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Comparative effects on hemodynamics of enoximone (MDL 17,043), dobutamine and nitroprusside in severe congestive heart failure.

To assess their comparative effects on hemodynamics, nitroprusside, dobutamine and enoximone were sequentially administered to 10 patients with severe congestive heart failure. Nitroprusside, dobutamine (at 10 micrograms/kg/min) and enoximone (at 2 mg/kg) increased stroke volume index to a similar extent (31%, 34% and 36%, respectively). Enoximone produced less tachycardia than dobutamine and, consequently, a smaller improvement in cardiac index. Mean arterial pressure was not altered by dobutamine but was reduced 9% by enoximone, 2 mg/kg. This finding accounts for the larger (although not significant) increase in left ventricular stroke work index observed with dobutamine compared with enoximone. Ventricular filling pressures and vascular resistances were significantly decreased by all 3 drugs (p = 0.001). All 3 drugs improved cardiac pump function when assessed by the increase in stroke index to a similar extent; however, enoximone (2 mg/kg) resulted in less hypotension than nitroprusside (mean arterial pressure -9% vs -22%, p = 0.0001) and in less tachycardia than dobutamine 10 micrograms/kg/min. Those differences in mode of action account for the variations observed in the heart rate-blood pressure product (dobutamine 10 micrograms/kg/min, +18%, enoximone 2 mg/kg, -5%, p = 0.003). Enoximone thus appears to be of great value in the management of severe congestive heart failure by its combination of vasodilatory and inotropic properties. Enoximone (2 mg/kg) provides a clinically significant increase in cardiac index, a clear reduction of ventricular filling pressures, a moderate reduction of mean arterial pressure and only minor changes of heart rate and of rate pressure product.

Aged↗

Primate beta-defensins--structure, function and evolution.

Host defense peptides (HDPs) are endogenous antibiotics that play a multifunctional role in the innate immunity of mammals. Among these, beta-defensins contribute to mucosal and epithelial defense, also acting as signal molecules for cellular components of innate and adaptive immunity. Numerous members of this family have been identified in mammalian and avian species, and genomic studies in human and mouse indicate a considerable complexity in their gene organization. Recent reports on the evolution of primate and rodent members of this family indicate quite a complex pattern of variation. In this review we briefly discuss the evolution of mammalian beta-defensins in relation to other types of defensins, and then concentrate on the evolution of beta-defensins 1 to 4 in primates. In particular, the surprisingly varied patterns of evolution, which range from neutral or weakly purifying, to positive selection to a high level of conservation are analyzed in terms of possible genetics, structural or functional implications, as well as to observed variations on the antimicrobial activity in vitro. The role of polymorphisms in the genes encoding for these host defense peptides in determining susceptibility to human diseases are also briefly considered.

Amino Acid Sequence↗

[Study of factors of biological variations acting on the concentration of the alpha-1-serous antitrypsin in a "common population" (author's transl)].

We established by nephelometry the serous concentration in an antitrypsin alpha-1 from an example of common population of th preventive Medicine Center of VAndoeuvre-lès-Nancy (675 adults men and women). First of all, the technical qualities of the equipment (replication : 0.06) to 1.1 per cent) and the dosage method (replication : 1,6 to 2,9 per cent, reproduction 3,4 to 4,3 per cent) were estimated. We showed that the technique was well connected with the electroimmunodiffusion (r : 0.90), but that was an important dissociation between the concentrations established by the two methods. The analytical variation being known, we approached the study of biological variations. The distribution of antitrypsin alpha-1 values is quite log-normal (median : 1,71 g/l, medium : 1,76 G/l). The main factors of biological variation observed are the sex (increase in 6 to 11 per cent in women), the age (decrease in 10 per cent between 20-30 years old and 40-50 years old women), the tobacco (increase in 9,5 per cent in the men smoking more than 20 cigarettes a day), the drinking of alcohol (decrease in 10 per cent for two sexes), the taking of oral contraceptives (increase in 29 per cent). These factors of biological variation should be taken in account at the time of producing the reference values, in addition of the analytical, pathological and genetic factors.

Adult↗

Tensile properties of nondegenerate human lumbar anulus fibrosus.

