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Biomedical subjects

A Timms

Publications and source records attributed to A Timms.

18 recordsLinked to original sources
PubMed2001

Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci.

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing "suggestive" or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.

Chromosome Mapping↗
PubMed2000

A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation.

Busulfan has been previously only available in an oral formulation due to its poor water solubility. We report the results of a phase I study of multiple escalating doses of intravenous busulfan (Spartaject Busulfan, Orphan Europe, Paris, France) for myeloablation prior to stem cell transplantation (SCT) in 12 patients with chronic myeloid leukemia, acute myeloid leukemia or acute lymphocytic leukemia. One patient received allogeneic SCT; the other 11 patients received autologous SCT. The first six patients received i.v. busulfan diluted in 50 ml of 0.9% normal saline and the last six patients received busulfan in a 500-ml 5% dextrose solution. All patients experienced profound myelosuppression and all but one demonstrated hematopoietic engraftment. Toxicity was mild or moderate and there were no toxic deaths attributable to busulfan. Of note, there were no cases of veno-occlusive disease of the liver. Busulfan plasma concentrations were determined by gas chromatography with electron capture detection and showed little intrapatient variability. In most cases there was no significant difference between the first and last dose PK parameters. These data suggest that dose adjustment based on first dose PK data could allow uniformity of busulfan dosing for patients receiving SCT.

Acute Disease↗
PubMed1998

Effect of endogenous carotenoids and defective RpoS sigma factor on spontaneous mutation under starvation conditions in Escherichia coli: evidence for the possible involvement of singlet oxygen.

Under starvation conditions, a variety of stationary phase genes are up-regulated under the control of the stationary phase sigma factor RpoS including at least two peroxidases and a protective DNA binding protein Dps. Previous work suggested that the reversion to prototrophy of certain amino acid auxotrophs of Escherichia coli that occurs when the bacteria are starved of a required amino acid results from the accumulation of oxidative damage to guanine residues in DNA. We report here that three strains lacking RpoS are indistinguishable from wild type in their ability to undergo this starvation-associated mutation, suggesting that basal levels of catalase activity are more than adequate in these strains, and that the induction of catalases and other proteins controlled by rpoS does not contribute to the protection of the DNA, at least in cells starved in early stationary phase. In comparison, the introduction of a plasmid specifying the production of singlet oxygen scavengers (carotenoids) in stationary phase cells led to a roughly twofold reduction in mutant yield. The results suggest that singlet oxygen may be an important endogenously produced mutagen in resting cells.

Amino Acids↗
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↗
PubMed1996

Serum beta 2-microglobulin at HIV-1 seroconversion as a predictor of severe immunodeficiency during 10 years of followup.

In order to examine the relevance of early immune activation to the long-term course of HIV infection, we evaluated the ability of the serum beta 2-microglobulin level measured in 63 haemophiliacs on average 4.9 months from HIV seroconversion to predict the rate of development of server immunodeficiency (CD4) lymphocyte count 50/mm3) or AIDS over the following 10 years. Patients with higher beta 2-microglobulin values tended to develop severe immunodeficiency/AIDS more rapidly than those with lower levels (relative risk 1.68 per 1 mg/L increase; 95% CI 1.26-2.26; p = 0.0004). Older patients also progressed more rapidly, and these two factors acted independently (relative risk 1.65 per 1 mg/L increase; 95% CI 1.21-2.72; p = 0.002 for beta 2-microglobulin and 1.22 per 10 years; 95% CI 1.01-1.48; p = 0.04 for age). These results provide further evidence that the long-term course of HIV infection can, to some extent, be predicted soon after infection. Older patients with high beta 2-microglobulin levels warrant close monitoring and consideration for early antiretroviral therapy.

Adolescent↗
PubMed1996

Increased numbers of primed activated CD8+CD38+CD45RO+ T cells predict the decline of CD4+ T cells in HIV-1-infected patients.

