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PubMed2004

Plasma RNA viral load is not associated with intrapatient quasispecies heterogeneity in HIV-1 infection.

The human immunodeficiency virus type 1 (HIV-1) viral set point has been associated with the rate of, disease progression and with the level of HIV-specific immune response. The analysis of the possible association between viral set point and quasispecies heterogeneity has important consequences in the understanding of HIV-1 in vivo evolution. In this study, we analyzed the association between intrapatient viral diversity and RNA viral load in 16 antiretroviral therapy-naive HIV-1-infected patients at a single time point, during the disease free period. Patients were separated into low and high viral load groups according to plasma RNA values. HIV-1 quasispecies complexity was assessed in the C2-V5 env region. The average intrapatient quasispecies heterogeneity in both groups was not significantly different (t-test, P > 0.05). However, while within the low viral load group both synonymous and non-synonymous mutations contribute to the variation observed, in the heterogeneity observed in the high viral load group there was an increase in the contribution of the non-synonymous mutations. Thus, this study show that although intrapatient quasispecies heterogeneity is not associated with viral set point in HIV-1 infection, some differences exist between the two groups in the pattern of mutation accumulation.

Amino Acid Substitution↗

PubMed1997

Practice variation in Swedish primary care.

OBJECTIVE: To study individual practice patterns of physicians working in primary health care for standardized simulated cases on their first visit, and relate them to resource consumption for diagnostic tests, drugs and sick leave from a combined perspective of the health care and social security systems. DESIGN: Postal questionnaire presenting six hypothetical working-age cases with symptoms of ailments common in primary care asking physicians to order diagnostic tests and procedures, drugs, follow-up appointments and sick pay. SETTING: Swedish primary health care centres. SUBJECTS: Two hundred randomly selected physicians. MAIN OUTCOME MEASURES: Activities taken by the physician-diagnostic and laboratory tests ordered, drugs prescribed, length of sick leave and the cost of these actions. RESULTS: Practice patterns varied considerably, corresponding to a six-fold difference in total cost between the "cheapest" and "most expensive" physician. The largest share was loss of production as estimated by the cost of prescribed sick leave. Physicians who practised further away from hospitals and those who had worked more years tended to prescribe more measures. However, this only explained a small portion of the observed variation, which may be due to different physician attitudes to taking risks. CONCLUSION: "Paper" cases of common medical ailments presented to primary care physicians revealed considerable differences in practice style, resulting in six-fold differences in cost of measures prescribed at first visits.

Adult↗

PubMed1982

Diurnal oscillations in plasma protein binding of valproic acid.

In view of the observed variation of valproic acid (VPA) free fraction (fp) during a dosing interval and the competitive binding effect of free fatty acids (FFA) in vitro, this study was designed to address the existence of diurnal variations in the fp of VPA. Six subjects were hospitalized at 7 a.m. for 25 h, and plasma samples were collected every 2 h. The protocol was repeated in 4 of the 6 subjects one week later. In vitro binding of VPA (100 micrograms/ml) was determined by equilibrium dialysis (14C-VPA), and FFAs were assayed colorimetrically. Phenytoin (PHT) binding was also determined for comparison. VPA fp ranged from 8.10 +/- 1.16 to 9.63 +/- 1.54. Intrasubject variability was also measured by the ratio of maximum to minimum fp values (fp max/fp min) over 24 h: This ratio ranged from 1.30 to 1.68 (mean +/- %SD = 1.51 +/- 7.7%, n = 10). For PHT, fp ranged from 10.88 +/- 0.50 to 12.39 +/- 1.07, and fp max/fp min from 1.09 to 1.31 (1.17 +/- 5.1%, n = 10). The fp max was observed between 2 and 6 a.m. in 7 out of 10 cases for VPA and 5 out of 10 cases for PHT. FFA levels, although in the normal range, varied two- to fourfold within 24 h. A significant correlation was observed between mean FFA levels at each sampling time and the corresponding fp values for VPA (p less than 0.001), but not for PHT.

Adolescent↗

PubMed2006

Unfolding and refolding of bovine serum albumin at acid pH: ultrasound and structural studies.

