[New spirometric reference values for children and adolescents in Germany considering height and non-linear age effects: the LUNOKID-study]. / Neue spirometrische Referenzwerte für Kinder und Jugendliche in Deutschland unter Berücksichtigung der Größe und nichtlinearer Alterseffekte: Die LUNOKID-Studie.

BACKGROUND: Comparing children's lung function with reference values is important for diagnosing respiratory diseases. The values by Zapletal et al., commonly used nowadays, are not appropriate for the current stage of children's development. We have now developed new reference values and a lower limit of normal (LLN) for children in Germany, divided into small-range age and height categories. MATERIAL AND METHODS: We examined 4- to 18-year-old children in 3 German communities under field conditions. 1943 children were healthy and had a visually acceptable lung function which also fulfilled international quality criteria. We used the regression model LMS, which was introduced by Stanojevic and Quanjer in this context. RESULTS: There were significant differences between the measured lung function and the predicted values according to Zapletal et al. The lung function did not only depend on the child's height, but also in a non-linear way on the age. The variation coefficient did not depend on age. CONCLUSIONS: To avoid diagnostic errors, the currently often used reference values according to Zapletal et al. should no longer be used. The non-linear dependence on age corresponds to the recently published results by Stanojevic and Quanjer.

New criteria for impaired fasting glucose and screening for diabetes in cystic fibrosis.

Cystic fibrosis-related diabetes mellitus (CFRD) is the most frequent comorbidity in cystic fibrosis. Its clinical relevance is stressed by the association with increased mortality, and decreased pulmonary and nutritional status. An annual oral glucose tolerance test (OGTT) is recommended as a screening test for CFRD, but this is often not realised because of its time- and resource-consuming nature. Therefore, alternative approaches are welcome. In 2003, the American Diabetes Association (ADA) lowered the cut-off point separating normal from elevated fasting plasma glucose from <6.1 mmol x L(-1) to <5.6 mmol x L(-1), suggesting the performance of an OGTT only in those with impaired fasting glucose (IFG; range 5.6-6.0 mmol x L(-1)). The current authors tested whether this approach was reliable for the early identification of patients with CFRD. OGTTs from 1,128 patients (53% males; 47% females; median age 17.1 yrs) were available for analysis. A total of 101 (8.9%) OGTTs were classified as diabetic. The new ADA criteria for IFG increased the sensitivity to 82% (versus 65%) and decreased the specificity to 70% (versus 94%) compared with the old criteria used to identify patients with diabetic OGTTs. In conclusion, the American Diabetes Association approach of using impaired fasting glucose as an indication for performing selective oral glucose tolerance tests is definitely unsuitable when aiming at the early identification of patients with cystic fibrosis-related diabetes mellitus, and it cannot replace annual oral glucose tolerance tests.

Alternative splicing in the ligand binding domain of mouse ApoE receptor-2 produces receptor variants binding reelin but not alpha 2-macroglobulin.

LR7/8B and ApoER2 are recently discovered members of the low density lipoprotein (LDL) receptor family. Although structurally different, these two proteins are derived from homologous genes in chicken and man by alternative splicing and contain 7 or 8 LDL receptor ligand-binding repeats. Here we present the cDNA for ApoER2 cloned from mouse brain and describe splice variants in the ligand binding domain of this protein, which are distinct from those present in man and chicken. The cloned cDNA is coding for a receptor with only five LDL receptor ligand-binding repeats, i.e. comprising repeats 1-3, 7, and 8. Reverse transcriptase-polymerase chain reaction analysis of mRNA from murine brain revealed the existence of two additional transcripts. One is lacking repeat 8, and in the other repeat 8 is substituted for by a 13-amino acid insertion with a consensus site for furin cleavage arising from an additional small exon present in the murine gene. None of the transcripts in the mouse, however, contain repeats 4-6. In murine placenta only the form containing repeats 1-3 and 7 and the furin cleavage site is detectable. Analysis of the corresponding region of the murine gene showed the existence of 6 exons coding for a total of 8 ligand binding repeats, with one exon encoding repeats 4-6. Exon trapping experiments demonstrated that this exon is constitutively spliced out in all murine transcripts. Thus, the murine ApoER2 gene codes for receptor variants harboring either 4 or 5 binding repeats only. Recombinant expression of the 5-repeat and 4-repeat variants showed that repeats 1-3, 7, and 8 are sufficient for binding of beta-very low density lipoprotein and reelin, but not for recognition of alpha(2)-macroglobulin, which binds to the avian homologue of ApoER2 harboring 8 ligand binding repeats.

