PubMed Health⌕ Search

Biomedical subjects

Andrew Carr

Publications and source records attributed to Andrew Carr.

At least 37 records · Page 2Linked to original sources
PubMed2005

In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA.

BACKGROUND: Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described. METHODS: We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks. RESULTS: We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues. CONCLUSIONS: Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.

Adipose Tissue↗
PubMed2005

Buffalo hump seen in HIV-associated lipodystrophy is associated with hyperinsulinemia but not dyslipidemia.

Accumulation of dorsocervical fat, or a "buffalo hump" (BH), is commonly reported in adults with HIV-associated lipodystrophy (HIVLD). The pathogenesis underlying this aspect of a syndrome characterized by loss of subcutaneous fat from other body sites is poorly understood. We aimed to identify risk factors for a BH in HIV-infected adults in cross-sectional analyses of 2 HIV-infected ambulatory populations. The first group (Australian Lipodystrophy Prevalence Survey [APS]) consisted of 1348 Australian HIV-infected adults (95% male) irrespective of changes in body composition. The second group (Lipodystrophy Case Definition [LDCD] study) comprised 417 subjects (83% male) with at least 1 reported moderate or severe feature of HIVLD. A BH was reported in 24 (2%) APS subjects and 79 (19%) LDCD study subjects. A BH was not an isolated finding. Patients with a BH had a high prevalence of other features of HIVLD, similar to lipodystrophic patients without a BH, such as facial lipoatrophy reported in 100% and 61% BH-positive subjects from the APS and LDCD study, respectively. In both groups, those with a BH had higher fasting insulin (P<or=0.007), a higher body mass index (P<or=0.003), a higher waist/hip ratio (P<or=0.001), higher limb fat (P<or=0.003), and higher systolic blood pressure (P<0.05). On multivariate analysis, higher serum insulin, systolic blood pressure, age, and duration of exposure to ritonavir were independently associated with a BH in the APS group. In the LDCD group, higher insulin, diastolic blood pressure, and duration of exposure to zidovudine were independently associated with a BH. There was no association between a BH and hyperlipidemia. These data show that a BH is associated with other physical features of the lipodystrophy phenotype and suggest that hyperinsulinemia, a feature common to HIVLD, obesity, and hypercortisolism, is an important component of this phenotype, thus warranting closer monitoring of BH-positive patients for glucose intolerance and diabetes.

Adult↗
PubMed2005

Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population.

OBJECTIVE: A compelling genetic association with osteoarthritis (OA) of 2 functional alleles in the aspartic acid (D) repeat of the asporin gene was recently reported in a Japanese population. Allele D13 of the repeat encoded OA protection, whereas allele D14 encoded OA susceptibility. The 2 alleles mediate differences in the capacity of asporin to inhibit the cartilage growth factor transforming growth factor beta, with the D14 allele being a particularly potent inhibitor. Our objective was to assess whether the D repeat is associated with OA in UK Caucasians. METHODS: The repeat was genotyped in 1,247 patients who had undergone elective joint replacement of the hip or the knee due to end-stage primary OA and in 748 age-matched controls. RESULTS: The D13 allele was more common in controls, and the D14 allele was more common in patients. However, this trend was significant only for men who had undergone hip replacement (P = 0.016, odds ratio 1.48, 95% confidence interval 1.09-2.01). CONCLUSION: Our data suggest that the asporin polymorphism is not a major influence on OA etiology in Caucasians. The results of our study do not question the veracity of the Japanese report. Instead, our study highlights the complex, heterogeneous nature of OA genetic susceptibility.

Aged↗
PubMed2005

Long-term survival and concomitant gene expression of ribozyme-transduced CD4+ T-lymphocytes in HIV-infected patients.

