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Biomedical subjects

M Nelson

Publications and source records attributed to M Nelson.

At least 19 recordsLinked to original sources

Non-nucleoside reverse transcriptase inhibitors: a review.

Non-nucleoside reverse transcriptase inhibitors form the backbone of antiretroviral treatment for many HIV-infected individuals. The tolerability, pill burden and efficacy associated with this class of agents make them a frequent choice for first-line therapy. Here we review nevirapine and efavirenz in terms of efficacy, resistance and toxicity, focusing particularly on the use of nevirapine to prevent mother-to-child transmission in developing countries.

Antiretroviral Therapy, Highly Active↗

A quantitative model of error accumulation during PCR amplification.

The amplification of target DNA by the polymerase chain reaction (PCR) produces copies which may contain errors. Two sources of errors are associated with the PCR process: (1) editing errors that occur during DNA polymerase-catalyzed enzymatic copying and (2) errors due to DNA thermal damage. In this study a quantitative model of error frequencies is proposed and the role of reaction conditions is investigated. The errors which are ascribed to the polymerase depend on the efficiency of its editing function as well as the reaction conditions; specifically the temperature and the dNTP pool composition. Thermally induced errors stem mostly from three sources: A+G depurination, oxidative damage of guanine to 8-oxoG and cytosine deamination to uracil. The post-PCR modifications of sequences are primarily due to exposure of nucleic acids to elevated temperatures, especially if the DNA is in a single-stranded form. The proposed quantitative model predicts the accumulation of errors over the course of a PCR cycle. Thermal damage contributes significantly to the total errors; therefore consideration must be given to thermal management of the PCR process.

Base Sequence↗

Influence of tea drinking on manganese intake, manganese status and leucocyte expression of MnSOD and cytosolic aminopeptidase P.

OBJECTIVE: Since black tea contains high levels of manganese (Mn), we investigated the relationship between dietary Mn intake, circulating Mn levels and leucocyte expression of two Mn-dependent enzymes in tea drinkers and non-tea drinkers. DESIGN: We assessed Mn intakes (food frequency questionnaire), fasting whole blood and plasma Mn levels, and quantitative expression of peripheral blood mononuclear cell Mn-dependent superoxide dismutase (MnSOD) and cytosolic aminopeptidase-P (cAP-P). SETTING AND SUBJECTS: In total, 24 tea drinkers (> or = 1 l black tea/day) and 28 non-tea drinkers were recruited from the staff and students of King's College London by circular email. RESULTS: Dietary Mn intakes (mean (range)) were significantly lower (P < 0.0001) in non tea drinkers (3.2 mg/day (0.5-6.5)) than tea drinkers (5.5 mg/day (2-12) or 10 mg/day (5-20) depending upon the value used for Mn levels of black tea). Whole blood, plasma Mn levels and expression of MnSOD and cAP-P did not differ between the groups. In a continuous analysis, whole blood Mn levels and expression of MnSOD correlated inversely but no other parameters associated with each other. CONCLUSIONS: Tea drinking is a major source of dietary Mn and intakes commonly exceed proposed adequate intake values of 1.8-2.3 mg Mn/day and, on occasion, exceed upper limits of 10-11 mg/day. Dietary Mn intake has little influence on markers of Mn status or expression of Mn-dependent enzymes. Fasting whole blood Mn levels and leucocyte expression of MnSOD could, together, be further investigated as markers of Mn status.

Adult↗

Dietary patterns and their socio-demographic determinants in 10 European countries: data from the DAFNE databank.

OBJECTIVE: To describe the dietary patterns of 10 European countries and their socio-demographic determinants, using the comparable between-countries DAFNE data. DESIGN: Analysis of standardized and postharmonized data collected through the national household budget surveys. SETTING: Nationally representative surveys undertaken in 10 European countries, generally in the second half of the 1990s. RESULTS: The differences in the fruit and vegetable consumption previously identified between Mediterranean and Northern European countries seem to be leveling out, particularly in relation to fruit consumption. Pulses, however, still characterize the diet of the Mediterraneans. Straying from their traditional food choices, Mediterraneans recorded high availability of unprocessed red meat, while Central and Northern Europeans preferably consumed meat products. The household availability of beverages (alcoholic and non-alcoholic) is generally higher among Central and Northern European populations. Principal component (PC) analysis led to the identification of two dietary patterns in each of the 10 countries. The first was similar in all countries and indicated 'wide-range' food buyers. The second was slightly more varied and described 'beverage and convenience' food buyers. PC1 was common among households of retired and elderly members, while PC2 was common among households located in urban or semi-urban areas and among adult Scandinavians living alone. CONCLUSIONS: The dietary patterns identified point towards a progressive narrowing of dietary differences between North and South European countries. The comparable between-countries DAFNE data could prove useful in ecological studies, in the formulation of dietary guidelines and public health initiatives addressing specific population groups. SPONSORSHIP: European Commission.

