART). DESIGN: Longitudinal cohort study. SETTING: A comprehensive care haemophilia centre. PATIENTS: A group of 111 haemophilic men who seroconverted to HIV in the period 1979 to 1985. RESULTS: The cohort has been followed since 1979. By 30 April 1999, 57 of the 111 men had developed AIDS and 65 had died: Kaplan-Meier rates of 57.0% [95% confidence interval (CI) 46.9-67.0) and 65.1% (95% CI 52.7-77.4) by 19.5 years, respectively. AIDS rates have declined since 1997 but death rates have remained high, largely owing to deaths from non-HIV-related causes. Thirty-five patients remain alive and under follow-up at the clinic. The 28 men who had received ART had lower CD4 cell counts than the seven patients who had not received ART, but the two groups were otherwise similar. In total, 21 patients are known to have started HAART while under care at the centre. By 10-12 months after starting HAART, viral loads dropped by 2.06 log10 copies/ml and CD4 cell counts increased by 60 x 10(6) cells/l. In 10 out of 18 patients with viral loads initially > 400 copies/ml, a viral load below this level was attained; four had changed therapy at the time. CONCLUSIONS: While the decision to initiate HAART in haemophilic men should be made carefully because of the possible adverse events, our results suggest that a good response rate was achieved in this group of men.

Anti-HIV Agents↗
PubMed2000

Cytomegalovirus seropositivity and human immunodeficiency virus type 1 RNA levels in individuals with hemophilia.

The effect of cytomegalovirus (CMV) seropositivity on the course of human immunodeficiency virus (HIV) type 1 RNA levels and HIV disease progression was assessed in a cohort of 109 hemophilic men infected with HIV-1 for a median of 12.7 years. There was no evidence of higher HIV RNA levels in the first year after HIV seroconversion (P=. 88) or faster rates of increase over infection (P=.20) in the 59 CMV-seropositive individuals than in the CMV-seronegative individuals. In univariate analyses, CMV seropositivity was associated with significantly faster progression to AIDS and death (relative hazards of 1.58 and 2.22, respectively). These effects were unchanged after adjusting for the RNA level, but they were reduced after adjusting for the CD4 cell count, age at seroconversion, and calendar year of follow-up. Thus, the effect of CMV seropositivity on clinical progression remains significant in this cohort but does not appear to be mediated through an increase in HIV RNA levels.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Course of viral load throughout HIV-1 infection.

HIV-1 RNA levels are routinely monitored as part of patient management. However, little is known about the course of HIV-1 RNA levels over the entire period of infection. The aim of this study was to investigate the course of HIV-1 RNA levels in a cohort of men with hemophilia who were observed for up to 17 years after HIV-1 seroconversion, and to assess the risk of HIV disease progression at any HIV-1 RNA level. Viral loads were measured on annual stored serum samples in 107 men with hemophilia A using the Roche Amplicor Monitor assay with non-B primers. On average, HIV-1 RNA levels increased significantly by 0.11 log10 per year over the course of HIV infection. This rate of increase was significantly faster in those who developed AIDS or died over the subsequent 12 to 17 year period, and in those who were older at HIV- 1 seroconversion. The risk of developing AIDS and death remained low when the HIV-1 RNA level was below 4 log10 copies/ml, but increased rapidly thereafter, supporting current guidelines for the initiation of antiretroviral therapy after the viral load has exceeded this level.

CD4 Lymphocyte Count↗
PubMed2000

Type 1 von Willebrand disease - a clinical retrospective study of the diagnosis, the influence of the ABO blood group and the role of the bleeding history.

This clinical retrospective study investigated the difficulties in diagnosing type 1 von Willebrand disease (VWD). A total of 246 patients previously diagnosed with type 1 VWD were reclassified into 'possible' type 1 VWD (patients with low levels of VWF adjusted for the blood group and either a significant bleeding history or family history) and 'definite' type 1 VWD, requiring low levels of von Willebrand factor (VWF), a bleeding history and inheritance. On reclassification, only 144/246 (59%) patients had low VWF levels adjusted for blood group, 88/246 (36%) patients met all the criteria for 'definite' type 1 VWD and 51/246 (21%) patients were 'possible' type 1 VWD. A significant proportion of patients, 102/246 (42%), remained an indeterminate group with blood type O, VWF levels between 35 and 50 U/dl and personal and/or family bleeding history. This subgroup might require reclassification as 'not VWD'. However, a similar bleeding tendency was found in two matched groups of patients of blood groups O and non-O and VWF levels between 35 and 50 U/dl. These results suggest that the use of ABO adjusted ranges for VWF levels might not be essential for diagnosis, because bleeding symptoms may depend on the VWF level regardless of the ABO type. Of the diagnostic criteria, the bleeding history was of prime importance in the clinical decision to diagnose and treat type 1 VWD. These observations could help in the reconsideration of how the criteria for diagnosing type 1 VWD could be adjusted in order to maximize their clinical relevance.

ABO Blood-Group System↗
PubMed2000

The effects of the 32-bp CCR-5 deletion on HIV transmission and HIV disease progression in individuals with haemophilia.

The chemokine receptor CCR5 is an important co-receptor for cell fusion. A 32-bp deletion of the CCR5 gene, leading to complete absence of functional CCR5 expression, has been associated with resistance to human immunodeficiency virus (HIV) infection in homozygotes and slower HIV disease progression in heterozygotes. The objectives of this study were to assess the effects of this 32-bp deletion on transmission of HIV infection and on HIV disease progression in haemophilic individuals. Six HIV-negative patients from our centre, known to have been exposed to infectious factor VIII concentrates, have been analysed. Three of these patients possess the CCR5 32-bp deletion, two patients being homozygous. The presence of the CCR5 32-bp gene deletion has also been analysed in 71 HIV-positive patients. In this group of patients, there was a lower than expected incidence of the 32-bp deletion. Those who possess the 32-bp deletion progress to AIDS more slowly than those who do not (P = 0.05, log-rank test). Rates of CD4 loss were slower in those heterozygous for the gene deletion. We confirm that heterozygosity for the 32-bp gene deletion in CCR5 is partially protective against initial infection with HIV. In those heterozygous patients who became infected with HIV, disease progression was slower.

Acquired Immunodeficiency Syndrome↗