BACKGROUND: An anti-HIV-1 tat ribozyme, termed Rz2, has been shown to inhibit HIV-1 infection/replication and to decrease HIV-1-induced pathogenicity in T-lymphocyte cell lines and normal peripheral blood T-lymphocytes. We report here the results of a phase I gene transfer clinical trial using Rz2. METHODS: Apheresis was used to obtain a peripheral blood cell population from each of four HIV-negative donors. After enrichment for CD4+ T-lymphocytes, ex vivo expansion and genetic manipulation (approximately equal aliquots of the cells were transduced with the ribozyme-containing (RRz2) and the control (LNL6) retroviral vector), these cells were infused into the corresponding HIV-1-positive twin recipient. Marking was assessed over an initial 24-week period and in total over an approximate 4-year period. RESULTS: The gene transfer procedure was shown to be safe, and technically feasible. Both RRz2- and LNL6-gene-containing peripheral blood mononuclear cells (PBMC) were detected at all time points examined to 4 years. There was concomitant gene construct expression in the absence of the need for ex vivo peripheral blood cell stimulation and there was no evidence of immune elimination of the neoR T-lymphocytes nor of silencing of the Moloney murine leukemia virus long terminal repeat. CONCLUSIONS: The proof of principle results reported here demonstrate safety and feasibility of this type of gene transfer approach. While not specifically tested, T-lymphocytes containing an anti-HIV gene construct may impact on HIV-1 viral load and CD4+ T-lymphocyte count, potentially representing a new therapeutic modality for HIV-1 infection.

Adult↗
PubMed2005

Sex differences in the associations of HIV disease characteristics and body composition in antiretroviral-naive persons.

BACKGROUND: Data on associations of body composition with HIV disease characteristics are limited. OBJECTIVE: We compared sex-specific associations between HIV disease characteristics and body composition in an racially-ethnically diverse cohort of antiretroviral-naive patients. DESIGN: The study was a cross-sectional analysis of participants enrolled in a metabolic substudy of a multicenter trial. Regional fat was measured, and total body fat (TBF) was derived by using the Durnin-Womersley formula (DWF) and bioelectrical impedance analysis (BIA). Body cell mass (BCM) was measured by BIA. RESULTS: Among 422 participants, 22% were women, 60% were African American, and 36% had prior AIDS-defining illnesses. Mean (+/-SD) age was 38.2 +/- 9.6 y, CD4+ count was 215 +/- 184 cells/mm3, and HIV RNA log10 was 5.0 +/- 0.8 copies/mL. On multivariate analysis, women with AIDS-defining illness had significantly (P < 0.005) lower regional body fat and TBF (BIA: -9.5 kg; DWF: -7.3 kg) but nonsignificantly lower BCM (-1.3 kg) than did women without such illnesses, whereas men with AIDS-defining illness had significantly (P < 0.005) lower BCM (-1.7 kg) but nonsignificantly lower TBF (BIA: -1.3 kg; DWF: -1.83 kg) than did men without such illnesses (P < 0.05 for sex differences in TBF). Significant negative associations of HIV RNA with BCM (-0.9 kg/log RNA; P = 0.03), TBF by BIA (-1.4 kg/log RNA; P = 0.05) and by DWF (-1.6 kg/log RNA; P = 0.01), and regional fat were observed in men only. CONCLUSIONS: The effect of prior AIDS illness on body fat differed significantly between the sexes: women with prior AIDS-defining illness had significantly less fat than did women without such illnesses. An independent effect of HIV viremia on BCM and fat was seen in men. These distinctions may be due to inherent biological differences between the sexes.

Adipose Tissue↗
PubMed2005

Influence of rosiglitazone on flow-mediated dilation and other markers of cardiovascular risk in HIV-infected patients with lipoatrophy.