Adolescent↗

Highly active anti-retroviral therapy (HAART)-induced maintenance of adaptive but not innate immune parameters is associated with protection from HIV-induced mortality.

Immunosuppression induced by the human immunodeficiency virus (HIV-1) increases the risk of death. We measured the influence of immunological and virological factors and the type of highly active anti-retroviral therapy (HAART) on this risk. Adaptive (lymphocyte) and innate (natural killer) immune correlates and maximum HIV viral loads were assessed for association with mortality using univariate and multivariate analyses. The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI) on mortality were also examined in a prospectively recorded cohort of 9621 HIV-infected individuals. From this entire cohort, 5873 HIV infected individuals (61%) have been followed-up in the HAART era and of these 499 (8.5%) have died. In multivariate analyses, CD4 counts below the 50th centile and CD8 and CD19 counts below the 25th centile were significantly associated with mortality, as was increased age (P < 0.001). Innate immune subset levels had no effect on mortality. A maximum HIV viral load greater than the 75th centile was also associated independently with mortality (P < 0.035). Exposure to either a PI or an NNRTI-containing HAART regimen, or both together, was protective against death compared with no anti-retrovirals (P < 0.001). Effective HAART-induced maintenance of the adaptive immune system (CD4, CD8 and CD19 counts) protects from HIV-related mortality.

Adult↗

Pulmonary Kaposi sarcoma in the era of highly active antiretroviral therapy.

OBJECTIVE: Since the introduction of highly active antiretroviral therapy (HAART) there has been a dramatic reduction in the incidence of Kaposi sarcoma (KS) and an improvement in survival. We wished to examine whether the outcome in pulmonary KS (pKS) has also altered. METHODS: In a single-institution cohort of 1140 HIV-positive patients with KS, 305 patients were diagnosed in the HAART era (1996-2004). We examined the clinicopathological features and outcomes of these patients, of whom 25 had pKS and 280 did not. RESULTS: Patients with pKS had lower CD4 cell counts at the time of KS diagnosis (Mann-Whitney U-test P=0.005). The incidence of pKS was higher in African patients than in non-African patients in this sample (Fisher's test, P=0.001). There were no significant differences in age, gender, plasma HIV-1 viral load or prior HAART treatment at the time of KS diagnosis. Five-year overall survival in the pKS group was 49% [95% confidence interval (CI) 26-73%] as compared with 82% (95% CI 76-87%) for the non-pKS group (log rank, P<0.0001). CONCLUSION: PKS remains an ominous diagnosis in the era of HAART, with a median survival of just 1.6 years.

AIDS-Related Opportunistic Infections↗

Management of advanced HIV disease in patients with tuberculosis or hepatitis co-infection.

Advanced human immunodeficiency virus (HIV) disease can be defined as a cluster of differentiation 4 (CD4) count <50 cells/mm(3) or the presence of an acquired immunodeficiency syndrome (AIDS)-defining illness. In the UK and Ireland, the number of patients who present with advanced HIV disease is increasing, with 301/977 (31%) of patients presenting late (<200 CD4 cells/mm(3)). Many patients who present with advanced HIV disease will have comorbid conditions, such as hepatitis B or C or tuberculosis (TB), which complicates the choice of therapy. This article reviews the evidence and some clinical scenarios for specific patient groups who may present with advanced HIV disease: those with comorbid TB, hepatitis B or hepatitis C. The aim is to offer practical advice on therapeutic options for treatment-naïve patients who present with advanced HIV disease on the basis of available clinical evidence.

Antiretroviral Therapy, Highly Active↗

Novel anti-hepatitis B agents: A focus on telbivudine.

