[The biomarkers BNP and NT-proBNP]. / Die Biomarker BNP und NT­proBNP.

The present review of the biomarkers BNP and NT-pro-BNP is published in the series "biomarkers" of the Zentralblatt für Arbeitsmedizin, Arbeitsschutz und Ergonomie, which deals with the increasing use of the determination of specific markers in so-called manager preventive and check-up examinations. In principle, BNP and NT-pro-BNP are fundamentally suitable as markers for diagnosing acute and chronic heart failure and for assessing the course. In this context these show a high sensitivity and specificity.

Taxator-tk: precise taxonomic assignment of metagenomes by fast approximation of evolutionary neighborhoods.

MOTIVATION: Metagenomics characterizes microbial communities by random shotgun sequencing of DNA isolated directly from an environment of interest. An essential step in computational metagenome analysis is taxonomic sequence assignment, which allows identifying the sequenced community members and reconstructing taxonomic bins with sequence data for the individual taxa. For the massive datasets generated by next-generation sequencing technologies, this cannot be performed with de-novo phylogenetic inference methods. We describe an algorithm and the accompanying software, taxator-tk, which performs taxonomic sequence assignment by fast approximate determination of evolutionary neighbors from sequence similarities. RESULTS: Taxator-tk was precise in its taxonomic assignment across all ranks and taxa for a range of evolutionary distances and for short as well as for long sequences. In addition to the taxonomic binning of metagenomes, it is well suited for profiling microbial communities from metagenome samples because it identifies bacterial, archaeal and eukaryotic community members without being affected by varying primer binding strengths, as in marker gene amplification, or copy number variations of marker genes across different taxa. Taxator-tk has an efficient, parallelized implementation that allows the assignment of 6 Gb of sequence data per day on a standard multiprocessor system with 10 CPU cores and microbial RefSeq as the genomic reference data.

Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children.

BACKGROUND: Trivalent formulations of an experimental, cold-adapted, intranasal influenza (CAIV) vaccine have been shown to be safe, immunogenic and efficacious in young children. METHODS: We evaluated the safety and immunogenicity of three consistency lots of CAIV in children 12 to 36 months of age randomized to one of five groups: Groups 1, 2 and 3 received separate lots containing A/Shenzhen/227/95 (H1N1), A/Wuhan/359/95(H3N2) and B/Harbin/7/94-like viral strains. Group 4 received an earlier efficacy trial lot which included a different H1N1 strain (A/Texas/36/91-like); and Group 5 received placebo. We performed strain-specific serum hemagglutination inhibition antibody levels against type A (H3N2 or H1N1) or type B as appropriate. RESULTS: Overall 474 children received 2 doses, 2 months apart. Each lot was well-tolerated, and there were no significant group differences between consistency lots in the proportion of children with fever and local or systemic reactions after vaccination. The 3 consistency lots were not statistically different with regard to immunogenicity as measured by seroconversion or absolute geometric mean titer. Immune responses were more robust among initially seronegative children and for H3N2 and B strains than for H1N1 strains. After 2 doses of vaccine 97, 84 and 62% had hemagglutination inhibition titers > or = 1/32 against A/H3N2, B and H1N1 strains, respectively. For A/H3N2 only, immune responses after 1 dose of vaccine are similar to those seen after 2 doses. CONCLUSIONS: Each consistency lot of CAIV is as or more immunogenic than a lot used in a large efficacy trial.

Acoustic-phonetic context considerations for speech recognition testing of hearing-impaired listeners.

OBJECTIVE: To test for differences in the identification of consonants in carrier sentences versus in VCVs extracted from the sentences, as a function of listeners' hearing-loss categories: moderate, severe, profound. To examine whether pauses inserted in the sentences will facilitate identification of the consonants. DESIGN: Voiced stops and fricatives were identified by 11 listeners with moderate hearing losses and by 7 listeners with severe losses (between subjects design) for the conditions of consonants in sentences and in VCVs extracted from the sentences (repeated measures). Nine of these listeners also identified the consonants in the sentences with pauses. Six normal-hearing listeners were tested for the consonants in the extracted VCVs and the sentences. Voiceless stops and fricatives were identified by 4 listeners with profound losses, 18 with severe losses, and 8 with moderate losses (between subjects) for the conditions of extracted VCVs and the sentences (repeated measures). All listeners were selected on the basis of their hearing levels. RESULTS: The listeners with moderate to severe hearing loss identified the voiced stops and fricatives more poorly when the syllables were in the carrier sentences than when extracted. Insertion of the pauses in the sentence did not improve performance significantly. The normal hearing listeners showed no differences in consonant identification between the two conditions, perhaps due to "ceiling effects". The voiceless stops and fricatives were also identified more poorly when in the extracted VCVs than in the carrier sentences by other listeners with moderate to profound hearing loss. CONCLUSIONS: Listeners with moderate or greater hearing loss can show poorer identification of consonants that are embedded midway in carrier sentences than when the acoustically identical consonants are in VCVs extracted from the sentences. The performance reduction for the consonants in sentences is not relieved from insertion of brief artificial pauses in the sentences. Further research is needed determine whether hearing-impaired listeners' identification of consonants in target words of clinical word recognition tests is facilitated when the words are extracted from carrier phrases.