BACKGROUND: Antiretroviral therapy for HIV infection is commonly complicated by lipoatrophy, insulin resistance and dyslipidaemia. In HIV-uninfected adults with insulin resistance or type 2 diabetes, thiazolidinediones can lower blood pressure and improve both insulin sensitivity and endothelial function. This study sought to investigate the effects of rosiglitazone on endothelial function and other markers of cardiovascular risk in patients with HIV-related lipoatrophy. METHODS: HIV-infected, lipoatrophic adults receiving antiretroviral therapy were randomized to receive either rosiglitazone 4 mg or matched placebo, twice daily. Percentage flow-mediated forearm arterial dilation (FMD%) was measured at weeks 0, 12, 24 and 48, together with other markers of vascular risk (blood pressure, lipids, glycaemic parameters, adiponectin and leptin). RESULTS: Out of 64 enrolled adults, 44 (69%) attended all visits (23 rosiglitazone, 21 placebo). Relative to placebo, at week 48, rosiglitazone decreased systolic blood pressure (8 mmHg, P=0.03), insulin (3 microIU/ml, P=0.02), insulin resistance (P=0.03) and leptin (0.6 ng/ml, P=0.02), whilst adiponectin was increased (3.3 microg/lml, P<0.0001). However, rosiglitazone increased total cholesterol (49.1 mg/dl, P=0.001), low-density lipoprotein cholesterol (23.5 mg/dl, P=0.01) and triglycerides (146 mg/dl, P=0.06). Mean baseline FMD% for the entire cohort was moderately impaired (4.5%). Compared with baseline, mean on-treatment FMD% increased by 0.8% with rosiglitazone and decreased by 0.3% with placebo, (mean difference 1.1%, 95% CI -0.2 to 2.5, P=0.09). CONCLUSIONS: Rosiglitazone has minimal effect on flow-mediated dilation in HIV-infected lipoatrophic adults. However, despite worsening of the lipid profile, the overall effect of rosiglitazone on the cardiovascular risk profile in these subjects was positive.

Adult↗
PubMed2005

Population survey comparing older adults with hip versus knee pain in primary care.

BACKGROUND: Knee pain is nearly twice as prevalent as hip pain in elderly people, yet knee replacement is far less common than hip replacement. AIM: To investigate whether systematic differences in the primary care management of hip versus knee problems might explain the disparate rates of joint replacement. DESIGN OF STUDY: Cross-sectional, population-based postal survey. SETTING: Random sample of 5500 Oxfordshire residents aged 65 years and above. METHOD: Screening questions were used to identify symptomatic individuals: "During the past 12 months, have you had pain in or around either of your hips/knees on most days for 1 month or longer?". Standard (Lequesne) severity ratings were obtained for each hip and knee. Logistic regression was used to estimate odds ratios (ORs) for "knee cases" versus "hip cases" for selected healthcare services and attitudes toward replacement. RESULTS: Among 3341 responders, 212 hip cases and 612 knee cases were identified. Knee pain led to a GP consultation more often than hip pain (OR = 1.76, P = 0.04), but specialist referral was no more likely (OR = 0.85, P = 0.57). Similar percentages of hip and knee cases would agree to hip/knee replacement surgery if it was offered, but hip and knee cases differed in their views on the general success of joint replacement. CONCLUSIONS: Some variations in primary care management for hip versus knee pain were apparent. People with hip pain were mostly positive about replacement outcomes, whereas people with knee pain were more uncertain about replacement. Attitudes appeared to be influenced by knowing someone who had undergone such surgery.

Aged↗
PubMed2005

Methodological considerations in human studies of gene expression in HIV-associated lipodystrophy.

In the majority of cases, HIV-associated lipodystrophy, lipoatrophy in particular, becomes clinically apparent only after months or years of continuous exposure to antiretroviral medications and, once developed, is difficult to reverse. Many lipid-related side effects of antiretroviral medications result from drug-induced changes in gene expression. As our understanding of the pathogenic mechanisms underlying HIV-associated lipodystrophy improves, it is important to be able to explore changes at a molecular level in order to fully elucidate the mechanisms whereby antiretroviral drugs exert their toxicities. Monitoring changes in gene expression in vivo may enable physicians to identify, predict or prevent drug toxicities early, before irreversible changes in body composition occur. However, monitoring changes in gene expression at a population level presents many methodological challenges that need to be addressed, over and above the considerable intra- and inter-individual variability inherent in the cellular expression of any gene. Careful collection and processing of adequate biological samples, robust laboratory processes and assays, and appropriate study design can help overcome many of these difficulties.