Although preventable by vaccination, hepatitis B infection is common, affecting more than 350 million individuals worldwide. Chronic hepatitis B infection is associated with the complications of chronic liver disease including cirrhosis and hepatocellular carcinoma. Current agents designed to target hepatitis B are hindered by the development of resistance, poor tolerability or limited efficacy and a demand for new agents and strategies continues. This review focuses on telbivudine, a novel agent in the fight against hepatitis B.

Antiviral Agents↗

A single centre cohort experience with a new once daily antiretroviral drug.

BACKGROUND: Atazanavir, an azadipeptide protease inhibitor (PI) with once daily dosing, a lack of insulin resistance, lipid increase, and gastrointestinal toxicities, is approved in combination with other antiretrovirals for the treatment of patients infected with HIV. Unboosted atazanavir is also used in highly active antiretroviral therapy (HAART) naive patients. METHODS: The study prospectively followed up an established cohort of patients who received atazanavir, and for whom one year of follow up data were available. RESULTS: It was found that use of atazanavir in intent to treat and on treatment analyses, maintained and led to virological suppression and increases in CD4 count in both PI naive and experienced patients. Virological failure occurred in 7% of patients and the main toxicity was hyperbilirubinaemia, which led to treatment withdrawal in 2%. Its efficacy and safety profile was similar to that seen in previous randomised studies investigating its use. CONCLUSIONS: These data should provide reassurance for clinicians wishing to introduce a new antiretroviral into an established cohort.

Anti-HIV Agents↗

The presentation and survival of patients with non-cutaneous AIDS-associated Kaposi's sarcoma.

BACKGROUND: Acquired immune deficiency syndrome related Kaposi's sarcoma (AIDS-KS) remains a significant cause of morbidity and mortality. We describe for the first time a proportion of patients with AIDS-KS who presented with no evidence of cutaneous disease. PATIENTS AND METHODS: From our cohort of 5932 individuals infected with the human immunodeficiency virus (HIV-1) treated in the HAART era, 319 were identified with KS. Of these, 11 patients (5.4%) were diagnosed with KS without the presence of any cutaneous disease. We compared their survival, clinical, immunological and virological characteristics to other individuals with KS. RESULTS: There were no statistically significant differences in survival, CD4 count or HIV viral load at KS presentation. We observed that tumour-associated oedema (P = 0.046) and non-oral gastrointestinal KS (P = 0.042) were significantly more common in patients with non-cutaneous KS. Only one case of non-cutaneous KS was observed prior to the era of highly active anti-retroviral therapy (HAART). CONCLUSIONS: Non-cutaneous KS is a recognisable condition; patients should be treated with the standard of care as their prognosis is not inferior. This is likely to reflect a strong immune response, in the era of HAART.

Acquired Immunodeficiency Syndrome↗

Mycobacterial immune reconstitution inflammatory syndrome in HIV-1 infection after antiretroviral therapy is associated with deregulated specific T-cell responses: beneficial effect of IL-2 and GM-CSF immunotherapy.

BACKGROUND: With the advent of antiretroviral therapy (ART) cases of immune reconstitution inflammatory syndrome (IRIS) have increasingly been reported. IRIS usually occurs in individuals with a rapidly rising CD4 T-cell count or percentage upon initiation of ART, who develop a deregulated immune response to infection with or without reactivation of opportunistic organisms. Here, we evaluated rises in absolute CD4 T-cells, and specific CD4 T-cell responses in 4 HIV-1+ individuals presenting with mycobacterial associated IRIS who received in conjunction with ART, IL-2 plus GM-CSF immunotherapy. METHODS: We assessed CD4 T-cell counts, HIV-1 RNA loads, phenotype for naïve and activation markers, and in vitro proliferative responses. Results were compared with those observed in 11 matched, successfully treated asymptomatic clinical progressors (CP) with no evidence of opportunistic infections, and uninfected controls. RESULTS: Median CD4 T-cell counts in IRIS patients rose from 22 cells/microl before initiation of ART, to 70 cells/microl after 8 months of therapy (median 6.5 fold increase). This coincided with IRIS diagnosis, lower levels of naïve CD4 T-cells, increased expression of immune activation markers, and weak CD4 T-cell responses. In contrast, CP had a median CD4 T-cell counts of 76 cells/microl at baseline, which rose to 249 cells/microl 6 months post ART, when strong T-cell responses were seen in > 80% of patients. Higher levels of expression of immune activation markers were seen in IRIS patients compared to CP and UC (IRIS > CP > UC). Immunotherapy with IL-2 and GM-CSF paralleled clinical recovery. CONCLUSION: These data suggest that mycobacterial IRIS is associated with inadequate immune reconstitution rather than vigorous specific T-cell responses, and concomitant administration of IL-2 and GM-CSF immunotherapy with effective ART may correct/augment T-cell immunity in such setting resulting in clinical benefit.

