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Biomedical subjects

Andrew Phillips

Publications and source records attributed to Andrew Phillips.

At least 19 recordsLinked to original sources
PubMed2007

Temporal trends in postseroconversion CD4 cell count and HIV load: the Concerted Action on Seroconversion to AIDS and Death in Europe Collaboration, 1985-2002.

OBJECTIVE: To determine whether early postseroconversion CD4 cell counts and human immunodeficiency virus (HIV) loads have changed over time. METHODS: Our analysis was based on 22 cohorts of people with known dates of seroconversion from Europe, Australia, and Canada (Concerted Action on Seroconversion to AIDS and Death in Europe Collaboration). We focused on individuals seroconverting between 1985 and 2002 who had the first CD4 cell count (n=3687) or HIV load (n=1584) measured within 2 years of seroconversion and before antiretroviral use. Linear regression models were used to assess time trends in postseroconversion CD4 cell count and HIV load. Trends in time to key thresholds were also assessed, using survival analysis. RESULTS: The overall median initial CD4 cell count was 570 cells/ microL (interquartile range [IQR], 413-780 cells/ microL). The median initial HIV load was 35,542 copies/mL (IQR, 7600-153,050 copies/mL; on log(10) scale, 3.9-5.2 log(10) copies/mL). The postseroconversion CD4 cell count changed by an average of -6.33 cells/ microL/year (95% confidence interval [CI], -8.47 to -4.20 cells/ microL/year; P<.001), whereas an increase was observed in log(10) HIV load (+0.044 log(10) copies/mL/year; 95% CI, +0.034 to +0.053 log(10) copies/mL/year). These trends remained after adjusting for potential confounders. The probability of progressing to a CD4 cell count of <500 cells/ microL by 24 months from seroconversion increased from 0.66 (95% CI, 0.63-0.69) for individuals who seroconverted before 1991 to 0.80 (95% CI, 0.75-0.84) for those who seroconverted during 1999-2002. CONCLUSION: These data suggest that, in Europe, there has been a trend of decrease in the early CD4 cell count and of increase in the early HIV load. Additional research will be necessary to determine whether similar trends exist in other geographical areas.

Adult↗
PubMed2007

Prevalence and predictors of antiretroviral drug resistance in newly diagnosed HIV-1 infection.

OBJECTIVES: To determine prevalence and predictors of antiretroviral drug resistance in newly diagnosed individuals with HIV-1 infection, using a systematic approach to avoid selection bias. METHODS: Plasma samples from all persons diagnosed HIV-1 seropositive at a large London centre between April 2004 and February 2006 underwent sequencing of HIV-1 reverse transcriptase (RT) and protease genes. Subtype was assigned by phylogenetic analysis. Resistance was scored according to the IAS-USA list (2005) modified to include T215revertants and exclude isolated E44D or V118I and minor protease mutations. Recent seroconversion was identified by HIV antibody avidity testing. RESULTS: The cohort of 239 included 169 (70.7%) males, 126 (52.7%) homosexuals, 118 (49.5%) persons of white ethnicity and 144 (60.0%) persons born outside the UK. Subtypes included B 134 (56.1%), C 46 (19.2%), A 17 (7.1%), other non-B 42 (17.6%). The prevalence of resistance mutations was 17/239 (7.1%; 95% confidence interval 4.5-11.1%), comprising 10/239 (4.2%) nucleoside/nucleotide RT inhibitor (NRTI); 4/239 (1.7%) non-nucleoside RT inhibitor (NNRTI) and 4/239 (1.7%) protease inhibitor (PI) associated mutations. Dual-class (NRTI + PI) resistance mutations were detected in 1/239 (0.4%) person. The prevalence of resistance mutations was 7/85 (8.2%) and 10/154 (6.5%) in persons with recent and established infection, respectively. In multivariate analysis, having been born in the UK and high CD4 count, but not gender, age, risk group, ethnicity or subtype, were independent predictors of resistance. CONCLUSIONS: In an unselected UK cohort, subtypes other than B accounted for 43.9% of new HIV-1 diagnoses. The prevalence of resistance mutations was 7.1% and highest in those born in the UK.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Reconstitution of herpes simplex virus-specific T cell immunity in HIV-infected patients receiving highly active antiretroviral therapy.