Temporal and spectral cue use for initial plosive voicing perception by hearing-impaired children and normal-hearing children and adults.

The influence of voice-onset time (VOT) and vowel-onset characteristics on the perception of the voicing contrast for initial plosive consonants was examined for hearing-impaired children, and normal-hearing children and adults. Listeners identified spoken 'DAD'--'TAD' stimuli controlled for VOT and vowel onset characteristics. Only six of 16 hearing-impaired children appropriately identified the exemplar DAD and TAD stimuli used as endpoints of VOT continua. For this group of six hearing-impaired children, a longer VOT than for the normal-hearing listeners was required to elicit /t/ rather than /d/ percepts. The VOT region of perceptual cross-over in labelling widened progressively from normal-hearing adults to normal-hearing children to hearing-impaired children. Generally, longer VOTs were required to yield /t/ perception in the context of the DAD vowel than with the TAD vowel. These 'vowel stem' effects on VOT boundary were inconsistent for the hearing-impaired children, and weaker for the normal-hearing children than for the adults. These spoken stimuli produced results for VOT cue use that generally parallel those obtained in studies with synthetic stimuli.

Functional limitations among home health care users in the National Health Interview Survey Supplement on Aging.

A case-control study compared home health care (HHC) users from the 1984 Supplement on Aging to users of other community services and of no community service, matched on age and gender. Examination of specific activities of daily living (ADLs), instrumental activities of daily living (IADLs), and sociodemographic variables showed that HHC users were significantly more limited than controls in every ADL and IADL. In multivariate analyses, HHC use was significantly associated with three ADLs (dressing, going outside, bathing), two IADLs (shopping, heavy housework), and poor health status.

Improving practicing physicians' knowledge of geriatric mental health issues.

Elderly patients are most likely to seek mental health care from primary care physicians. Ironically, recent research findings show that primary care physicians fail to adequately detect mental health problems in their older patients. These findings raise questions about: 1) the adequacy of geriatric mental health training for physicians and 2) the possible methods for improving practicing physicians' knowledge and skills in detecting, treating, and referring patients with mental health needs. With a projected doubling in the number of people older than age 65 in the next 40 years, it is even more important that recognition and treatment of geriatric mental health problems be made a priority for primary care physicians.

Factors influencing hospital patients' preferences in the utilization of life-sustaining treatments.

Ninety-seven elderly hospitalized patients were asked about their preferences for several treatments under three hypothetical levels of future cognitive functioning: intact, confused, and unconscious. Levels of cognitive functioning and depression were also assessed. Sixty-six percent of the patients were more likely to want treatment if they expected to be cognitively intact than when a future condition involved impaired cognition; 36% did not want any treatment in at least 75% of the conditions; and 16% wanted treatment in at least 75% of the conditions studied. A minority (12%) did not show any pattern in their preferences. The absence of a definite pattern was related to lower levels of education and to higher levels of depressive symptoms. Patients self-reported their preferences for treatments being influenced most by their personal values, religion, and by experiences with illnesses of others.

The utilization of the durable power of attorney for health care among hospitalized elderly patients.

OBJECTIVE: To explore the potential use of the durable power of attorney for health care (DPAHC), considerations in executing a DPAHC, and influences in making decisions related to it. DESIGN: Interview with follow up. SETTING: A teaching hospital. SUBJECTS: 37 males, 60 females, aged 64-97. METHODS: Interview of ninety-seven hospitalized patients and followup telephone interview of those who had not originally executed a DPAHC after 3 months. Patients were asked whom they would appoint as an agent for health care decisions, how this person was related to them, and why they chose this person. Patients' cognitive functioning and level of depression were assessed. RESULTS: Most patients (65%) chose their closet relative to make health care decisions for them if they were unable to. Reasons for choosing this person included: the agent knew the patient best, was the closest relative, and was most accessible geographically. Over half of the participants had not discussed their feelings about health care decisions with anyone. Sixteen percent had previously executed a durable power of attorney for health care, and 46% said they intended to execute one. Executing a durable power of attorney for health care was associated with higher levels of cognitive functioning but not with level of depression. CONCLUSIONS: Both an understanding of advanced directives and a general outlook on matters of life and death seem to affect people's utilization of the DPAHC. The ability to execute a DPAHC and the choice of an agent are affected by individuals' interpersonal relations.