OBJECTIVE: To look for surrogate markers in HIV-1 infection that can predict the decline of CD4+ T cells. METHODS: Multiparameter flow cytometric analyses of CD8+ lymphocytes were performed. These cells were investigated for their expression of the activation marker CD38+ within the naive (CD45RA+) and primed (CD45RO+) subsets. Serial CD4 counts were plotted for each patient and the straight line that best fitted was obtained using least squares regression. Differences in rate of decline were tested using analysis of variance, after each patient was weighted by the reciprocal of the variance. RESULTS: Baseline levels of percentages of CD8+CD38+ T lymphocytes predict the CD4 decline in HIV-1-infected patients. Within the CD8+ subset, the primed CD8+CD38+CD45RO+ population was responsible for this prediction. Conversely, the naive CD8+CD38+CD45RA+ population was not predictive. Patients who initially showed a percentage of CD8+CD38+ T lymphocytes above the median (> 25%) had a more marked decline in CD4+ T cells when compared to individuals with percentages of CD8+CD38+ T lymphocytes below the median value (79.3 and 21.2 x 10(6)/l mean CD4 cell decline per year, respectively). Similarly, percentages of CD8+CD38+CD45RO+ T cells above the median value (> 7%) were also associated with a more rapid decline (69.4 and 14.2 x 10(6)/l mean CD4+ cell decline per year). These results were statistically significant after adjustment for the baseline CD4 count and beta 2-microglobulin levels. CONCLUSIONS: Percentages of activated CD8+ cells expressing CD38+ can predict the rate of decline (slope) of the CD4+ T cells. This resides in the CD45RO+ primed population. An early prediction of the CD4+ slope will allow the clinician to target treatment to those patients that are most likely to benefit.

ADP-ribosyl Cyclase↗
PubMed1994

Beta-2 microglobulin as a predictor of prognosis in HIV-infected men with haemophilia: a proposed strategy for use in clinical care.

Whilst the prognostic value of serum beta-2 microglobulin (s-beta 2m) is well documented, the lack of a simple strategy for its use means that it is rarely ever measured in clinical practice. The prognosis associated with s-beta 2m at two different points in HIV infection, as defined by the CD4 count, was studied in a cohort of 111 men with haemophilia registered at the Royal Free Hospital School of Medicine, London. At CD4 counts of 0.5 and 0.2 x 10(9)/l, a raised s-beta 2m level was significantly associated with an increased risk of developing AIDS (P = 0.002 and 0.022 respectively, adjusted for the patient's age). Kaplan-Meier progression rates to AIDS by 4.5 years after a CD4 count of 0.5 x 10(9)/l were 57% (95% CI 32-82%) in those with s-beta 2m levels of 3 mg/l or more, but 20% (95% CI 4-36%) in those with s-beta 2m levels of less than 3 mg/l. By 3.5 years after a CD4 count of 0.2 x 10(9)/l, Kaplan-Meier progression rates to AIDS were 75% (95% CI 52-98%) in those with s-beta 2m levels of 3.8 mg/l or more, and 47% (95% CI 29-66%) in those with s-beta 2m levels of less than 3.8 mg/l. In the absence of acute viral infections, a raised s-beta 2m indicates those who will tend to progress to AIDS more rapidly than those with lower s-beta 2m levels and the same CD4 count. S-beta 2m levels in general are likely to be higher in haemophilia patients than in other, non-haemophilic risk groups. Whilst care should be taken, therefore, when applying our chosen cut-off values to non-haemophilic patients, our findings support the introduction of prophylaxis and antiviral therapies at a higher CD4 count in those with raised s-beta 2m levels relative to other patients in the same risk group whilst delaying treatment in those with lower CD4 counts, but relatively normal s-beta 2m levels.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis.

With the advent of standard flow cytometric methods using two-colour fluorescence on samples of whole blood, it is possible to establish the ranges of CD3, CD4 and CD8 T lymphocyte subsets in the routine laboratory, and also to assist the definition of HIV-1-related deviations from these normal values. In 676 HIV-1-seronegative individuals the lymphocyte subset percentages and absolute counts were determined. The samples taken mostly in the morning. The groups included heterosexual controls, people with various clotting disorders but without lymphocyte abnormalities as well as seronegative homosexual men as the appropriate controls for the HIV-1-infected groups. The stability of CD4% and CD8% values was demonstrated throughout life, and in children CD4 values less than 25% could be regarded as abnormal. The absolute counts of all T cell subsets decreased from birth until the age of 10 years. In adolescents and adults the absolute numbers (mean +/- s.d.) of lymphocytes, CD3, CD4 and CD8 cells were 1.90 +/- 0.55, 1.45 +/- 0.46, 0.83 +/- 0.29 and 0.56 +/- 0.23 x 10(9)/l, respectively. In patients with haemophilia A and B the mean values did not differ significantly. In homosexual men higher CD8 levels were seen compared with heterosexual men and 27% had an inverted CD4/CD8 ratio but mostly without CD4 lymphopenia (CD4 less than 0.4 x 10(9)/l). However, some healthy uninfected people were 'physiologically' lymphopenic without having inverted CD4/CD8 ratios. When the variations 'within persons' were studied longitudinally over a 5-year period, the absolute CD4 counts tended to be fixed at different levels. As a marked contrast, over 60% of asymptomatic HIV-1+ patients exhibited low CD4 counts less than 0.4 x 10(9)/l together with inverted CD4/CD8 ratios. Such combined changes among the heterosexual and HIV-1-seronegative homosexual groups were as rare as 1.4% and 3%, respectively. For this reason, when the lymphocyte tests show less than 0.4 x 10(9)/l CD4 count and a CD4/CD8 ratio of less than unity, the individuals need to be investigated further for chronicity of this disorder, the signs of viral infections such as HIV-1 and other causes of immunodeficiency.