Production of herpes simplex virus (HSV)-specific interferon- gamma by peripheral-blood mononuclear cells (PBMCs) of HSV-seropositive healthy donors and human immunodeficiency virus-infected persons was determined by use of ELISPOT. The mean +/- SD number of spot-forming cells/10(6) PBMCs was 314 +/- 74 in 11 healthy donors, 360 +/- 69 in 3 long-term nonprogressors (LTNPs), 186 +/- 52 in 9 newly diagnosed patients, and 181 +/- 59 in 33 patients who were receiving highly active antiretroviral therapy (HAART) for a median period of 30 months (range, 1-109 months). In 9 patients monitored prospectively while receiving virologically and immunologically successful first-line HAART, the number of spot-forming cells increased by 5.6/month (95% confidence interval, 1.2-9.9 [P=.01]) and 21.3/100 CD4 cells/mm(3) gained (95% confidence interval, 13.8-28.7 [P<.0001]). Responses were correlated with LTNP status and CD4 cell count.

Adolescent↗
PubMed2006

Factors associated with the development of opportunistic infections in HIV-1-infected adults with high CD4+ cell counts: a EuroSIDA study.

BACKGROUND: Limited data exist on factors predicting the development of opportunistic infections (OIs) at higher-than-expected CD4(+) cell counts in human immunodeficiency virus (HIV) type 1-infected adults. METHODS: Multivariate Poisson regression models were used to determine factors related to the development of groups of OIs above their respective traditional upper CD4(+) cell count thresholds: group 1 (>or=100 cells/ microL), OIs caused by cytomegalovirus, Mycobacterium avium complex, and Toxoplasma gondii; group 2 (>or=200 cells/ microL), Pneumocystis pneumonia and esophageal candidiasis; and group 3 (>or=300 cells/ microL), pulmonary and extrapulmonary tuberculosis. RESULTS: In groups 1, 2, and 3, 71 of 9,219, 125 of 7,934, and 36 of 7,838 patients, respectively, developed >or=1 intragroup OI. The strongest predictor of an OI in groups 1 and 2 was current CD4(+) cell count (for group 1, incidence rate ratio [IRR] per 50% lower CD4(+) cell count, 5.37 [95% confidence interval {CI}, 3.71-7.77]; for group 2, 4.28 [95% CI, 2.98-6.14]). Injection drug use but not current CD4(+) cell count predicted risk in group 3. Use of antiretroviral treatment was associated with a lower incidence of OIs in all groups, likely by reducing HIV-1 RNA levels (IRR per 1-log(10) copies/mL higher HIV-1 RNA levels for group 1, 1.50 [95% CI, 1.15-1.95]; for group 2, 1.68 [95% CI, 1.40-2.02]; and for group 3, 1.89 [95% CI, 1.40-2.54]). CONCLUSION: Although the absolute incidence is low, the current CD4(+) cell count and HIV-1 RNA level are strong predictors of most OIs in patients with high CD4(+) cell counts.

AIDS-Related Opportunistic Infections↗
PubMed2005

Constitutive models for impacted morsellised cortico-cancellous bone.

Constitutive models are developed, based on the results of confined compression testing, to describe the visco-elastic, and non-linear elasto-plastic behaviour of morsellised cortico-cancellous bone (MCB). It is found that the elastic modulus, E of MCB can be expressed as a linear function of the applied pressure, p. E varied from 3 to 30N/mm(2) for pressures up to 1N/mm(2). The visco-elastic behaviour of MCB can be described using a fourth-order Prony series. The plastic behaviour of MCB can be described using a Drucker Prager Cap (DPC) yield criterion, in which consolidation behaviour is described using an exponential function. The developed relationships allow MCB to be included in a realistic manner in finite element models, for example of the acetabular construct, following revision hip arthroplasty, carried out using the Slooff-Ling impaction grafting technique.

Bone Substitutes↗
PubMed2005

Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study.

