Showing papers by "University of Göttingen published in 1997"

SHELXL: high-resolution refinement.

Abstract: Publisher Summary SHELXL-93 was originally written as a replacement for the refinement part of the small-molecule program SHELX-76. The program is designed to be easy to use and general for all space groups and uses a conventional structure-factor calculation rather than a fast Fourier transform (FFT) summation. The latter would be faster but in practice involves some small approximations and is not suitable for the treatment of anomalous dispersion or anisotropic thermal motion. The price to pay for the extra precision and generality is that SHELXL is much slower than programs written specifically for macromolecules. This is compensated for, to some extent, by the better convergence properties, reducing the amount of manual intervention required. A new version, SHELXL-97, was released in May 1997; this is the version described in the chapter. The changes are primarily designed to make the program easier to use for macromolecules. Advances in cryogenic techniques, area detectors, and the use of synchrotron radiation enable macromolecular data to be collected to higher resolution than was previously possible. In practice, this tends to complicate the refinement because it is possible to resolve finer details of the structure. It is often necessary to model alternative conformations, and in a few cases, even anisotropic refinement is justified.

The cellular prion protein binds copper in vivo

Abstract: The normal cellular form of prion protein (PrPC) is a precursor to the pathogenic protease-resistant forms (PrPSc) believed to cause scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease. Its amino terminus contains the octapeptide PHGGGWGQ, which is repeated four times and is among the best-preserved regions of mammalian PrPC. Here we show that the amino-terminal domain of PrPC exhibits five to six sites that bind copper (Cu(II)) presented as a glycine chelate. At neutral pH, binding occurs with positive cooperativity, with binding affinity compatible with estimates for extracellular, labile copper. Two lines of independently derived PrPC gene-ablated (Prnp0/0) mice exhibit severe reductions in the copper content of membrane-enriched brain extracts and similar reductions in synaptosomal and endosome-enriched subcellular fractions. Prnp0/0 mice also have altered cellular phenotypes, including a reduction in the activity of copper/zinc superoxide dismutase and altered electrophysiological responses in the presence of excess copper. These findings indicate that PrPC can exist in a Cu-metalloprotein form in vivo.

Inflammatory central nervous system demyelination: Correlation of magnetic resonance imaging findings with lesion pathology

Abstract: Magnetic resonance imaging (MRI) is widely used to evaluate and monitor disease activity in inflammatory demyelinating central nervous system (CNS) diseases such as multiple sclerosis. The present study aimed at correlating MRI findings with histological parameters in 6 cases of biopsy-proven inflammatory demyelination of the CNS. The earliest stages of demyelinating activity manifested as almost isointense lesions with a massive gadolinium-DTPA (Gd-DTPA) enhancement in T1-weighted scans. In T2-weighted scans, early active lesions formed a border of decreased intensity compared with the lesion center and the perifocal edema. The morphological correlate of this pattern in our patients was activated macrophages in the zone of myelin destruction at the plaque border. Late active lesions were hypointense in T1 and hyperintense in T2 scans. Inactive demyelinated and remyelinating lesions were hyperintense in T2 scans and enhanced inhomogenously after Gd-DTPA application. T1 scans revealed major differences in the degree of hypointensity that correlated with the extent of axonal damage, extracellular edema, and the degree of demyelination or remyelination.

Variation of sensitivity, specificity, likelihood ratios and predictive values with disease prevalence

Abstract: The sensitivity, specificity and likelihood ratios of binary diagnostic tests are often thought of as being independent of disease prevalence. Empirical studies, however, have frequently revealed substantial variation of these measures for the same diagnostic test in different populations. One reason for this discrepancy is related to the fact that only few diagnostic tests are inherently dichotomous. The majority of tests are based on categorization of individuals according to one or several underlying continuous traits. For these tests, the magnitude of diagnostic misclassification depends not only on the magnitude of the measurement or perception error of the underlying trait(s), but also on the distribution of the underlying trait(s) in the population relative to the diagnostic cutpoint. Since this distribution also determines prevalence of the disease in the population, diagnostic misclassification and disease prevalence are related for this type of test. We assess the variation of various measures of validity of diagnostic tests with disease prevalence for simple models of the distribution of the underlying trait(s) and the measurement or perception error. We illustrate that variation with disease prevalence is typically strong for sensitivity and specificity, and even more so for the likelihood ratios. Although positive and negative predictive values also strongly vary with disease prevalence, this variation is usually less pronounced than one would expect if sensitivity and specificity were independent of disease prevalence.