Serum albumin is the most abundant protein in the circulatory system. The ability of albumins to undergo a reversible conformational transition, observed with changes in pH, is conserved in distantly related species, suggesting for it a major physiological role possibly related to the transport of small molecules including drugs. We have followed changes of bovine serum albumin (BSA) in volume by densimetry and in adiabatic compressibility during its conformational transition from pH 7-2, using ultrasound measurements. In parallel, circular dichroism was measured. The volume and adiabatic compressibility decrease from pH 4 to 2. The change in ellipticity shows a decrease over the same pH range from 70% to 40% of its alpha-helix content. Sorbitol, at concentrations from 0 to 2 M, led to the progressive restoration of BSA volume and compressibility values, as well as a substantial recovery of its original alpha-helix content. This finding implies that the compressibility variation observed reflects the conformational changes during the transition. The mutual interactions of the mechanical properties and structural features of BSA reported here are important in biotechnology for research in material sciences and for the design and the development of new, tailor-made drug carriers.

Computer Simulation↗

PubMed1986

Natural history of asthma in patients requiring long-term systemic corticosteroids.

To study the natural history of corticosteroid-dependent asthma, we evaluated 40 randomly selected adult patients with severe asthma who were refractory to management with inhaled corticosteroids and bronchodilators and who required long-term prednisone therapy (mean duration, 6.2 +/- 5.1 years). During long-term observation, 13 patients (32.5%) significantly improved; ten (25%) of these tolerated discontinuation of long-term prednisone use and three (7.5%) had decreased prednisone requirements. Three patients (7.5%) had increased requirements for prednisone. Twenty-four patients (60%) had generally unchanged, long-term prednisone requirements; of note, eight of these had significant, but temporary intervals (mean, 3.2 years) when they could be managed without prednisone. Patients with mixed asthma were more likely to tolerate discontinuation of long-term prednisone; no other factors studied were predictive of the course of asthma. Although prior to our care many patients had a history of numerous emergency room visits and hospitalizations (some for life-threatening episodes of status asthmaticus), there were few emergency room visits and hospitalizations while under strict management by our service. Variations observed in the natural history of corticosteroid requirements in asthma must be considered in designing studies seeking to evaluate efficacy of new experimental therapies for asthma.

Administration, Inhalation↗

PubMed2002

Functional and ecological significance of rDNA intergenic spacer variation in a clonal organism under divergent selection for production rate.

It has recently been hypothesized that variation in the intergenic spacer (IGS) of rDNA has considerable developmental, evolutionary and ecological significance through effects on growth rate and body C : N : P stoichiometry resulting from the role of the IGS in production of rRNA. To test these ideas, we assessed changes in size and structure of the repetitive region of the IGS, juvenile growth rate (JGR), RNA and phosphorus (P) contents in clonal lineages of Daphnia pulex derived from a single female and subjected to divergent selection on weight-specific fecundity (WSF). As a result of selection, WSF diverged rapidly, with significant reductions within two generations. Other significant changes accompanying shifts in WSF were that juveniles produced by low-WSF females grew more rapidly and had higher RNA and P contents. An increased predominance of long IGS variants was observed in lineages with elevated JGRs and low WSF. The observed variations in IGS length were related to the number of subrepeat units carrying a promoter sequence in the repetitive region. These results strongly support the hypothesized relationships, indicate a genetic mechanism for the evolution of such associations and demonstrate that Daphnia (and perhaps other parthenogens) possess considerable potential for rapid adaptive change in major life-history traits.

Adaptation, Physiological↗

PubMed1997

DRB4 promoter polymorphism in DR7 individuals: correlation with DRB4 pre-mRNA and mRNA levels.