OBJECTIVE: To examine whether the level of primary resistance to HIV drugs is increasing in the United Kingdom. DESIGN: Multicentre observational study. SETTING: All virology laboratories in the United Kingdom carrying out tests for HIV resistance as part of routine clinical care. PARTICIPANTS: 2357 people infected with HIV who were tested for resistance before receiving antiretroviral therapy. MAIN OUTCOME MEASURE: Prevalence of drug resistance on basis of the Stanford genotypic interpretation system. RESULTS: Over the study period (February 1996 to May 2003), 335 (14.2%, 95% confidence interval 12.8% to 15.7%) samples had mutations that conferred resistance to one or more antiretroviral drugs (9.3% high level resistance, 5.9% medium level resistance). The prevalence of primary resistance has increased markedly over time, although patterns are specific to drug class; the largest increase was for non-nucleoside reverse transcriptase inhibitors. In 2002-3, the prevalence of resistance to any antiretroviral drug to nucleoside or nucleotide reverse transcriptase inhibitors, to non-nucleoside reverse transcriptase inhibitors, or to protease inhibitors was 19.2% (15.7% to 23.2%), 12.4% (9.5% to 15.9%), 8.1% (5.8% to 11.1%), and 6.6% (4.4% to 9.3%), respectively. The risk of primary resistance was only weakly related to most demographic and clinical factors, including ethnicity and viral subtype. CONCLUSIONS: The United Kingdom has one of the highest reported rates of primary resistance to HIV drugs worldwide. Prevalence seems still to be increasing and is high in all demographic subgroups.

Adolescent↗
PubMed2005

Expression, purification, and renaturation of bone morphogenetic protein-2 from Escherichia coli.

Homodimeric bone morphogenetic protein-2 (BMP-2) is a member of the transforming growth factor beta superfamily that has been used for bone grafting. We were interested in exploring the functions of BMP-2 in other disease areas and focused on expressing and purifying active BMP-2 proteins. We have developed a new approach which involves using FoldIt refolding buffer to refold BMP-2 followed by a heparin affinity column to separate correctly folded dimer from monomer. A high yield of 29.4 mg BMP-2 dimer per gram cell wet weight was achieved. The purified BMP-2 dimer was shown to possess the same level of activity as BMP-2 from CHO cells as tested by the induction of alkaline phosphatase activity in C2C12 cells. This approach has potential application in refolding and purifying other homodimeric proteins.

Animals↗
PubMed2005

KNOX action in Arabidopsis is mediated by coordinate regulation of cytokinin and gibberellin activities.

The shoot apical meristem (SAM) is a pluripotent group of cells that gives rise to the aerial parts of higher plants. Class-I KNOTTED1-like homeobox (KNOX) transcription factors promote meristem function partly through repression of biosynthesis of the growth regulator gibberellin (GA). However, regulation of GA activity cannot fully account for KNOX action. Here, we show that KNOX function is also mediated by cytokinin (CK), a growth regulator that promotes cell division and meristem function. We demonstrate that KNOX activity is sufficient to rapidly activate both CK biosynthetic gene expression and a SAM-localized CK-response regulator. We also show that CK signaling is necessary for SAM function in a weak hypomorphic allele of the KNOX gene SHOOTMERISTEMLESS (STM). Additionally, we provide evidence that a combination of constitutive GA signaling and reduced CK levels is detrimental to SAM function. Our results indicate that CK activity is both necessary and sufficient for stimulating GA catabolic gene expression, thus reinforcing the low-GA regime established by KNOX proteins in the SAM. We propose that KNOX proteins may act as general orchestrators of growth-regulator homeostasis at the shoot apex of Arabidopsis by simultaneously activating CK and repressing GA biosynthesis, thus promoting meristem activity.

Arabidopsis↗
PubMed2005

Estimating HIV-1 drug resistance in antiretroviral-treated individuals in the United Kingdom.

Good estimates of the prevalence of human immunodeficiency virus drug resistance are important for assessing requirements for new drug classes and modeling the spread of resistance. However, little consensus exists on optimal methodologies to generate such data. To compare methodologies, we used the national data set of resistance tests from >4000 patients in the United Kingdom performed between 1998 and 2002. When single-time-point analysis (method 1) was used, the proportion of tests with any form of resistance was approximately 80%, with little time trend. When a cumulative model of resistance (method 2) was used and placed in the context of all treated patients, the prevalence of any resistance increased by year, reaching 17% of treated patients in 2002. Method 2 also nearly doubles estimates of numbers of individuals infected with multiclass drug-resistant virus. Our results identify an urgent need for new drugs within existing classes and new classes of antiretroviral therapy.

Anti-HIV Agents↗
PubMed2005

Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy.