Absence of integrin alpha 7 causes a novel form of muscular dystrophy.

Abstract: Integrin alpha 7 beta 1 is a specific cellular receptor for the basement membrane protein laminin-1 (refs 1,2), as well as for the laminin isoforms -2 and -4 (ref. 3). The alpha 7 subunit is expressed mainly in skeletal and cardiac muscle and has been suggested to be involved in differentiation and migration processes during myogenesis. Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle. In adult muscle, the alpha 7A and alpha 7B subunits are concentrated in myotendinous junctions but can also be detected in neuromuscular junctions and along the sarcolemmal membrane. To study the potential involvement of alpha 7 integrin, during myogenesis and its role in muscle integrity and function, we generated a null allele of the alpha 7 gene (Itga7) in the germline of mice by homologous recombination in embryonic stem (ES) cells. Surprisingly, mice homozygous for the mutation are viable and fertile, indicating that the alpha 7 beta 1 integrin is not essential for myogenesis. However, histological analysis of skeletal muscle revealed typical symptoms of a progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The observed histopathological changes strongly indicate an impairment of function of the myotendinous junctions. These findings demonstrate that alpha 7 beta 1 integrin represents an indispensable linkage between the muscle fibre and the extracellular matrix that is independent of the dystrophin-dystroglycan complex-mediated interaction of the cytoskeleton with the muscle basement membrane.

Decreased motor inhibition in Tourette's disorder: evidence from transcranial magnetic stimulation.

Abstract: Objective: Fluctuating motor and vocal tics are the diagnostic feature of Tourette’s disorder. The pathophysiology of tics is still unclear. One major hypothesis is a deficient inhibitory control through the cortical-striatal-thalamic-cortical motor loop. The authors tested this hypothesis by investigating motor cortex excitability through use of the technique of transcranial magnetic stimulation. Method: Twenty patients with Tourette’s disorder and a comparison group of 21 healthy subjects were studied. Focal transcranial magnetic stimulation was applied to the left motor cortex, and surface electromyography (EMG) was recorded from the right abductor digiti minimi muscle. As measures of motor cortex excitability, motor threshold, cortical silent period, and intracortical inhibition and facilitation were studied. The peripheral silent period and the maximum M wave after supramaximal electrical stimulation of the ulnar nerve at the wrist were also determined. Results: Motor threshold and peripheral motor excitability were normal in the Tourette’s disorder group, but the cortical silent period was shortened and the intracortical inhibition reduced. A subgroup analysis of the patients with Tourette’s disorder revealed that these abnormalities were seen mainly when tics were present in the EMG target muscle or in patients without neuroleptic treatment. Age, sex, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and sensory urges had no significant effect on motor excitability. Conclusions: Findings are consistent with the hypothesis that tics in Tourette’s disorder originate either from a primarily subcortical disorder affecting the motor cortex through disinhibited afferent signals or from impaired inhibition directly at the level of the motor cortex or both. (Am J Psychiatry 1997; 154:1277‐1284)

National rates and regional differences in sensitization to allergens of the standard series : Population-adjusted frequencies of sensitization (PAFS) in 40,000 patients from a multicenter study (IVDK)