Adolescent↗
PubMed1991

Serial CD4 lymphocyte counts and development of AIDS.

Low CD4 lymphocyte counts are associated with increased risk of progression to AIDS in human immunodeficiency virus (HIV) infection. We investigated the extent to which the timing of progression to AIDS can be explained solely in terms of decline of the CD4 lymphocyte count in 111 haemophiliacs followed for up to 11 years since infection with HIV. A median of 10 CD4 lymphocyte counts were made per patient. By applying a simple linear model for the decline in CD4 lymphocyte counts over time, we estimated the date of development of AIDS in 96 patients who had at least 5 determinations. 84% (81 of 96) of patients were correctly classified as to development of AIDS before Jan 1, 1990 (p less than 0.0001), with this model. The results suggest that differences in the time at which patients with HIV will progress to AIDS can largely be explained by differences in rates of decline of CD4 lymphocyte counts.

Acquired Immunodeficiency Syndrome↗
PubMed1991

More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts.

The tendency for older people with HIV infection to progress more rapidly to AIDS than younger people was studied in a group of 111 anti-HIV-positive haemophiliacs followed for up to 10 years from seroconversion. After 7 years of seropositivity, those aged over 30 years at the time of the first positive anti-HIV test had a cumulative progression rate to AIDS of 50%, compared with only 12% for those aged 10-19 years (Kaplan-Meier estimates). Overall, the relative risk of developing AIDS by any given time after seroconversion was 1.45 for each 10 year increase in age (p = 0.002; 95% confidence limits of 1.15, 1.85; Cox proportional hazards model). After adjustment for the CD4+ T-cell count (median of 10 count measurements per patient, fitted as a time-dependent covariate), the relative risk fell to 1.31 but remained statistically significant (p less than 0.05; 95% confidence limits of 1.03, 1.67). This implies that older people may be at higher risk of progression than their younger counterparts, even if their CD4+ T-cell counts are the same. Hence, prophylaxis against opportunistic infections may be indicated at higher CD4+ T-cell counts in older people than in younger people.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Inhibition of alloresponsive naive and memory T cells by CD7 and CD25 antibodies and by cyclosporine.

Human naive and memory T cells can be isolated from each other by their CD45RA and CD45RO expression, respectively. This enables the assessment of their differential sensitivities to immunosuppressive agents for the first time. We have investigated the ability of cyclosporine or CD7 and CD25 antibodies to selectively block alloantigen stimulated naive and memory T cells in vitro. CD7 antibodies blocked the proliferation of naive (P less than 0.025) but not memory T cells in a primary MLR. CD25 antibody inhibited both naive and memory subsets but a significantly greater effect was found on the memory T cells (P less than 0.005). The constitutive CD7 and CD25 antigen expression on resting naive or memory T cells was related to the inhibitory activities of these antibodies on both subsets. Accordingly, naive T cells expressed more CD7 antigen than memory cells while memory T cells displayed low levels of CD25 antigen that was absent from naive populations before activation. Cyclosporine, like CD25 antibody, inhibited both subsets in a primary MLR but had a greater effect on memory cells (P less than 0.02). Memory T cells, therefore, are more dependent than naive cells on IL-2 for proliferation. There was great individual variation in the ability of CsA to block the MLR. The simultaneous addition of CD25 or CD7 antibody together with CsA, however, enhanced the MLR inhibition as the effects of all three were additive. This suggested interference by these agents at different points during T cell activation. Thus, in CsA sensitive individuals, one-tenth of the optimal CsA concentration together with CD25 antibody maintained maximum immunosuppression in vitro. These results demonstrate the possibility of using CD7 and CD25 antibodies for selective inhibition of naive or memory T cells and also the possibility of augmenting the inhibition of and reducing the CsA concentration required for clinically effective immunosuppression.