OBJECTIVE: To assess hepatitis C virus (HCV) antibody prevalence in the EuroSIDA cohort, along with survival, human immunodeficiency virus (HIV)-1 disease progression, virologic response (plasma HIV-1 RNA load of < 500 copies/mL), and CD4 cell count recovery by HCV serostatus in patients initiating highly active antiretroviral therapy (HAART). RESULTS: HCV serostatus at or before enrollment was available for 5957 patients; 1960 (33%) and 3997 (67%) were HCV seropositive and seronegative, respectively. No association between an increased incidence of acquired immunodeficiency syndrome-defining illnesses or death and HCV serostatus was seen after adjustment for other prognostic risk factors known at baseline (adjusted incidence rate ratio [IRR], 0.97 [95% confidence interval {CI}, 0.81-1.16]). However, there was a large increase in the incidence of liver disease-related deaths in HCV-seropositive patients in adjusted models (IRR, 11.71 [95% CI, 6.42-21.34]). Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]) and immunologic response, whether measured as a > or = 50% increase (RH, 0.94 [95% CI, 0.77-1.16]) or a > or = 50 cells/microL increase (RH, 0.92 [95% CI, 0.77-1.11]) in CD4 cell count after HAART initiation. CONCLUSIONS: HCV serostatus did not affect the risk of HIV-1 disease progression, but the risk of liver disease-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to HAART were not affected by HCV serostatus.

Adult↗
PubMed2005

Interruption of highly active antiretroviral therapy in HIV clinical practice: results from the Italian Cohort of Antiretroviral-Naive Patients.

OBJECTIVES: To investigate the frequency of a first therapy interruption (TI) > or = 12 weeks, to identify the factors associated with TI and with therapy resumption, and to compare the risk of developing clinical events during TI and during continuous therapy. METHODS: Observational study of 3142 patients who started a first highly active antiretroviral therapy (HAART) regimen. End points were time to (1) first TI of > or = 12 weeks, (2) subsequent therapy resumption, and (3) development of new AIDS-related events or death. RESULTS: Over a median follow-up period of 41 months (interquartile range: 18-60 months), 721 patients (22.9%) interrupted HAART for > or = 12 weeks, with a probability of 28.6% (95% confidence interval [CI]: 26.7-30.6) by 4 years from the date of therapy initiation. Patient decision (47.4%) and toxicity (24.0%) were the main reasons for TI. Women, injection drug users, and patients with a higher current CD4 cell count were more likely to interrupt. The median time to therapy resumption was 12 months (95% CI: 11-14). The higher the current CD4 count, the slower was the rate of resuming therapy; conversely, patients who stopped because of failure and those with a pre-HAART viral load >100,000 copies/mL resumed therapy sooner. Two hundred eighty-one patients experienced clinical progression at a rate of 2.6 per 100 person-years (pys) (95% CI: 2.3-3.0) while patients were on therapy and 3.5 per 100 pys (95% CI: 2.4-4.8) during TI. The adjusted relative hazard of clinical progression associated with TI was 2.75 (95% CI: 1.14-6.65; P = 0.03). CONCLUSIONS: TI occurring in clinical practice is associated with an increased risk of clinical progression; hence, it should be discouraged outside strictly experimental settings.

Adult↗
PubMed2005

When to start therapy.

Explore the source record for details and available documents.

Antiretroviral Therapy, Highly Active↗
PubMed2005

The changing incidence of AIDS events in patients receiving highly active antiretroviral therapy.

BACKGROUND: Although the incidence of most AIDS events declines after initiation of highly active antiretroviral therapy (HAART), this decline is more rapid for some conditions than others. We herein describe the decline in incidence of AIDS-defining events among 12,574 antiretroviral-naive individuals who started HAART in the Antiretorviral Therapy Cohort Collaboration and determined whether the rate of decline is similar for events with different etiologies. METHODS: Rates of AIDS were calculated for the periods 0 to 3, 4 to 6, 7 to 12, 13 to 24, and 25 to 36 months after starting HAART. Changes in incidence over time were investigated using Poisson regression. RESULTS: During 22 958 person-years of follow-up, 928 AIDS events developed (25.3% viral, 24.6% bacterial, 20.7% fungal, 8.1% protozoal, and 21.2% other). The incidence of any AIDS event declined from 129.3 (95% confidence interval [CI], 116.7-141.8) per 1000 person-years in the first 3 months to 13.2 (95% CI, 9.4-17.0) in the third year after starting HAART (P<.001). The rate of decline in incidence was greatest for events with a viral etiology (87.0% per year) and lowest for those with a fungal etiology (54.0% per year). In the third year, fungal events represented 37.0% of AIDS events that occurred. After adjustment for the CD4 count and human immunodeficiency virus 1 RNA level, changes in the incidence of bacterial and viral events from months 0 to 6 and 7 to 12 remained significant, suggesting that changes in these markers did not fully explain the changes in incidence seen. CONCLUSION: Although the incidence of all AIDS-defining events decreased substantially after starting HAART, the pattern of decline was most pronounced for events with a viral etiology.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Modification of the ionizing radiation response in living cells by an scFv against the DNA-dependent protein kinase.