DRB genes encode proteins which play an important role in the immune response, and variation in their expression levels may be of functional immunological significance. To date, HLA class II gene promoter polymorphism has been analyzed almost exclusively in Epstein-Barr virus (EBV)-transformed B-cell lines. While previous studies have established important paradigms with regard to the mechanisms in DRB gene expression, the role of DRB4 promoter polymorphism in the variation of DRB4 expression levels, if any, is still unclear. We analyzed the effects of a previously described polymorphism in the promoter and 5' untranslated region of the DRB4 locus in peripheral blood mononuclear cells (PBMCs) from nine healthy DR7 individuals using the RNase protection assay. The RNase protection analyses showed that the location of transcription initiation is not affected. The DRB4 alleles show a threefold difference in pre-mRNA and a corresponding fivefold difference in mRNA levels in PBMCs. These data show that the DRB4 promoter polymorphism is associated with differential gene expression of this locus. The difference in pre-mRNA levels is directly affected by this DRB4 promoter polymorphism. The additional difference in mRNA levels is the result of post-transcriptional regulation. Therefore, the DRB4 promoter polymorphism may explain the previously observed variation in HLA class II DRB4 gene expression levels among different healthy DR7 individuals.

Alleles↗

PubMed1993

Cost of gentamicin assays carried out by microbiology laboratories.

AIMS: To assess the current range of prices charged for gentamicin assays in United Kingdom laboratories; and to examine the laboratories' likely response to increases or decreases in the demand for the service. METHODS: A postal survey of the 420 members of the Association of Medical Microbiologists was used to establish the range of prices charged for aminoglycoside assays. Additionally, eight private institutions were contacted to determine what the private sector was charging for aminoglycoside assays. Reagent costs in the NHS laboratories were calculated by dividing the total cost of all aminoglycoside assay kits by the number of samples analysed. RESULTS: The NHS and the private institutions both showed a wide price variation. Prices charged to an in-hospital requester for a peak and trough assay ranged from 5.00 pounds to 68.20 pounds (n = 44), and to an external private hospital, under a bulk service contract, from 5.00 pounds to 96.00 pounds (n = 47). Prices charged by private laboratories ranged from 49.00 pounds to 84.00 pounds (n = 8). There was a log linear correlation in the NHS laboratories between the reagent costs per assay and the number of assays performed per year, and most laboratories thought that their price per assay would be sensitive to increases or decreases in demand. Laboratories which had purchased their assay machines had lower reagent costs per assay but higher repair and maintenance costs. Overall, number of assays performed and method of payment for assay machinery only accounted for 44.8% of the observed variation in assay kit costs. CONCLUSIONS: The price range for gentamicin assays in the United Kingdom is wide and is only partially explained by the number of assays performed. Most laboratories believe that they would experience a reduction in unit cost as output increases. The currently offered range of prices is, in part, due to variation in the laboratories' approach to costing the service provided and some laboratories charge prices which do not even cover the cost of assay kits. Overall, we believe that prices charged should be as close as possible to the marginal cost of the tests performed.

Clinical Laboratory Techniques↗

PubMed2002

Unique genetic variation revealed by a microsatellite polymorphism survey in ten wild-derived inbred strains.

Here we report on a genome polymorphism survey using 254 microsatellite markers in ten recently wild-derived inbred strains. Allele size analysis showed that the rate of polymorphism of these wild-derived mouse strains when compared with any of the common laboratory strains is on average 79.8%. We found 632 wild-derived alleles that were not present in the common laboratory strains, representing a 61% increase over the genetic variation observed in the laboratory strains. We also found that on average 14.5% of the microsatellite alleles of any given wild-derived inbred strain were unique. Our results indicate that the recently wild-derived mouse strains represent repositories of unique naturally occurring genetic variability and may prove invaluable for the study of complex phenotypes and in the construction of new mouse models of human disease.

Alleles↗

PubMed1993

Influence of demographic factors on antithrombin III activity in a healthy population.

Antithrombin III (AT III) activity has been measured in 9669 healthy blood donors (5525 male and 4144 female). The distribution of AT III is approximately 'normal' with mean 105.6 IU/dl and standard deviation 11.2; however, definite age and sex related variations are evident. Pre-menopausal females have lower mean AT III compared to their male contemporaries who have remarkably stable mean AT III until 45 years, after which there is a gradual decline. In contrast, post-menopausal females have higher mean AT III than both males of the same age and younger pre-menopausal females. Concurrent hormone replacement therapy inhibits this rise. The use of hormonal preparations is associated with a 4 IU/dl reduction of mean AT III in younger females but not in those over 30 years. Smoking may result in a mild increase in AT III of doubtful clinical significance. On-going genetic and family studies are expected to predict a prevalence rate of congenital AT III deficiency in excess of the previously reported figure of 0.02%. The authors consider these observed variations as minor and recommend the use of a single reference range for AT III activity, but that particular care be taken when interpreting results in pill-taking females and the elderly.