Antibodies, Monoclonal↗
PubMed1990

The development of primed/memory CD8+ lymphocytes in vitro and in rejecting kidneys after transplantation.

In normal individuals, 80 +/- 5% of circulating CD8+ T cells express CD45RA, and 20 +/- 7% of these cells express CD45R0 antigens. After activation, CD8+ cells expressing CD45RA decrease to 56-67% while those expressing CD45R0 increase to 38-67%. Although precursors of alloantigen-specific cytotoxic T cells were found in both CD8+, CD45RA+ and CD8+, CD45R0+ subsets, the specific effector cells were exclusively CD8+, CD45R0. Allospecific cytotoxic CD8+ clones were also entirely CD45R0+. A lectin-dependent cytotoxic (LDC) assay unmasked a hierarchy of killing after alloactivation which was CD8+, CD45R0+ greater than CD8+, CD45RA+ greater than CD4+, CD45R0+ greater than CD4+, CD45RA+. The phenotype of CD8+ T cells in rejecting kidneys was similar to in vitro alloantigen-activated CD8+, CD45R0+ cells and cytotoxic CD8+ clones. Firstly there was an increase in the relative proportions of CD45R0+ (60 +/- 8%) and a decrease in CD45RA+ (35 +/- 10%) CD8+ cells relative to circulating CD8+ subsets. In the rejecting grafts, 34 +/- 9% of the CD8+ cells were also DR+ indicative of recent activation. Furthermore, 16% (range 4-35%) of rejecting CD8+ cells were Ki67+ suggesting that these cells were proliferating. Finally, 17% (range 4-53%) of T cells in rejecting kidneys simultaneously expressed both CD45RA and CD45R0 markers. These results show that in vitro alloantigen-activated CD8+, CD45R0+ cells represent a primed/memory cytotoxic population. In addition, they provide indirect evidence that a proportion of CD8+ cells in rejecting kidneys were actively switching from a naive to a memory phenotype in vivo in a manner analogous to that in vitro.

Antibodies, Monoclonal↗
PubMed1989

Prediction of progression to AIDS by analysis of CD4 lymphocyte counts in a haemophilic cohort.

Serial CD4 lymphocyte counts were recorded in 112 anti-HIV-positive haemophiliacs who were followed for up to 8 years after seroconversion. The patients remained at low risk of developing AIDS until their CD4 lymphocyte count fell to 0.25 X 10(9)/l. From this point, the risk increased as their count approached zero. Using this result and on the assumption (which is evaluated) that the underlying trend over time in CD4 lymphocyte counts is linear, the predicted rate of progression to AIDS was calculated for the cohort. It was estimated that 73% (95% confidence limits 60-86%) of the cohort will develop AIDS within 15 years of HIV-seropositivity. During 8 years of follow-up, this cohort had shown similar rates of progression to AIDS to other cohorts--haemophilic and otherwise--suggesting that this estimate may well have general applicability. The method described could be used to plan the provision of health-care resources for groups of anti-HIV-positive patients as it allows the number of new cases of AIDS to be predicted year by year, even when the patients' dates of seroconversion are unknown.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Cellular events during memory T-cell activation in vitro: the UCHL1 (180,000 MW) determinant is newly synthesized after mitosis.

After T-cell activation, a switch of leucocyte common antigen (LCA) expression occurs which is detected by the disappearance of CD45R and the appearance of UCHL1 positivity. Upon activation of CD45R+ T cells by phytohaemagglutinin (PHA), the IL-2 receptor (IL-2R) develops at 15 hr and blast cells enter the S phase at 20 hr, while remaining UCHL1-. At 40 hr, mitotic cells continue to express CD45R determinants, but weak UCHL1 reactivity is now detectable on 15-20% of these cells. By inhibiting the separation of daughter cells with cytochalasin B, it can be demonstrated that the UCHL1 antigen is newly synthesized in the Golgi apparatus before insertion into the membrane after the first mitosis. At 65 hr after activation, 80% of proliferating cells are UCHL1+. T cells undergo a similar development during allogeneic activation, and specific alloresponsive cells, tested in secondary mixed lymphocyte reaction (MLR), become greatly enriched among the proliferating UCHL1+ cells. Conversely, after a primary MLR, residual CD45R+ T cells are unresponsive to the original stimulus but can still proliferate in response to unrelated alloantigens. These results clarify both the time-course of the acquisition of UCHL1 antigen during the proliferative cycle of activated T cells, and indicate the shift of antigen responsive T-cell populations from the CD45R+ to the UCHL1+ pool.