STUDY DESIGN: The in vitro tensile behavior of multiple-layer samples of anulus fibrosus were investigated from nondegenerate intervertebral discs. OBJECTIVES: To quantify the intrinsic tensile behavior of nondegenerate anulus fibrosus and the variations with position and age in the intervertebral disc. SUMMARY OF BACKGROUND DATA: Tension is an important loading mode in the anulus fibrosus. The tensile behavior of single- and multiple-layer samples of anulus fibrosus has been shown to vary with specimen orientation, position in the disc, and environmental conditions. Little is known of the changes in these site-specific tensile properties of the anulus with aging or degeneration of the intervertebral disc. METHODS: Multiple-layer specimens of anulus fibrosus were harvested with an orientation parallel to the circumference of the disc. Constant strain rate and uniaxial tensile tests were performed in 0.15 mol/l NaCl at slow strain rates to measure the intrinsic properties of the collagen-proteoglycan matrix of the anulus fibrosus. The tensile modulus, failure stress, failure strain, and strain energy density were determined. Statistical analyses were done to evaluate regional and age-related differences in these properties. RESULTS: Significant radial and circumferential variations in the intrinsic tensile properties of anular samples were detected. The anterior anulus fibrosus had larger values for tensile moduli and failure stresses than the posterolateral anulus. Also, the outer regions of the anulus had greater moduli and failure stresses and lower failure strains than the inner regions. Strain energy density did not vary significantly with region. Significant, but very weak, correlations were detected between tensile properties and age of the intervertebral disc. CONCLUSIONS: The observed variations in tensile behavior of multiple-layer anulus samples indicate that larger variations in tensile modulus and failure properties occur with radial position in the disc than from anterior to posterolateral regions. This pattern is likely related to site-specific variations in the tensile properties of the single-layer samples of anulus fibrosus lamellae and the organization of successive lamellae and their interactions. The results of the present study suggest that factors other than age, such as compositional and structural variations in the disc, are the most important determinants of tensile behavior of the anulus fibrosus.

Adult↗

Community income and surgical rates in the Netherlands.

BACKGROUND: The study describes variations in use of surgical procedures by community income in the Netherlands. From the literature it is known that surgical rates have a socioeconomic gradient. Both positive and negative associations of socioeconomic factors of patients (for example, income, education) with surgical rates have been reported. The question raised here is: how do (possible) socioeconomic variations in surgery in the Netherlands compare with variations observed elsewhere? DATA AND METHODS: The data comprised Dutch hospital discharges and population estimates for 1999. Socioeconomic status was indicated by a patient's income and based on the average family income of the postcode area of residence. Poisson regression was used to compute relative incidence (odds ratios) for 10 common surgical procedures. The model included age, gender, degree of urbanisation, and province of residence. RESULTS: The association between surgical rates and community level income is rather weak. For half of the surgical rates the authors observed higher utilisation rates in communities with low income levels, but the differences are small. The range of odds ratios in the lowest income quintile group (compared with the group with the highest income) observed is: 0.87 to 1.18. Men from a low income community received more appendicectomies (1.18), cholecystectomies (1.12), knee replacements (1.06), and prostatectomies (1.14) and less tonsillectomies (0.90). Women from a low income community received more appendicectomies (1.12), caesarean sections (1.18), hip and knee replacements (1.05,1.17), and hysterectomies (1.14). Whereas they received less coronary artery bypass grafts (0.92), cholecystectomies (0.87), and tonsillectomies (0.92). CONCLUSIONS: Compared with findings reported in the international literature, this study indicates that variations in use of surgical procedures by community income in the Netherlands are comparatively small. Because of lack of data the authors could not study the influence of variations in need for surgical care by community income, but as the incidence of conditions requiring surgical interventions generally is higher in lower income groups, it is suspected some degree of underutilisation exists in these groups.

Female↗

Characterization of an inducible porter required for L-proline catabolism by Escherichia coli K12.

L-Proline can serve as sole source of carbon and nitrogen for the growth of Escherichia coli K12 and other Enterobacteria. L-Proline uptake and L-proline oxidase are subject both to catabolite repression and to specific induction by L-proline or glycyl-L-proline, although their regulation is not strictly coordinate. A strain defective for L-proline uptake due to a lesion at the locus putP does not show elevated uptake activity either on relief of catabolite repression or when grown on glycyl-L-proline as nitrogen source. The apparent Km for L-proline uptake decreases up to 14-fold as uptake Vm increases when cells are induced for both L-proline uptake and L-proline oxidase; cells with increased uptake activity, alone, do not show an altered Km. Although L-proline is metabolized during the uptake measurements, uptake is always active. The observed variations in uptake Km are unlikely to result from the escape of radioactive L-proline metabolites or from reversal of the transport reaction during the uptake measurements. We conclude that the L-proline porter encoded in putP is responsible for 80 to 90% of the constitutive and for the inducible L-proline uptake activity of wild-type bacteria. Although this porter is amplified in cells induced for L-proline catabolism, the observed values for uptake Vm may not be taken as a direct indicator of porter concentration.