Abstract: Sensitization rates to contact allergens vary between centers and are influenced by sex and age. Eliminating the latter 2 factors by standardization of data by age and sex, the present analysis addresses possible differences between centers remaining after elimination of these confounders, and analyzes other factors which might influence rates, e.g., the MOAHL index. Overall standardized rates were well within the range reported in previous studies and may be regarded as representing the rates of the "patch test population" in Central Europe (e.g., nickel sulfate 12.9%, fragrance mix 10.5%, balsam of Peru 7.3%, thimerosal 5.6%). For this analysis, data of those departments which contributed more than 2000 patients, or of those with extreme proportions concerning sex, age and occupational cases were selected. Patients from these 10 departments differed considerably with regard to the items of the MOAHL index and with regard to standardized rates. The items of the MOAHL index proved to be suitable for describing different patch test populations and for explaining some differences between centers. Only 'atopic dermatitis' seems to have little influence on (standardized) rates. Face dermatitis is not yet represented in the MOAHL index, but should be included, together with age > 40 years, in an extended index (acronym: MOAHLFA). Regional allergen exposure (with striking differences between East Germany, West Germany and, to a lesser extent, Austria) seems to have a great influence on the sensitization pattern observed in a department. In addition, sociological factors may influence sensitization rates, which is exemplified by high rates of nickel allergy in a socially defined subgroup. Future studies should focus on these factors, as well as on factors concerning patch test practices and quality control.

Automated Gas Chromatographic System for Rapid Analysis of the Atmospheric Trace Gases Methane, Carbon Dioxide, and Nitrous Oxide

Abstract: To study the fluxes of the radiative active trace gases CH{sub 4}, CO{sub 2}, and N{sub 2}O, a gas sampling and analytical device was developed. It is a useful tool for accurate gas sampling in the field and enables the subsequent fully automated analysis of the gas samples in the laboratory. The computer-controlled analytical system consists of a gas chromatograph equipped with a flame ionization detector (FID), an electron capture detector (ECD), and a pressure-controlled autosampler for 64 sample containers. The system automates sample injection, the analysis of CH{sub 4}, CO{sub 2}, and N{sub 2}O in each sample and the subsequent evacuation of the sample containers. It is equipped with a second alternative sample inlet for manual syringe injection. This inlet is suitable for analyzing small volumes of gas samples (3 mL). The gas sampling system for use in the field consists of evacuated sample bottles (100 mL) with Teflon cocks combined with a small battery-driven field sampler with a pressure sensor. This device enables an on-site control of the vacuum integrity of the sample bottles during sampling and purging of the dead volumes between the sampler induction pipe and the sample container. 11 refs., 4 figs.

Bjerknes forces between small cavitation bubbles in a strong acoustic field

Abstract: The mutual interaction between small oscillating cavitation bubbles ${(R}_{0}l10\ensuremath{\mu}\mathrm{m})$ in a strong acoustic field (${P}_{a}g1\mathrm{bar},$ $f=20\mathrm{kHz}$) is investigated numerically. We assume spherical symmetry and a coupling of the bubble oscillations. Our results show that the strength and even the directions of the resulting secondary Bjerknes forces differ considerably from predictions of the well-known linear theory. This is of immediate consequence for understanding and modeling structure formation processes in acoustic cavitation and multibubble sonoluminescence.

Representation theory and sheaves on the bruhat-tits building

Abstract: © Publications mathématiques de l’I.H.É.S., 1997, tous droits réservés. L’accès aux archives de la revue « Publications mathématiques de l’I.H.É.S. » (http:// www.ihes.fr/IHES/Publications/Publications.html) implique l’accord avec les conditions générales d’utilisation (http://www.numdam.org/conditions). Toute utilisation commerciale ou impression systématique est constitutive d’une infraction pénale. Toute copie ou impression de ce fichier doit contenir la présente mention de copyright.

Hetero diels-alder reactions in organic chemistry

Abstract: The hetero Diels-Alder reaction is one of the most important methods for the synthesis of heterocycles. In this article an overview is given for the period since 1989 describing the reaction of heterobutadienes such as oxabutadienes, thiabutadienes, azabutadienes, diaazabutadienes, nitroso-alkenes and nitroalkenes as well as of heterodienophiles such as carbonyls, thiocarbonyls, imines, iminium salts, azo- and nitroso compounds. In addition, several other less common hetero Diels-Alder reactions such as cycloadditions of thiaazabutadienes, oxaazabutadienes, dioxabutadienes, dithiabutadienes, oxathiabutadienes, diazaoxabutadienes as well as the use of N-sulfinyl-phosphaalkynes and other dienophiles are mentioned. A main point of discussion is the stereoselectivity of the reactions and the preparation of enantiopure compounds either using dienes and dienophiles carrying a chiral auxiliary or employing chiral Lewis acids. A point stressed is the synthesis of natural products using hetero Diels-Alder reactions leading to carbohydrates, alkaloids, terpenes, antibiotics, mycotoxins, cytochalasans, antitumor agents and several other classes of natural products.