Characterization of patients with primary peroneus longus tendinopathy: a review of twenty-two cases.

Between 1985 and 1996 we treated 22 patients with a diagnosis of PLT which was confirmed by MRI and/or surgery. This review identifies the shared clinical traits and associated pathology of our patients. Clinically, 82% of the patients had a cavo-varus hindfoot position. This finding was supported by measurements of the calcaneal pitch angle and the calcaneal-lst metatarsal angle which both showed the patients in this study to be in the 90th percentile for the general population for arch height. The combined MRI and surgical findings revealed injury to the peroneus longus at the cuboid notch in 17 of 22 cases. The subgroup of surgical findings demonstrated that all 6 complete tears occurred at the cuboid notch, while 8 of 9 (89%) of the partial tears involved the region of the lateral calcaneal process. In addition, the surgical findings showed 7 of the cases (33%) to have associated peroneus brevis tendon involvement, with an increased incidence when the longus pathology occurred at the cuboid notch. The findings predicated by MRI correlated well with the surgical findings, but there was a tendency for MRI to predict a more severe level of pathology. A grading system developed to compare the MRI and surgical findings is presented. This study facilitates making the diagnosis of PLT by drawing attention to the common characteristic of the cavo-varus foot position and the common locations of tendon injury.

The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2.

Correct positioning of neurons during embryonic development of the brain depends, among other processes, on the proper transmission of the reelin signal into the migrating cells via the interplay of its receptors with cytoplasmic signal transducers. Cellular components of this signaling pathway characterized to date are cell surface receptors for reelin like apolipoprotein E receptor 2 (ApoER2), very low density lipoprotein receptor (VLDLR), and cadherin-related neuronal receptors, and intracellular components like Disabled-1 and the nonreceptor tyrosine kinase Fyn, which bind to the intracellular domains of the ApoER2 and VLDL receptor or of cadherin-related neuronal receptors, respectively. Here we show that ApoER2, but not VLDLR, also binds the family of JNK-interacting proteins (JIPs), which act as molecular scaffolds for the JNK-signaling pathway. The ApoER2 binding domain on JIP-2 does not overlap with the binding sites for MLK3, MKK7, and JNK. These results suggest that ApoER2 is able to assemble a multiprotein complex containing Disabled-1 and JIPs, together with their binding partners, to the cell surface of neurons. This complex might participate in ApoER2-specific reelin signaling and thus would explain the different phenotype of mice lacking the ApoER2 from that of VLDLR-deficient mice.

The low-density lipoprotein receptor family: genetics, function, and evolution.

With ever increasing sophistication in molecular biological approaches, the low-density lipoprotein receptor supergene family continues to grow rapidly. From the well-defined key role of these receptors in lipoprotein metabolism, the new members move the field into many different and diverse physiologic and developmental areas. We observe an expansion of the functional spectrum of the family members, which is due to 1) the binding to their extracellular domains of more and more components lacking homology to apolipoproteins, and 2) the recently uncovered interaction of the receptors' cytoplasmic tails with adaptor proteins that are part of signaling pathways. As this review attempts to describe, the task of delineation of the evolutionary history of the gene family may be aided by concepts that consider events, both divergent and convergent, within and between the intra- and extracellular domains.

Avian and murine LR8B and human apolipoprotein E receptor 2: differentially spliced products from corresponding genes.

Apolipoprotein E-mediated lipid metabolism in the central nervous system plays an important role in cholesterol and phospholipid homeostasis of this organ, which is separated from the circulation by the blood-brain barrier. Moreover, in late-onset familial Alzheimer disease the frequency of the apolipoprotein E4 allele is significantly increased and the apoprotein is localized to extracellular plaques, one of the histological hallmarks of this disease. Recently, two distinct novel members of the low-density lipoprotein (LDL) receptor family, with the potential to bind apolipoprotein E and preferentially expressed in brain, have been characterized from human (D. Kim et al., 1996, J. Biol. Chem. 271: 8373-8380) and chicken and mouse (S. Novak, et al., 1996, J. Biol. Chem. 271: 11732-11736). The human receptor, termed "apolipoprotein E receptor 2," is a seven ligand-binding repeat receptor harboring a unique insertion in the cytoplasmic domain of the protein. The novel receptor characterized in chicken and mouse was found to have eight binding repeats without such a cytoplasmic insertion. Despite the overall identity of more than 73%, based upon their structural differences (seven versus eight ligand-binding repeats) these receptors have been considered independent entities. However, here we demonstrate that both receptors in fact are encoded by corresponding genes and that differential splicing gives rise to structurally and possibly functionally distinct variants of this brain-specific member of the LDL receptor family.