CCAAT-Enhancer-Binding Proteins↗
PubMed2004

The incubation period of acute retroviral syndrome as a multistep process: a parametric survival analysis.

A long duration of acute retroviral syndrome (ARS) and a short incubation of ARS (IncARS) are independent predictors of a fast progression to AIDS. The first objective of this study was to validate previous estimates of IncARS by comparing durations between health care workers (HCWs) accidentally infected by HIV and individuals infected by other routes (non-health care workers [N-HCWs]). The second objective was to use parametric survival models to generate hypotheses on various steps occurring during the IncARS. Data from a prospective cohort of patients with documented ARS and from individuals with ARS as the result of accidental exposure to HIV were analyzed. Nonparametric and parametric survival models were used to describe the incubation of ARS. No differences were found for the median IncARS between 34 HCWs (21.5 days) and 70 N-HCWs (21.5 days) (log-rank test, P = 0.72). According to survival models, IncARS can be modeled with a gamma and/or lognormal model with means of 26.4 days and 26.7 days, respectively. The gamma model suggests that 3 sequential stages are present during the IncARS, which is compatible with basic science investigations identifying crossing of the epithelial barrier by the virus, the virus-host cell interactions, and the viral systemic dissemination.

Cohort Studies↗
PubMed2004

Prospective study of elderly people comparing treatments following first primary care consultation for a symptomatic hip or knee.

BACKGROUND: Symptomatic knee problems in elderly people are considerably more common than hip problems, yet far more hips are replaced. OBJECTIVE: The purpose of this study was to investigate whether systematic differences occur in early primary care management of elderly patients who first consult with hip versus knee symptoms. METHODS: A prospective analysis was carried out of anonymized records in the MediPlus general practice database. This was a 3 year (1996-1998) prospective study of 310,843 patients aged 65+ regarding consultations about a new hip or knee problem. Survival analysis techniques were used to analyse time to and frequency of various interventions. RESULTS: A total of 1410 new hip and 3152 new knee consulters were identified. Baseline characteristics of the two groups were very similar. By 3 years following the first consultation, more of the hip cases had referral to a specialist (38.2% hips versus 31.5% knees, P <0.001) and joint replacement (9.6% hips versus 1.8% knees, P <0.001) recorded. Non-steroidal anti-inflammatory drug (NSAID) prescribing was high for both groups, with approximately 51% prescribed one of the safer forms and approximately 15% prescribed one with a lower safety record within 3 years. CONCLUSION: Rates of specialist referral and joint replacement in older people are much lower, or slower, for those with symptomatic knees relative to hips. In the absence of surgery, prescriptions for pain killers are similar for both groups. Elderly people with symptomatic knees are therefore at increased risk of drug side effects relative to those with symptomatic hips. This may represent another facet of unmet need for surgery in people with knee disease.

Aged↗
PubMed2004

Rhodanine-3-acetic acid derivatives as inhibitors of fungal protein mannosyl transferase 1 (PMT1).

The first inhibitors of fungal protein: mannosyl transferase 1 (PMT1) are described. They are based upon rhodanine-3-acetic acid and several compounds have been identified, for example, 5-[[3-(1-phenylethoxy)-4-(2-phenylethoxy)phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid (5a), which inhibit Candida albicans PMT1 with IC(50)s in the range 0.2-0.5 microM. Members of the series are effective in inducing changes in morphology of C. albicans in vitro that have previously been associated with loss of the transferase activity. These compounds could serve as useful tools for studying the effects of protein O-mannosylation and its relevance in the search for novel antifungal agents.

Candida albicans↗
PubMed2004

Changes in mitochondrial DNA in peripheral blood mononuclear cells from HIV-infected patients with lipoatrophy randomized to receive abacavir.

It has been suggested that lipoatrophy associated with exposure to nucleoside analogues is caused by depletion of mitochondrial DNA (mtDNA). The aim of the present study was to determine whether switching treatment from a thymidine analogue to abacavir was associated with an increase in the mtDNA copy number in peripheral blood mononuclear cells (PBMCs). Of 111 patients with lipoatrophy who were randomized to have treatment switched to abacavir or to continue treatment with thymidine analogues, 94 patients had PBMCs obtained at baseline and at weeks 4, 12, and 24, for quantification of the mtDNA copy number. During the 24-week study, there was no significant change in mtDNA copy numbers in PBMCs in either treatment group, despite improvement in peripheral lipoatrophy among patients whose treatment was switched to abacavir.