Dens invaginatus: aetiology, classification, prevalence, diagnosis, and treatment considerations.

Abstract: Summary Dens invaginatus is a malformation of teeth probably resulting from an infolding of the dental papilla during tooth development. Affected teeth show a deep infolding of enamel and dentine starting from the foramen coecum or even the tip of the cusps and which may extend deep into the root. Teeth most affected are maxillary lateral incisors and bilateral occurrence is not uncommon. The malformation shows a broad spectrum of morphologic variations and frequently results in early pulp necrosis. Root canal therapy may present severe problems because of the complex anatomy of the teeth. Aetiology, prevalence, classification, and therapeutic considerations including root canal therapy, apical surgery and prevention of pulpal involvement are reviewed.

Disruption of Nuclear Lamin Organization Alters the Distribution of Replication Factors and Inhibits DNA Synthesis

Abstract: The nuclear lamina is a fibrous structure that lies at the interface between the nuclear envelope and the nucleoplasm. The major proteins comprising the lamina, the nuclear lamins, are also found in foci in the nucleoplasm, distinct from the peripheral lamina. The nuclear lamins have been associated with a number of processes in the nucleus, including DNA replication. To further characterize the specific role of lamins in DNA replication, we have used a truncated human lamin as a dominant negative mutant to perturb lamin organization. This protein disrupts the lamin organization of nuclei when microinjected into mammalian cells and also disrupts the lamin organization of in vitro assembled nuclei when added to Xenopus laevis interphase egg extracts. In both cases, the lamina appears to be completely absent, and instead the endogenous lamins and the mutant lamin protein are found in nucleoplasmic aggregates. Coincident with the disruption of lamin organization, there is a dramatic reduction in DNA replication. As a consequence of this disruption, the distributions of PCNA and the large subunit of the RFC complex, proteins required for the elongation phase of DNA replication, are altered such that they are found within the intranucleoplasmic lamin aggregates. In contrast, the distribution of XMCM3, XORC2, and DNA polymerase α, proteins required for the initiation stage of DNA replication, remains unaltered. The data presented demonstrate that the nuclear lamins may be required for the elongation phase of DNA replication.

Prediction of Success From a Multidisciplinary Treatment Program for Chronic Low Back Pain

Abstract: Study design The study included 90 disabled patients with chronic low back pain recruited from a pain clinic who were admitted to an 8-week program of functional restoration and behavioral support. Initial evaluations included a medical examination, rating of the physical impairment, a personal interview, a visual analogue scale to record pain intensity, an assessment of limitations for daily activities, a pain disability index, a depression and psychovegetative scale, and a scale to evaluate general living standards. The physical assessment included different flexibility measurements, measurement of power and endurance through standardized exercises, and measurements of isokinetic trunk and lifting strength and general endurance. The measurements were repeated at the end of the 8-week program and thereafter an intervals of 6 and 12 months. Final analyses were carried out on 82 patients. Objectives To determine whether objective or subjective signs most influence the outcome of rehabilitation. Summary of background data In recent years, several studies have shown that active and intensive multimodal treatment of chronic low back pain is successful. Until now there has been lack of information about which patients will respond to the therapy and what is the most effective part of treatment. Methods Prognostic factors (return to work, pain intensity, self-assessment of treatment success by patients) were tested by studying variance and regression analyses for their ability to predict treatment outcome. Results Certain factors were identified that had a significant impact on determining the probability of a patient's return to work and the reduction of pain intensity. These factors included self-evaluation for predicting a return to work, the length of absence from work, application for pension, and a decrease is disability after treatment. Overall satisfaction with treatment was best determined by the number of medical consultations before treatment, the extent of disability, previous measures taken for coping with the disease, and reduction of disability during treatment. Medical background, medical diagnosis, and physical impairment had no predictive value. Physical variables (i.e., mobility, strength, endurance, and physical performance) also demonstrated only limited predictive value. Conclusion This study has demonstrated that the most important variable in determining a successful treatment of chronic low back pain is the reduction of subjective feelings of disability in patients.