The non-homologous end joining pathway uses pre-existing proteins to repair DNA double-strand breaks induced by ionizing radiation. Here we describe manipulation of this pathway in living cells using a newly developed tool. We generated a single chain antibody variable fragment (scFv) that binds to the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in the pathway. In contrast to existing pharmacologic inhibitors, the scFv binds a newly defined regulatory site outside the kinase catalytic domain. Although the scFv inhibits kinase activity only modestly, it completely blocks DNA end joining in a cell-free system. Microinjection of the scFv sensitizes human cells to radiation, as measured by a reduction in efficiency of colony formation and induction of apoptosis at an otherwise sublethal dose of 1.5 Gy. The scFv blocks non-homologous end joining in situ at a step subsequent to histone gamma-H2AX focus formation but preceding gamma-H2AX dephosphorylation. Blockage occurs in cells exposed to as little as 0.1 Gy, indicating that DNA-PKcs is essential for double-strand break repair even at low radiation doses. The ability to modify the radiation response in situ in living cells provides a link between biochemical, genetic and cytologic approaches to the study of double-strand break repair intermediates.

Apoptosis↗
PubMed2003

Definition of loss of virological response in trials of antiretroviral drugs.

Definition of the time of loss of virological response is important when designing a viral load endpoint for trials of antiretroviral drugs. We assessed whether, in patients who achieved a viral load below 50 copies/ml, two consecutive values above 50 copies/ml was really indicative of loss of response. It was common for the viral load to return to below 50 copies/ml with no change in regimen, suggesting that a higher threshold for defining the loss of response is required.

Anti-HIV Agents↗
PubMed2002

The gibberellin pathway mediates KNOTTED1-type homeobox function in plants with different body plans.

BACKGROUND: The shoot apical meristem (SAM) is an indeterminate structure that gives rise to the aerial parts of higher plants. Leaves arise from the differentiation of cells at the flanks of the SAM. Current evidence suggests that the precise regulation of KNOTTED1-like homeobox (KNOX) transcription factors is central to the acquisition of leaf versus meristem identity in a wide spectrum of plant species. Factors required to repress KNOX gene expression in leaves have recently been identified. Additional factors such as the CHD3 chromatin remodeling factor PICKLE (PKL) act to restrict meristematic activity in Arabidopsis leaves without repressing KNOX gene expression. Less is known regarding downstream targets of KNOX function. Recent evidence, however, has suggested that growth regulators may mediate KNOX activity in a variety of plant species. RESULTS: Here we show that reduced activity of the gibberellin (GA) growth regulator pathway promotes meristematic activity, both in the natural context of KNOX function in the SAM and upon ectopic KNOX expression in Arabidopsis leaves. We show that constitutive signaling through the GA pathway is detrimental to meristem maintenance. Furthermore, we provide evidence that one of the functions of the KNOX protein SHOOTMERISTEMLESS (STM) is to exclude transcription of the GA-biosynthesis gene AtGA20ox1 from the SAM. We also demonstrate that AtGA20ox1 transcript is reduced in the pkl mutant in a KNOX-independent manner. Moreover, we show a similar interaction between KNOX proteins and GA-biosynthesis gene expression in the tomato leaf and implicate this interaction in regulation of the dissected leaf form. CONCLUSIONS: We suggest that repression of GA activity by KNOX transcription factors is a key component of meristem function. Transfer of the KNOX/GA regulatory module from the meristem to the leaf may have contributed to the generation of the diverse leaf morphologies observed in higher plants.

Arabidopsis↗