Journal Article↗

Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma.

PURPOSE: A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. RESULTS: After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

Adult↗

Comparison of gatifloxacin, moxifloxacin and ciprofloxacin for treatment of experimental Burkholderia pseudomallei infection.

OBJECTIVES: To compare the efficacy of moxifloxacin, gatifloxacin and ciprofloxacin for the post-exposure prophylaxis and treatment of experimental Burkholderia pseudomallei infection. The presence of persistent infection in treated animals and the rate of relapse following dexamethasone treatment were also investigated. METHODS: BALB/c mice were inoculated subcutaneously with 1.75 x 10(6) cfu of B. pseudomallei strain 576. Gatifloxacin, moxifloxacin and ciprofloxacin (100 mg/kg) were given orally at 12 hourly intervals for 14 days starting at 6 h, 7 days or 12 days post-challenge. Control mice did not receive antibiotic therapy. RESULTS: No regimen gave 100% protection. Prophylaxis was most effective when started 6 h post-challenge, with survival rates at 42 days for ciprofloxacin, gatifloxacin and moxifloxacin being 58%, 75% and 75%, respectively. For treatment started at day 7 post-challenge, survival rates were 17%, 11% and 44%, respectively. When antibiotic treatment was delayed until day 12 post-challenge, survival rates fell to 21%, 17% and 28%, respectively. Following dexamethasone treatment of survivors at 42 days post-challenge, relapses occurred in all treatment groups. CONCLUSIONS: Fluoroquinolones do not provide good post-exposure protection against infection with B. pseudomallei. The newer agents moxifloxacin and gatifloxacin are not significantly better than ciprofloxacin for this purpose.

Animals↗

Crop yield and light/energy efficiency in a closed ecological system: Laboratory Biosphere experiments with wheat and sweet potato.

Two crop growth experiments in the soil-based closed ecological facility, Laboratory Biosphere, were conducted from 2003 to 2004 with candidate space life support crops. Apogee wheat (Utah State University variety) was grown, planted at two densities, 400 and 800 seeds m-2. The lighting regime for the wheat crop was 16 h of light-8 h dark at a total light intensity of around 840 micromoles m-2 s-1 and 48.4 mol m-2 d-1 over 84 days. Average biomass was 1395 g m-2, 16.0 g m-2 d-1 and average seed production was 689 g m-2 and 7.9 g m-2 d-1. The less densely planted side was more productive than the denser planting, with 1634 g m-2 and 18.8 g m-2 d-1 of biomass vs. 1156 g m-2 and 13.3 g m-2 d-1; and a seed harvest of 812.3 g m-2 and 9.3 g m-2 d-1 vs. 566.5 g m-2 and 6.5 g m-2 d-1. Harvest index was 0.49 for the wheat crop. The experiment with sweet potato used TU-82-155 a compact variety developed at Tuskegee University. Light during the sweet potato experiment, on a 18 h on/6 h dark cycle, totaled 5568 total moles of light per square meter in 126 days for the sweet potatoes, or an average of 44.2 mol m-2 d-1. Temperature regime was 28 +/- 3 degrees C day/22 +/- 4 degrees C night. Sweet potato tuber yield was 39.7 kg wet weight, or an average of 7.4 kg m-2, and 7.7 kg dry weight of tubers since dry weight was about 18.6% wet weight. Average per day production was 58.7 g m-2 d-1 wet weight and 11.3 g m-2 d-1. For the wheat, average light efficiency was 0.34 g biomass per mole, and 0.17 g seed per mole. The best area of wheat had an efficiency of light utilization of 0.51 g biomass per mole and 0.22 g seed per mole. For the sweet potato crop, light efficiency per tuber wet weight was 1.33 g mol-1 and 0.34 g dry weight of tuber per mole of light. The best area of tuber production had 1.77 g mol-1 wet weight and 0.34 g mol-1 of light dry weight. The Laboratory Biosphere experiment's light efficiency was somewhat higher than the USU field results but somewhat below greenhouse trials at comparable light levels, and the best portion of the crop at 0.22 g mol-1 was in-between those values. Sweet potato production was overall close to 50% higher than trials using hydroponic methods with TU-82-155 at NASA JSC. Compared to projected yields for the Mars on Earth life support system, these wheat yields were about 15% higher, and the sweet potato yields averaged over 80% higher.