Cells, Cultured↗
PubMed1988

Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells.

A group of mAb recognizing the 200- and/or 220-kDa determinants (CD45R) of the leukocyte common Ag such as 2H4, WR16, MD4.3, and SN130 cross-block each other showing that they recognize a closely related epitope. The antibody UCHL1 reacts with a 180-kDa determinant of the leukocyte common Ag and exhibits a reciprocal T subset distribution pattern to the CD45R group. Peripheral blood T cells were 40% positive for UCHL1 and 58 to 65% positive for the CD45R antibodies; less than 1% of cells stained for both. On activation of CD45R+,UCHL1- T cells by PHA, up to 40% of cells became positive for both CD45R and UCHL1 by day 3. By day 7, CD45R+,UCHL1- cells fell from 90 to less than 21% whereas UCHL1+,CD45R- cells rose from 2 to 93%. Conversely, PHA-stimulated UCHL1+,CD45R- cells remained UCHL1+,CD45R- during the 7 days in culture showing that phenotypic change was unidirectional from CD45R+ to UCHL1+. In primary allogeneic mixed lymphocyte reactions, activated CD45R+ T cells also showed a change to UCHL1+. When these cells were rechallenged by the original alloantigen, the UCHL1+ cells showed 7- to 20-fold greater proliferation than the CD45R+ cells on day 3 after rechallenge. The recovery of virtually all alloantigen induced secondary proliferative response in the UCHL1+,CD45R- T cell population suggests that UCHL1 identifies a primed population of T cells which may include memory cells.

Antibodies, Monoclonal↗
PubMed1988

Autologous bone marrow transplantation in acute lymphoblastic leukemia--preclinical immunologic studies.

Immunologic aspects of autologous bone marrow transplantation (ABMT), immunodiagnosis, patient monitoring, and the purging of bone marrow have been studied in individual patients. It was demonstrated that the most sensitive method for detecting lymphoid cells which show the phenotypes of ALLs of B or T lineage was double immunofluorescence staining for nuclear terminal transferase (TdT) and B or T lineage antigens. With the help of these sensitive tests in the presence of rabbit complement (C'), MAbs CD10 (RFAL3 of IgM class), CD19 (SB4 of IgM class), and their cocktail were capable of eliminating greater than 3 log blast cells of B lineage ALL in 84%, 75.5%, and 90% of cases, respectively. The same reagents lysed 26.8%, 0%, and 45% of blasts in the presence of human C'. CD7 (RFT2, IgG2) eliminated greater than 3 log T-ALL blast cells in 73% of cases. The proliferative fractions of leukemic blasts were also TdT+ and sensitive to lysis with MAb and C'. On the basis of these observations MABs were selected for purging in 36 patients undergoing ABMT in first remission (10 patients considered to be at a high risk of relapse), second and third remissions (23 and 2 patients), and without entering into remission (1 patient). The efficacy of eliminating the MAb-reactive cells from the bone marrow inoculum was also documented in five patients. By the use of sensitive immunologic assay (TdT/cytoplasmic CD3 double staining) in patients with T-ALL, no residual leukemia (less than 10(-4] could be detected at the time of transplantation. Following an observation period of 5-34 months, 24 of the 36 patients are alive and well with no procedure-related mortality.

Antibodies, Monoclonal↗
PubMedDate not supplied

Prognosis in malignant glioma: a retrospective study of biopsy specimens by flow cytometry.

The DNA ploidy of a series of 78 gliomas has been estimated by flow cytometry using cell suspensions prepared from paraffin embedded material. Apart from two oligodendrogliomas the tumours were all astrocytomas. Forty-nine (63%) tumours were found to have a diploid DNA distribution and 29 (37%) an aneuploid DNA distribution. The two oligodendrogliomas were both DNA aneuploid. No correlation was found between DNA ploidy and histological grade or DNA ploidy and survival. Both ploidy groups appear to have responded equally to therapy. In this study the factors associated with a short survival were advancing age and the presence of vascular endothelial proliferation, while the DNA ploidy and the cytological features do not appear as useful in predicting survival when examining biopsy material.

Adult↗