Quantitative analysis of Drosophila period gene transcription in living animals.

To determine the in vivo regulatory pattern of the clock gene period (per), the authors recently developed transgenic Drosophila carrying a luciferase cDNA fused to the promoter region of per. They have now carried out noninvasive, high time-resolution experiments allowing high-throughput monitoring of circadian bioluminescence rhythms in individual living adults for several days. This immediately solved several problems (resulting directly from individual asynchrony within a population) that have accompanied previous biochemical experiments in which groups of animals were sacrificed at each time point. Furthermore, the authors have developed numerical analysis methods for automatically determining rhythmicity associated with bioluminescence records from single flies. This has revealed some features of per gene transcription that were previously unappreciated and provides a general strategy for the analysis of rhythmic time series in the study of molecular rhythms.

Temporal and spatial expression patterns of transgenes containing increasing amounts of the Drosophila clock gene period and a lacZ reporter: mapping elements of the PER protein involved in circadian cycling.

Rhythmic oscillations of the PER protein, the product of the Drosophila period (per) gene, in brain neurons of the adult fly are strongly involved in the control of circadian rhythms. We analyzed temporal and spatial expression patterns of three per-reporter fusion genes, which share the same 4 kb regulatory upstream region but contain increasing amounts of per's coding region fused in frame to the bacterial lacZ gene. The fusion proteins contained either the N-terminal half (SG), the N-terminal-two-thirds (BG), or nearly all (XLG) of the PER protein. All constructs led to reporter signals only in the known per-expressing cell types within the anterior CNS and PNS. Whereas the staining intensity of SG files was constantly high at different Zeitgeber times, the in situ signals in BG and XLG files cycled with approximately 24 hr periodicity in the PER-expressing brain cells in wild-type and per01 loss of function files. Despite the rhythmic fusion-gene expression within the relevant neurons of per01 BG files, their locomotor activity in light/dark cycling conditions and in constant darkness was identical to that of per01 controls, uncoupling protein cycling from rhythmic behavior. The XLG construct restored weak behavioral rhythmicity to (otherwise) per01 files, indicating that the C-terminal third of PER (missing in BG) is necessary to fulfill the biological function of this clock protein.

Staining in the brain of Pachymorpha sexguttata mediated by an antibody against a Drosophila clock-gene product: labeling of cells with possible importance for the beetle's circadian rhythms.

Central nervous system ganglia within the head of the beetle Pachymorpha sexguttata were labeled using an antibody that recognizes an evolutionarily conserved region of the period (per) gene product of Drosophila melanogaster. per and the protein it encodes (PER) are believed to play a central role in the generation of endogenous circadian rhythms in flies; therefore anti-PER-mediated immunoreactivity may help to uncover cellular components of the circadian clock system in that insect and in others. In the beetle, application of this antibody led to the staining of a distinct set of neurons located in the optic lobes and the central brain, plus small numbers of putative glial cells in the optic lobes. Neuronal perikarya (including their nuclei in a few cases), the axons, and terminal regions of the neurons were stained. The network formed by these labeled cells and processes are candidates for the neuronal basis of the beetle's circadian clock system: the pacemaker region situated next to the medulla neuropil, its connection to the apparent site of Zeitgeber input, and putative efferent pathways projecting to control centers of various effector systems. Anti-PER-mediated labeling and that resulting from application to beetle specimens of an antiserum against pigment-dispersing hormone (PDH) were compared; in the Drosophila brain all "PDH cells" express the per gene as well. In the beetle, however, the set of "PER cells" and PDH ones is at least in part nonoverlapping. The hypothesis that neurons stained by application of anti-PER participate in the control of the beetle's circadian rhythms is discussed in the context of previous electrophysiological and immunohistochemical studies. Also considered are analogies to, and differences from, labeling of the PER protein in fruit flies and PER-like immunoreactivity in other animals.