Biological Transport, Active↗

Seasonal abundance of two armyworm species, Spodoptera exitgua (Hübner) and Spodoptera litura (F.) in the Philippines.

The two armyworm species Spodoptera exigua (Hübner) and S. litura (F.) are Important pests on several agricultural crops in the tropics. Knowledge about species abundance is important for the development of integrated pest management strategies. During 1998 and 1999 population densities were recorded weekly using pheromone traps at San Leonardo and Munoz (Province Nueva Ecija, 150 km north of Metro Manila) on the Philippine island Luzon. Furthermore, meteorological conditions and natural enemies were observed. Both armyworm species were present year-round at both observation sites. No differences in numbers of male insects trapped in pheromone traps between seasons were found for S. litura. Contrary, numbers of male S. exigua trapped during rainy season was significant higher than during dry season. Rainfall explained between 30 and 40% of trapped moths and has to be considered when monitoring population density with pheromone traps. Parasitism rates were below 5% in both years and for both species and can not explain the high variation observed in population densities.

Animals↗

Variations of interferon inactivators and/or inhibitors in human serum and their relationship to interferon therapy.

Anti-interferon (IFN) activities of normal human sera and sera from cases suspected of viral infection were determined. Of the normal sera tested (57), 65% presented anti-IFN activities against IFN-alpha and/or -beta preparations; 61% against IFN-beta and 32% against IFN-alpha. Of the sera from suspected virus-infected individuals (44), 82% presented anti-IFN activity to IFN-beta and 57% to IFN-alpha with the majority of sera (91%) exerting anti-IFN activities to IFN-alpha and/or -beta preparation. The observed variations of anti-IFN alpha and beta activities of human sera appear to be reproducible and should be taken into consideration in the clinical application of IFN.

Humans↗

Development of a non-human primate sub-clinical model of heparin-induced thrombocytopenia: platelet responses to human anti-heparin-platelet factor 4 antibodies.

The purpose of this study was to characterize the responses of human and non-human primate (Macaca mulatta) platelets to anti-heparin-platelet factor 4 (AHPF4) antibodies. Due to the variations observed in the functionality and immunoglobulin isotypes in patients with heparin-induced thrombocytopenia (HIT), we used highly characterized human AHPF4 antibodies to study platelet activation responses. Using ELISA and 14C-serotonin release assay (SRA) systems, three patients' plasmapheresis fluid with similar responses to these assays were pooled. This pool was then used to study the platelet activation responses of human and primate platelets in the HIT platelet aggregation assay, a flow cytometry assay, and a variation of the aggregation assay in which glycoprotein IIb/IIIa inhibitors were supplemented. In the plasmapheresis fluid from three patients, the most significant AHPF4 immunoglobulin isotype present (based on optical density readings) was IgG, with less IgM (p < 0.001) and IgA (p < 0.001). The SRA yielded equivalent platelet activation results in all three patients. Using this pool in the platelet aggregation assay, without any heparin present, there was less percent aggregation (p < 0.001) with human platelets (11.8 +/- 2.35, n = 5) compared to the primate platelets (54.3 +/- 10.2, n = 9). In presence of 0.4 U/ml heparin, both platelet types had similar percent aggregations (p > 0.05). Three glycoprotein IIb/IIIa receptor inhibitors were used to evaluate the similarities in platelet activation. Eptifibatide was found to be a strong inhibitor of both species' platelet types at concentrations greater than 0.01 microg/ml. This was not the case with tirofiban which inhibited both human and monkey platelets at concentrations greater than 0.025 microg/ml. Abciximab inhibited aggregation at concentrations greater than 6.25 microg/ml. These data indicate that phylogenetic similarities in platelets of humans and primates may be used to further characterize the pathophysiology of HIT syndrome.

Abciximab↗

Variation of incubation time in an in vitro drug susceptibility test of Plasmodium falciparum isolates studied in the Solomon Islands.