Anti-HIV Agents↗
PubMed2004

Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study.

OBJECTIVE: To determine if long-term improvement in HIV lipoatrophy can be attained by substitution of thymidine analogues zidovudine (ZDV) or stavudine (d4T) with abacavir (ABC). DESIGN: Long-term follow-up (104 weeks) of a randomized, open-label study. SETTING: Seventeen ambulatory HIV clinics in Australia and London. SUBJECTS: Patients with HIV lipodystrophy were randomized to switch from a thymidine analogue to ABC, while continuing all other antiretroviral therapy (ABC arm) (n = 42) or continue current therapy (ZDV/d4T arm) (n = 43). INTERVENTION: At week 24, all control patients could switch to ABC. Of the original 111 patients randomized, 85 had long-term follow-up data, with 77 having imaging data available at 104 weeks. MAIN OUTCOME MEASURE: The primary endpoint was time-weighted change in limb fat mass, measured by dual-energy X-ray absorptiometry (DEXA). RESULTS: At week 104, the mean increase in limb fat for the ABC and ZDV/d4T group was 1.26 +/- 2.02 kg and 0.49 +/- 1.38 kg, respectively. The time-weighted change for limb fat was significantly different between the two arms (0.43 kg; P = 0.008). On-treatment analysis demonstrated a trend for increased limb fat in patients in the ABC arm. Visceral fat accumulation, buffalo hump, self-assessed lipodystrophy or the lipodystrophy case definition score (LCDS) did not improve. CONCLUSIONS: In patients with moderate-to-severe lipodystrophy, significant improvements in subcutaneous fat continued over 104 weeks after switching from a thymidine analogue to ABC. Nevertheless, the lipodystrophy syndrome was still evident, indicating additional strategies need evaluating.

Absorptiometry, Photon↗
PubMed2004

No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lipodystrophy commonly complicates antiretroviral therapy of HIV-1 infection. Thiazolidinediones such as rosiglitazone promote subcutaneous fat growth in type 2 diabetics and adults with congenital lipodystrophy, and can prevent HIV-1 protease inhibitor toxicity to adipocytes in vitro. We postulated that rosiglitazone would improve HIV lipoatrophy. METHODS: 108 HIV-1-infected lipoatrophic adults on antiretroviral therapy were randomised to rosiglitazone 4 mg twice daily (n=53) or matching placebo (n=55) for 48 weeks. The study had 80% power to detect a 0.5 kg difference in changes in limb fat (using dual-energy X-ray absorptiometry) between groups at week 48 by intention-to-treat analysis, and a 0.7 kg difference within each protease inhibitor stratum. FINDINGS: Limb fat increased by 0.14 kg in the rosiglitazone group and 0.18 kg in the placebo group (mean difference -0.04 kg [95%CI -0.29 to 0.21]; p=0.74 by t test), with three participants (one on rosiglitazone and two controls), lost to follow-up. Rosiglitazone had no significant benefit on any other measure of lipodystrophy, despite large relative increases in plasma adiponectin (4.2 mmol/L [102%]; p<0.0001) and in three markers of insulin sensitivity (p=0.01 to 0.02). Six participants ceased study drug in each group, four participants (three on rosiglitazone and one control) for related adverse events. The main adverse effects, which seem to be almost unique to this population, were asymptomatic hypertriglyceridaemia (mean relative increase 0.9 mmol/L at week 48; p=0.04) and hypercholesterolaemia (1.5 mmol/L; p=0.001). INTERPRETATION: Rosiglitazone for 48 weeks did not improve lipoatrophy in HIV-1-infected adults receiving antiretroviral therapy. Use of less toxic antiretroviral treatment is necessary to prevent lipoatrophy.

Anemia↗