Novel features of drosophila period Transcription revealed by real-time luciferase reporting.

The rapid turnover of luciferase and the sensitive, non-invasive nature of its assay make this reporter gene uniquely situated for temporal gene expression studies. To determine the in vivo regulatory pattern of the Drosophila clock gene period (per), we generated transgenic strains carrying a luciferase cDNA fused to the promoter region of the per gene. This has allowed us to monitor circadian rhythms of bioluminescence from pacemaker cells within the head for several days in individual living adults. These high time-resolution experiments permitted neuronal per transcription and opens the door to vastly simplified experiments in general chronobiology and studies of temporally regulated transcription in a wide range of experimental systems.

Genetic differences in learning behavior in honeybees (Apis mellifera capensis).

Workers from colonies of Cape honeybees show marked phenotypic differences in performance in proboscis extension reflex (PER) conditioning. Analysis of these differences using parthenogenetic offspring groups permitted the estimation of genotypic values and revealed a high degree of genetic variability that is evident among related as well as unrelated bees. The results obtained from related groups are of particular importance, since they demonstrated the existence of strong genetic variability among individuals of the same colony. Quantitative analysis yielded high estimates of additive genetic effects and low estimates of dominance effects. Selection of individual workers resulted in an explicit increase in genetic variance of the next generation (G1). However, selection of bees from the parthenogenetic G1 generation, which was done to obtain parthenogenetic G2 offspring, did not lead to further improvement in selection. This observation suggests that recombination of linked genes underlying proboscis extension reflex was negligible during selection in parthenogenetic groups. Taken together with further behavioral analysis (Brandes and Menzel, 1990; Brandes et al., 1988), results from these quantitative genetic experiments suggest that additive genetic factors contribute significantly to variability among individuals for associative learning.

Aggregation behaviour of blood granulocytes in patients with periodontal disease.

This behaviour was studied in 17 patients with severe marginal periodontitis and in 16 healthy controls. Aggregation induced by platelet-activating factor (PAF-acether), a potent mediator of inflammation, was significantly enhanced in the patients, whereas no significant difference was observed between patients and controls when aggregation was induced by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP). When the patients were subdivided into categories of progressive adult periodontitis, juvenile or post-juvenile periodontitis, aggregation induced by PAF-acether was enhanced in all three subgroups. However, FMLP-induced aggregation was slightly increased only in progressive adult and post-juvenile periodontitis, but decreased in juvenile periodontitis.

[The phagocytic activity of the blood neutrophilic granulocytes in patients with marginal periodontitis]. / Phagozytotische Aktivität der neutrophilen Blutgranulozyten von Patienten mit marginaler Periodontitis.

The ingestion of opsonized zymosan particles by neutrophil blood granulocytes and the chemiluminescence in samples of whole blood, induced by zymosan, Streptococcus mutans as well as phorbol myristate acetate, as a measure of the generation of reactive oxygene species were studied in patients with various forms of marginal periodontitis. Compared to a control group the phagocytic activity was found to be enhanced in progressive adult periodontitis and diminished in juvenile periodontitis whereas no differences to controls were found in chronic nonprogressive or postjuvenile periodontitis. With respect to the height of the chemiluminescence signals increased values were only measured in chronic nonprogressive periodontitis after stimulation by phorbol myristate acetate. The results indicate that impairment of blood granulocyte functions may be a pathogenetic factor for the development and the progression of marginal periodontitis.

[Senior students at the University of Vienna (author's transl)]. / Das Seniorenstudium an der Universität Wien.

In connection with an attempt to open universities for elderly people a special counselling service was instituted at the University of Vienna in the year 1978. Older people who made use of this counselling service were mainly interested in introducing courses in arts and the humanities. Intensive unstructured interviews of about one hour were carried out with some of the participants. The interviews focussed mainly on schooling, occupational training, their past occupational preferences, occupational careers as well as social contacts. In a first analysis a distinction between intrinsic and extrinsic motivations was made. An example for intrinsic motivation is the retire for further education whereas extrinsic motivation is characterized by influences within the social environment like the attitude of the family toward the university attendance of the respondent and the gain in prestige which is very likely connected with this.