VCVs vs CVCs for stop/fricative distinctions by hearing-impaired and normal-hearing listeners.

Moderately to profoundly hearing-impaired (n = 30) and normal-hearing (n = 6) listeners identified [p, k, t, f, theta, s] in [symbol; see text], and [symbol; see text]s tokens extracted from spoken sentences. The [symbol; see text]s were also identified in the sentences. The hearing-impaired group distinguished stop/fricative manner more poorly for [symbol; see text] in sentences than when extracted. Further, the group's performance for extracted [symbol; see text] was poorer than for extracted [symbol; see text] and [symbol; see text]. For the normal-hearing group, consonant identification was similar among the syllable and sentence contexts.

The fatty-acid-induced conformational states of human serum albumin investigated by means of multiple co-binding of protons and oleic acid.

The binding of oleic acid to human serum albumin causes progressive changes in (a) the pK of some amino acid residues, as detected by pH-stat titration and (b) the induced molar ellipticities of albumin-bound drugs (diazepam and oxyphenbutazone), as measured by c.d. It is concluded that albumin undergoes several conformational transitions as the amount of oleic acid bound increases from 0 to about 9 molecules/molecule of protein. At least three different conformations of the protein seem to be involved. These conformations can be linked with the three classes of oleic acid-binding sites on albumin.

Binding of 99mTc(113Sn)-MDP to human serum albumin. The influence of various technetium, tin, and MDP concentrations.

The HSA-binding of 99mTc incubated as 99mTc(113Sn)-MDP depends in vitro on the presence of competing anions normally present in plasma and on the MDP and Tc concentration, but is independent of the Sn concentration. The HSA-binding of 113Sn depends on the MDP and Sn concentration; not on the Tc concentration. 99mTc(Sn)-MDP binds to HSA as a unit. The binding of 99mTc(Sn)-MDP to plasma proteins in vivo is much lower as calculated from in vitro experiments because of competition between 99mTc(Sn)-MDP and endogenous anions for the same binding-sites.

Three models of human language.

Three models of human language processing can be discerned in contemporary neurobiology: the Wernicke-Broca model, primarily derived from studies of stroke and other brain lesions; the model developed by Dr. George Ojemann from electrical stimulation mapping of the cerebral cortex; and the linguistic model, evolved from Noam Chomsky's linguistic theories. The Wernicke-Broca model employs a posterior-sensory anterior-motor conception of brain language processing that is substantially different from the more modular conception developed from electrical stimulation mapping. The linguistic model attempts to explain language in terms of hierarchical mental function.

The pH dependence of the thermodynamics of the interaction of diazepam with human serum albumin.

The heat effect associated with the binding of diazepam to human serum albumin has been measured from pH 5.5 to 9.5 using flow microcalorimetry. The number of protons released upon the binding of one molecule of diazepam to one molecule of albumin was determined from acid-base titration experiments. In addition, the heat associated with the combination of protons with serum albumin was measured calorimetrically. The results of the experiments using these two techniques were used to correct the measured heat of binding and to obtain what will be called here delta H0obs values. These delta H0obs values are strongly pH-dependent: up to pH 7.5 a value of -24.3 (+/- 0.5) kJ X mol-1 is found, whereas at pH 9.5 the value is -44.3 (+/- 1.2). This pH dependence is different from the pH dependence of the induced CD signal of the albumin-diazepam complex. A model is presented in which the pH dependence of delta H0obs is explained. This model takes into account the N-B (neutral to base) conformational change in albumin around neutral pH. Parameters in this model are KN and KB (representing the affinity of diazepam for albumin in the N and B conformation, respectively), delta H0N and delta H0B which are the corresponding standard enthalpy changes, f which represents the fraction of protein in the B conformation, and delta H0(N-B) which represents the heat associated with the N-B transition.

Evidence for the fatty acid-induced heterogeneity of the N and B conformations of human serum albumin.

The influence of oleic acid on the interaction between albumin and warfarin, oxyphenbutazone or diazepam has been studied by circular dichroism and equilibrium dialysis. The pH dependences of the molar ellipticity of the drug-albumin complexes and of the free fraction of drug are completely changed by the presence of oleic acid. This phenomenon is attributed to an oleic acid-induced conformational change in both the neutral (N) and the basic (B) conformation of albumin, a change to which the warfarin-oxyphenbutazone binding area and the diazepam binding site is sensitive. The oleic acid-induced conformational states of albumin, the so-called N* and B* conformations, show binding properties that are different from the binding properties of the N and B conformations.