Biomass↗

Soil and crop management experiments in the Laboratory Biosphere: an analogue system for the Mars on Earth(R) facility.

During the years 2002 and 2003, three closed system experiments were carried out in the "Laboratory Biosphere" facility located in Santa Fe, New Mexico. The program involved experimentation of "Hoyt" Soy Beans, (experiment #1) USU Apogee Wheat (experiment #2) and TU-82-155 sweet potato (experiment #3) using a 5.37 m2 soil planting bed which was 30 cm deep. The soil texture, 40% clay, 31% sand and 28% silt (a clay loam), was collected from an organic farm in New Mexico to avoid chemical residues. Soil management practices involved minimal tillage, mulching, returning crop residues to the soil after each experiment and increasing soil biota by introducing worms, soil bacteria and mycorrhizae fungi. High soil pH of the original soil appeared to be a factor affecting the first two experiments. Hence, between experiments #2 and #3, the top 15 cm of the soil was amended using a mix of peat moss, green sand, humates and pumice to improve soil texture, lower soil pH and increase nutrient availability. This resulted in lowering the initial pH of 8.0-6.7 at the start of experiment #3. At the end of the experiment, the pH was 7.6. Soil nitrogen and phosphorus has been adequate, but some chlorosis was evident in the first two experiments. Aphid infestation was the only crop pest problem during the three experiments and was handled using an introduction of Hyppodamia convergens. Experimentation showed there were environmental differences even in this 1200 cubic foot ecological system facility, such as temperature and humidity gradients because of ventilation and airflow patterns which resulted in consequent variations in plant growth and yield. Additional humidifiers were added to counteract low humidity and helped optimize conditions for the sweet potato experiment. The experience and information gained from these experiments are being applied to the future design of the Mars On Earth(R) facility (Silverstone et al., Development and research program for a soil-based bioregenerative agriculture system to feed a four person crew at a Mars base, Advances in Space Research 31(1) (2003) 69-75; Allen and Alling, The design approach for Mars On Earth(R), a biospheric closed system testing facility for long-term space habitation, American Institute of Aeronautics and Astronautics Inc., IAC-02-IAA.8.2.02, 2002).

Agriculture↗

Comparison between household budget survey and 24-hour recall data in a nationally representative sample of Polish households.

OBJECTIVE: Household budget survey (HBS) data are used regularly for nutritional epidemiological purposes. The validity of HBS data, however, is not well established. The aim of this project was to compare HBS and individual nutrition survey (INS) data in a nationally representative sample of Polish households. DESIGN: Estimates of food consumption and nutrient intake were compared between household food acquisition data collected over 1 month and a single 24-hour recall collected from every household member in a nationally representative sample of Polish households surveyed between September and November 2000. To facilitate the comparison, INS food consumption data excluded food eaten away from home and were modified using a computer program to estimate food 'as purchased' (including disaggregation of recipe data) and to allow for wastage. SETTING: Poland. SUBJECTS: Participants were 3716 individuals in 1215 households (representing co-operation rates of 86.2% and 89.2%, respectively). RESULTS: Good agreement was shown between median estimates of foods such as potatoes, vegetables (including processed), meat, meat products and poultry, and animal fats (excluding butter), but agreement was poor for bread and rolls, fruit, vegetable fats and oils, eggs and six other food groups. Estimates of energy and nutrient intake were within +/-10% with the exceptions of polyunsaturated fats, potassium and vitamin C. CONCLUSIONS: Possible reasons for differences in findings between the two surveys include survey bias (e.g. social approval bias leading to overreporting of fruit), seasonal variations (e.g. high potato purchases between September and November) and aspects of the methodology (e.g. HBS data were based on records collected over 1 month, whereas 24-hour recall data were based on recalls collected from all household respondents on only 1 day and averaged for each household type). HBSs provide useful data for epidemiological research, but findings need to be interpreted in the light of other data regarding consumption, and numerous factors that may affect consumption need to be taken into account.

Budgets↗