A study on chloroquine resistance of falciparum malaria was conducted in the Solomon Islands. Both in vitro and clinical tests were performed. In our regular studies of in vitro chloroquine susceptibility tests on Plasmodium falciparum from non-immuners in Japan, the threshold point to differentiate resistant and susceptible isolates was set at a 0. 114 microM chloroquine in the semi-micro culture system, and this point was also applicable in the study of the malaria parasite taken in the highly endemic malarious area with good coincidence with clinical observation. Variation in the incubation time (24-63) to reach the schizont stage of the isolated parasites were noted. It appeared that chloroquine resistant P. falciparum showed traits to reach the schizont stage within a shorter incubation period.

Animals↗

Genetic variants of proteins from the renin angiotensin system are associated with pressure load cardiac hypertrophy.

1. The relationship between the angiotensinogen (AGT) T174M, angiotensin converting enzyme (ACE) insertion/deletion (I/D) and the angiotensin II type 1 receptor (AT1) genetic markers and left ventricular hypertrophy was examined in normal subjects and those with aortic stenosis. 2. Subjects with aortic stenosis had higher left ventricular systolic pressure and relative wall thickness (RWT) compared with normal. However, within aortic stenosis subjects, left ventricular RWT did not correlate with left ventricular systolic pressure or with aortic valve area. 3. In subjects with aortic stenosis, left ventricular RWT was higher in those with ACE DD (P < 0.05) or AGT T174M (P < 0.06) compared with those with the ACE II or ID genotype or AGT TT174 genotype. No relationship was observed with any of the AT1 alleles. The ACE and AGT genetic markers independently predicted left ventricular RWT in aortic stenosis. No association was observed between these genotypes and left ventricular RWT in normal subjects. 4. The data suggest that the AGT T174M and ACE I/D genotypes may act together to influence the degree of hypertrophy in subjects with aortic stenosis. 5. In patients with aortic stenosis, genetic variants of proteins from the renin angiotensin system may be at least as important as left ventricular systolic pressure in determining the degree of left ventricular hypertrophy and could therefore explain the clinical variation observed in the progression to cardiac dysfunction.

Adult↗

HPRC2: A human pangenome reference with near-complete coverage of common genetic variation.

A pangenome reference overcomes the inherent limitation of any individual reference genome by integrating the variation present in a population. We present the Human Pangenome Reference Consortium's (HPRC) Release 2 (HPRC2), an openly available, second phase pangenome that is an approximately fivefold expansion in genome number over HPRC Release 1 (HPRC1) and measurable improvement in genome completeness, contiguity, and accuracy. Selecting samples with a principled algorithm prioritising common variant coverage, HPRC2 contributes 460 haplotypes that together capture over 99% of common variation observed in the All of Us Research Program v8 cohort. Combining high-coverage long and ultra-long reads with modern assemblers and polishers, we produce thousands of telomere-to-telomere (T2T) chromosomes, and relative to HPRC1 halve the number of structurally unreliable regions as well as individual base errors per haplotype. We complement the assemblies with whole genome multiple alignments and gene annotations, and derive formal pangenome coordinate systems for addressing off-reference variation, demonstrating that individual human genomes contain more than one hundred thousand variants not succinctly described with respect to existing reference genomes. We also present the first matched long-read backed pantranscriptome and panepigenome at this scale, provide continuous local-ancestry estimates spanning every genome, and outline a host of new tools and applications that leverage the pangenome resource for improved genomics analysis.

Journal Article↗

Premutation for the Martin-Bell syndrome analyzed in a large Sardinian family: II. Neuropsychological and behavioral data.

We describe the neuropsychological and behavioral profiles of 48 critical members of a previously reported Sardinian pedigree [Filippi et al., 1991], in which the fully manifested Martin-Bell syndrome (MBS), observed among males of the latest generations, is clearly the result of step-wise mutational events occurred repeatedly along the X-chromosome pathway linking all of them to a common ancestress, who must have been heterozygous for a fragile X (FRAX) premutation. We found that the unquestionable presence in the family of normal transmitting males and females could not be determined on the basis of neuropsychological and behavioral data alone. However, we think that the large variation observed in the expression of most diagnostic parameters among the MBS patients and their close female relatives in this family, could by itself be a connotation of the genome instability which characterizes the FRAX region in pedigrees segregating for the FRAX premutation(s) and mutation(s).

Behavior↗

Pharmacokinetic factors as causes of variability in response to non-steroidal anti-inflammatory drugs.