Adolescent↗

PubMed2006

Enhancing the comparability of costing methods: cross-country variability in the prices of non-traded inputs to health programmes.

BACKGROUND: National and international policy makers have been increasing their focus on developing strategies to enable poor countries achieve the millennium development goals. This requires information on the costs of different types of health interventions and the resources needed to scale them up, either singly or in combinations. Cost data also guides decisions about the most appropriate mix of interventions in different settings, in view of the increasing, but still limited, resources available to improve health. Many cost and cost-effectiveness studies include only the costs incurred at the point of delivery to beneficiaries, omitting those incurred at other levels of the system such as administration, media, training and overall management. The few studies that have measured them directly suggest that they can sometimes account for a substantial proportion of total costs, so that their omission can result in biased estimates of the resources needed to run a programme or the relative cost-effectiveness of different choices. However, prices of different inputs used in the production of health interventions can vary substantially within a country. Basing cost estimates on a single price observation runs the risk that the results are based on an outlier observation rather than the typical costs of the input. METHODS: We first explore the determinants of the observed variation in the prices of selected "non-traded" intermediate inputs to health programmes--printed matter and media advertising, and water and electricity--accounting for variation within and across countries. We then use the estimated relationship to impute average prices for countries where limited data are available with uncertainty intervals. RESULTS: Prices vary across countries with GDP per capita and a number of determinants of supply and demand. Media and printing were inelastic with respect to GDP per capita, with a positive correlation, while the utilities had a surprisingly negative relationship. All equations had relatively good fits with the data. CONCLUSION: While the preferred option is to derive costs from a random sample of prices in each setting, this option is often not available to analysts. In this case, we suggest that the approach described in this paper could represent a better option than basing policy recommendations on results that are built on the basis of a single, or a few, price observations.

Journal Article↗

PubMed1982

[Spasm of the coronary arteries].

Spontaneous spasm and methylergometrine maleate-provoked spasm are defined, the latter being observed in nearly all cases of so-called Prinzmetal angina, in approximately one out of three cases of angina at rest, and a certain number of cases of unstable angina: it has even been demonstrated during effort tests with coronarography. Several studies have demonstrated its possible implication in myocardial infarction. Continuous electrocardiogram recordings and isotopic studies have also shown the frequency of silent spasms, or those associated with other ECG modifications than an increased STT latency period. It is now well-established that this type of angina is provoked by reduction in myocardial oxygen supply. To explain the triggering mechanism of the spasm, various factors have been successively evoked: alpha- and beta-receptor disequilibrium, a vagal effect, the very important role played by thromboxane A2 of platelet origin. Emphasis is also placed on circadian variations observed during the spasm, but the course of spastic angina is often unpredictable, leading to necrosis or sudden death in a fairly large number of cases. Medical treatment is essentially by long-acting nitrate derivatives and calcium inhibitors (beta-blockers are considered, according to different teams, as being useless or even dangerous). Surgical treatment may be by aortocoronary shunt or transluminal angioplasty in cases that are stable with trinitrate compounds; associated plexectomy has given good results according to teams in Lille; while heart transplantation has been performed in rare cases. Choice of therapy is difficult in cases with apparently non-surgical moderate stenosis and recurrent spastic angina.

Angina Pectoris, Variant↗

PubMed1998

Low divergence in rDNA ITS sequences among five species of Fucus (Phaeophyceae) suggests a very recent radiation.