A study on the allosteric interaction between the major binding sites of human serum albumin using microcalorimetry.

The binding of warfarin and oxyphenbutazone to albumin has been studied at pH 6.8 and pH 9.2 by measuring the heat of binding of these ligands to their high-affinity binding sites on albumin (delta Ho'1). The -delta Ho'1 values for the binding of warfarin at pH 6.8 and 9.2 and oxyphenbutazone at pH 6.8 and 9.2 were found to be 16.9(+/- 0.6), 28.8(+/- 0.6), 10.5(+/- 0.4) and 17.4(+/- 0.6) kJmol-1, respectively. The Gibbs energies (delta Go'1) corresponding to these delta Ho'1 values cover a much smaller range. The pH dependences of delta Go'1 and delta Ho'1 are explained in terms of pK shifts in the albumin upon binding warfarin or oxyphenbutazone. Diazepam, which binds to a site on albumin which is different from the warfarin-oxyphenbutazone binding site, increases - delta Ho'1 for the binding of warfarin and oxyphenbutazone to albumin at pH 6.8, but it does not influence the -delta Ho'1 at pH 9.2. This phenomenon may be attributed to an allosteric interaction between the diazepam binding site and the warfarin binding site. This allosteric interaction must have its origin in a phenomenon other than the N-B transition.

Allosteric properties of the oxyphenbutazone--human serum albumin complex.

The conformational change of albumin which occurs around physiological pH, the so-called N-B transition, has been studied by measuring the induced circular dichroic signal of the oxyphenbutazone-albumin complex. This N-B transition has been characterized by a set of parameters according to the two-state model of Monod, Wyman and Changeux. The influence of calcium ions on the N-B transition has been interpreted in terms of a change in some of the parameters describing the two-state model, viz. a decrease of the apparent pK value of the histidines and of the apparent allosteric constant of the oxyphenbutazone-albumin complex. This apparent pK change increases with increasing Ca2+ concentration, whereas the apparent allosteric constant approaches a final value at 5 mM Ca2+. From acid-base titration curves of albumin in the presence and in the absence of Ca2+ it could be concluded that in the presence of Ca2+ less histidines are titratable than in the absence of Ca2+. Assuming that these histidines are not involved in the N-B transition it follows that at least four to five histidines are involved in the N-B transition.

A comparative study of some physico-chemical properties of human serum albumin samples from different sources--I. Some physico-chemical properties of isoionic human serum albumin solutions.

Human serum albumin samples from different sources were investigated. The fatty acid content of the albumin before and after deionization on a mixed bed ion-exchange column varied from sample to sample. When an albumin sample from one source was deionized under standard conditions the amount of fatty acid bound by the albumin was reduced to a reproducible amount. In samples from different sources, however, the amount bound varied considerably. Also the isoionic pH of the albumin varied from sample to sample. This variation could be attributed to the difference in the fatty acid content and the different number of titratable histidines and acid amino-acid residues in the albumin from different sources. It can be concluded from the specific conductance of these isoionic solutions that ions other than H-, OH and protein are effectively removed by a mixed bed ion-exchange column. The specific conductance of the albumin samples is directly related to the isoionic pH. Therefore, the isoionic pH and the specific conductance of the albumins reflect the heterogeneity of the albumin samples with respect to their primary structure and fatty acid content.

A comparative study of some physico-chemical properties of human serum albumin samples from different sources--II. The characteristics of the N-B transition and the binding behaviour with regard to warfarin and diazepam.

A comparative study of the N-B transition and the drug binding properties of human serum albumin samples from various sources has been carried out with the help of circular dichroism and equilibrium dialysis. It was found that when warfarin was used as a marker the midpoint pH and the cooperative nature of the N-B transition that occurs in the albumin around physiological pH varied with the albumin sample. The midpoint pH was found to be related to the cooperative nature of the albumin samples. A similar relationship has been found for allosteric proteins. However, when diazepam was used as a marker molecule for the N-B transition, variations in the midpoint pH and cooperative nature of the N-B transition disappeared. This is attributed to the strong allosteric effect of diazepam on binding. The affinity of warfarin for albumin depends strongly on the sample, but this is not the case with diazepam. The cooperative binding properties found for the albumin samples are compared with those found for the albumin in serum. After a discussion it is concluded that the cooperative binding properties of a particular albumin sample should be taken into account when that sample is used in binding studies.