Even the most widely used non-steroidal anti-inflammatory drugs (NSAID's) show considerable variations in their pharmacokinetic behaviour in volunteers and moreso in patients. An evaluation of the response-related pharmacokinetic parameters of the three presently most widely used NSAID's, namely diclofenac, indomethacin and piroxicam shows some obvious reasons: While the onset of absorption and the bioavailability of diclofenac varies considerably, we find relevant differences in the terminal plasma half-life of indomethacin and particularly piroxicam. Inter-patient variability in these parameters may contribute significantly to the observed variations in clinical response.

Anti-Inflammatory Agents↗

A functional SNP in the promoter region of TCOF1 is associated with reduced gene expression and YY1 DNA-protein interaction.

Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial malformation caused by null mutations in the TCOF1 gene. High inter and intra familial clinical variability, ranging from mild malar hypoplasia to perinatal death due to airway collapse is observed, but, to date, no genotype-phenotype correlation has been reported. Considering haploinsufficiency as the molecular mechanism underlying the disease, we have hypothesized that mutations in the promoter region of the gene, which has never been previously characterized, in trans with a pathogenic mutation, could modulate the phenotype. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. We screened 1.2 kbp of the TCOF1 5' flanking sequence in the DNA obtained from 21 patients and 51 controls and identified four new single nucleotide polymorphisms (SNPs), one of which (-346C>T), was proved to be functional, as it decreased the promoter activity by 38%. Electrophoretic mobility shift assay (EMSA) analysis demonstrated that the -346T allele impairs DNA-binding to the YY1 transcription factor. This promoter variant represents a candidate allele to explain the clinical variability in patients bearing TCS.

Alleles↗

Polymorphism in genes that influence sperm displacement.

Paternity of offspring of multiply inseminated females is in many organisms highly skewed, with an advantage generally going to the male that most recently mated. Variation in sperm competitive ability can result in strong natural selection, and one expects that a gene that offers an advantage in sperm displacement would, all else being equal, be rapidly fixed, leaving low equilibrium levels of variability in sperm competition. However, empirical studies have demonstrated genetic variation in sperm displacement, begging the question of how this variation can be maintained. Here we develop a population genetic model to find conditions that maintain polymorphism in alleles that influence sperm displacement. We consider a one-locus model in which allelic variants have pleiotropic effects on fecundity and mating ability in addition to sperm displacement. This model can admit more than one stable polymorphism, and we find conditions for protected polymorphism. Induced overdominance is not necessary for stable polymorphism. These results have direct bearing on the observed variation in the ability of resident sperm to defend against displacement.

Animals↗

Evidence for large decadal variability in the tropical mean radiative energy budget.

It is widely assumed that variations in Earth's radiative energy budget at large time and space scales are small. We present new evidence from a compilation of over two decades of accurate satellite data that the top-of-atmosphere (TOA) tropical radiative energy budget is much more dynamic and variable than previously thought. Results indicate that the radiation budget changes are caused by changes in tropical mean cloudiness. The results of several current climate model simulations fail to predict this large observed variation in tropical energy budget. The missing variability in the models highlights the critical need to improve cloud modeling in the tropics so that prediction of tropical climate on interannual and decadal time scales can be improved.

Journal Article↗

Comfort constrains graphic workspace: test results of a 3D forearm model.

Human movement performance is subject to many physical and psychological constraints. Analyses of these constraints may not only improve our understanding of the performance aspects that subjects need to keep under continuous control, but may also shed light on the possible origins of specific behavioral preferences that people display in motor tasks. The goal of the present paper is to make an empirical contribution here. In a recent simulation study, we reported effects of pen-grip and forearm-posture constraints on the spatial characteristics of the pen tip's workspace in drawing. The effects concerned changes in the location, size, and orientation of the reachable part of the writing plane, as well as variations in the computed degree of comfort in the hand and finger postures required to reach the various parts of this area. The present study is aimed at empirically evaluating to what extent these effects influence subjects' graphic behavior in a simple, free line-drawing task. The task involved the production of small back-and-forth drawing movements in various directions, to be chosen randomly under three forearm-posture and five pen-grip conditions. The observed variations in the subjects' choice of starting positions showed a high level of agreement with those of the simulated graphic-area locations, showing that biomechanically defined comfort of starting postures is indeed a determinant of the selection of starting points. Furthermore, between-condition rotations in the frequency distributions of the realized stroke directions corresponded to the simulation results, which again confirms the importance of comfort in directional preferences. It is concluded that postural rather than spatial constraints primarily affect subjects' preferences for starting positions and stroke directions in graphic motor performance. The relevance of the present modelling approach and its results for the broader field of complex motor behavior, including the manipulation of tools, is indicated briefly.

Adult↗