Sequences from the two ribosomal DNA internal transcribed spacers (ITS1 and ITS2) were compared among five species of Fucus. Based on the present taxon sampling, parsimony analysis showed that Fucus serratus is the sister-group of the remaining Fucus species when Ascophyllum nodosum was used as an outgroup. The topology of the tree was (Fucus serratus (F. lutarius (F. vesiculosus (F. spiralis + F. ceranoides)))). The extremely low variation observed suggests a very recent radiation of the genus which supports the view widely accepted that the Fucales are among the most evolutionarily advanced of the brown algae. We further note that sequence differences between Fucus and Ascophyllum were 28%: this does not rule out the utility of ITS sequences within the Fucaceae. The very low number of informative positions allows to demonstrate empirically that distance matrix methods group on the basis of symplesiomorphies.

Base Sequence↗

PubMed1982

Evidence for a relative excess of lysyl hydroxylase in chick embryo tendon and cartilage compared with bone and skin.

Various chick embryo tissues were incubated in vitro with a range of Zn2+ concentrations, and inhibition of the hydroxylations of collagen proline and lysine residues was studied in the intact tissues. At an constant inhibition level of proline hydroxylation, lysine hydroxylation proved to be inhibited more in the skin and bone than in the tendon and cartilage. The ratios of lysyl hydroxylase to prolyl hydroxylase activity were also distinctly lower in the former than in the latter. The variations observed in the reduction of lysine hydroxylation by Zn2+ thus correlate well with the differences seen in the enzyme activity ratios. No differences are found in the Ki values for Zn2+ between purified prolyl and lysyl hydroxylases or between the same enzymes from different tissues, and consequently the differences in lysine hydroxylation inhibition between the various tissues cannot be explained by differences in the kinetic constants. Recent studies also suggest that the existence of tissue-specific lysyl hydroxylase isoenzymes is improbable. The data thus suggest that there is a relative excess of lysyl hydroxylase activity in tissues such as tendon and cartilage, in which the lysine hydroxylation was less sensitive to Zn2+ inhibition, compared with skin and bone, where lysine hydroxylation was inhibited to a greater extent. These data are in a good agreement with the findings concerning variation in the reduction in lysine hydroxylation in different tissues with age or in the Ehlers-Danlos Syndrome Type VI.

Animals↗

PubMed2004

Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients.

The measurement of plasma clozapine concentrations is useful in assessing compliance, optimizing therapy, and minimizing toxicity. We measured plasma clozapine and norclozapine (N-desmethylclozapine) concentrations in samples from 3782 patients (2648 male, 1127 female). No clozapine was detected in 291 samples (227 patients, median prescribed dose 300 mg/d). In 4963 (50.2 %) samples (2222 patients); plasma clozapine concentration ranged from 10 to 350 ng/mL.Step-wise backward multiple regression analysis (37 % of the total samples) of log10 plasma clozapine concentration against log10 clozapine dose (mg/d), age (year), sex (male = 0, female = 1), cigarette smoking habit (nonsmokers = 0; smokers = 1), body weight (kg), and plasma clozapine/norclozapine ratio (clozapine metabolic ratio, MR) showed that these covariates explained 48% of the observed variation in plasma clozapine concentration (C = ng/mL x 10-3) (P < 0.001) according to the following equation: log 10 (C) = 0.811 log 10 (dose) + 0.332 (MR) + 69.42 X 10 (-3) (sex) + 2.263 x 10 (-3) (age) + 1.976 x 10(-3) (weight) - 0.171 (smoking habit) - 3.180. This model and its associated confidence intervals were used to develop nomograms of plasma clozapine concentration versus dose for male and female smokers and nonsmokers. Predicted plasma clozapine changes by +48% in nonsmokers, +17% in females, +/-8 % for every 0.1 change in MR (reference 1.32), +/-4% for every 5 years (reference 40 years), and +/-5 % for every 10 kg body weight (reference 80 kg). The nomograms can be used (i) to individualize dosage to achieve a given target plasma clozapine concentration, and (ii) for quantitative evaluation of adherence by estimating the likelihood of an observed concentration being achieved by a given dosage regimen. The model has been validated against published data.

Adult↗

PubMed1991

Use of sex-linked minisatellite fragments to investigate genetic differentiation and migration of North American populations of the peregrine falcon (Falco peregrinus).

The M13 repeat detects different levels of genetic variation in falcons. First, this minisatellite probe reveals typically highly variant restriction fragments that show no apparent unequal distribution between the sexes. Secondly, the M13 repeat detects sets of fragments that are only present in DNAs from female falcons. The level of polymorphism displayed by the sex-linked fragments is greatly reduced relative to most autosomal minisatellites. In addition, the size of these fragments (in kilobase pairs) is species-specific among Mauritius kestrels (Falco punctatus) and peregrines (Falco peregrinus). Variation observed at one o of the sex-linked fragments in peregrines has proven to be useful in distinguishing a subset of the tundrius subspecies of this endangered raptor. This correlation has enabled a genetic test to be used to examine the representation of tundrius peregrines during mass migration.

Animals↗

PubMed2003

Quality of care for children in commercial and Medicaid managed care.

CONTEXT: Many states have turned to commercial health plans to serve Medicaid beneficiaries and to achieve cost-containment goals. Assumptions that the quality of care provided to Medicaid beneficiaries through these programs is acceptable have not been tested. OBJECTIVE: To compare the quality of care provided to children and adolescents in commercial and Medicaid managed care in the United States. DESIGN, SETTING, AND POPULATION: Using 1999 data collected through the Health Plan Employer Data and Information Set, we examined reported quality-of-care indicators for children and adolescents. Results from 423 commercial and 169 Medicaid plans were compared. Matched pairs analyses were performed using data from each of the 81 companies serving both populations to control for corporate differences. Correlation coefficients and regression procedures were used to examine observed variations in health plan performance. MAIN OUTCOME MEASURES: Quality indicators including prenatal care, childhood immunizations, well-child visits, adolescent immunizations, and myringotomy and tonsillectomy rates. RESULTS: Using standard indicators of clinical performance, children and adolescents enrolled in Medicaid received worse care compared with their commercial counterparts. For most of the 81 health plans serving both populations, Medicaid enrollees had statistically significantly (P<.001) lower rates than commercial plans for clinical quality indicators (eg, childhood immunization rates of 69% vs 54%); for clinical access indicators (eg, well-child visits in the first 15 months of life, 53% vs 31%); and for common procedures (eg, myringotomies for children aged 0-4 years, 35 vs 2 per 1000 members). Conversely, some plans demonstrated equal and high-quality care for both populations. Regression models failed to identify consistent plan characteristics that explained the observed differences in quality of care. CONCLUSIONS: Most commercial health plans do not deliver high-quality care on a number of performance indicators for children enrolled in Medicaid. Policy makers and the public need plan-specific quality information to inform purchasing decisions.

Adolescent↗

PubMed2006

Type III effector diversification via both pathoadaptation and horizontal transfer in response to a coevolutionary arms race.

The concept of the coevolutionary arms race holds a central position in our understanding of pathogen-host interactions. Here we identify the molecular mechanisms and follow the stepwise progression of an arms race in a natural system. We show how the evolution and function of the HopZ family of type III secreted effector proteins carried by the plant pathogen Pseudomonas syringae are influenced by a coevolutionary arms race between pathogen and host. We surveyed 96 isolates of P. syringae and identified three homologs (HopZ1, HopZ2, and HopZ3) distributed among approximately 45% of the strains. All alleles were sequenced and their expression was confirmed. Evolutionary analyses determined that the diverse HopZ1 homologs are ancestral to P. syringae, and have diverged via pathoadaptive mutational changes into three functional and two degenerate forms, while HopZ2 and HopZ3 have been brought into P. syringae via horizontal transfer from other ecologically similar bacteria. A PAML selection analysis revealed that the C terminus of HopZ1 is under strong positive selection. Despite the extensive genetic variation observed in this family, all three homologs have cysteine-protease activity, although their substrate specificity may vary. The introduction of the ancestral hopZ1 allele into strains harboring alternate alleles results in a resistance protein-mediated defense response in their respective hosts, which is not observed with the endogenous allele. These data indicate that the P. syringae HopZ family has undergone allelic diversification via both pathoadaptive mutational changes and horizontal transfer in response to selection imposed by the host defense system. This genetic diversity permits the pathogen to avoid host defenses while still maintaining a virulence-associated protease, thereby allowing it to thrive on its current host, while simultaneously impacting its host range.

Adaptation, Biological↗