The Role of Macrophages in Wallerian Degeneration

Abstract: The present review focuses on macrophage properties in Wallerian degeneration. The identification of hematogenous phagocytes, the involvement of cell surface receptors and soluble factors, the state of activation during myelin removal and the signals and factors leading to macrophage recruitment into degenerating peripheral nerves after nerve transection are reviewed. The main effector cells in Wallerian degeneration are hematogenous phagocytes. Resident macrophages and Schwann cells play a minor role in myelin removal. The macrophage complement receptor type 3 is the main surface receptor involved in myelin recognition and uptake. The signals leading to macrophage recruitment are heterogenous and not yet defined in detail. Degenerating myelin and axons are suggested to participate. The relevance of these findings for immune-mediated demyelination are discussed since the definition of the role of macrophages might lead to a better understanding of the pathogenesis of demyelination.

Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs

Abstract: Transcranial magnetic stimulation was used to probe the acute effect of a single oral dose of various dopaminergic (levodopa, selegiline, bromocriptine) and antidopaminergic drugs (sulpiride, haloperidol) on motor cortex excitability in healthy volunteers. Motor threshold, intracortical inhibition and intracortical facilitation were tested in the abductor digiti minimi muscle. The latter two parameters were studied in a conditioning-test paired stimulus paradigm. The principal findings were an increase in intracortical inhibition by bromocriptine, and, conversely, a decrease in intracortical inhibition and an increase in intracortical facilitation by haloperidol. Effects peaked at delays consistent with the pharmacokinetics of the two drugs and were fully reversible. In conclusion, dopamine receptor agonists and antagonists can be considered inverse modulators of motor cortex excitability: the former enhance inhibition while the latter reduce it. The relation of the present findings to current models of motor excitability abnormalities in movement disorders will be discussed.

Dissection of Filamentous Growth by Transposon Mutagenesis in Saccharomyces cerevisiae

Abstract: Diploid Saccharomyces cerevisiae strains starved for nitrogen undergo a developmental transition from growth as single yeast form (YF) cells to a multicellular form consisting of filaments of pseudohyphal (PH) cells. Filamentous growth is regulated by an evolutionarily conserved signaling pathway that includes the small GTP-binding proteins Ras2p and Cdc42p, the protein kinases Ste20p, Ste11p and Ste7p, and the transcription factor Ste12p. Here, we designed a genetic screen for mutant strains defective for filamentous growth (dfg) to identify novel targets of the filamentation signaling pathway, and we thereby identified 16 different genes, CDC39, STE12, TEC1, WHI3, NAB1, DBR1, CDC55, SRV2, TPM1, SPA2, BNI1, DFG5, DFG9, DFG10, BUD8 and DFG16, mutations that block filamentous growth. Phenotypic analysis of dfg mutant strains genetically dissects filamentous growth into the cellular processes of signal transduction, bud site selection, cell morphogenesis and invasive growth. Epistasis tests between dfg mutant alleles and dominant activated alleles of the RAS2 and STE11 genes, RAS2Val19 and STE11-4, respectively, identify putative targets for the filamentation signaling pathway. Several of the genes described here have homologues in filamentous fungi, where they also regulate fungal development.

Entering New Fields: Exploratory Uses of Experimentation

Abstract: Starting with some illustrative examples, I develop a systematic account of a specific type of experimentation--an experimentation which is not, as in the "standard view", driven by specific theories. It is typically practiced in periods in which no theory or--even more fundamentally--no conceptual framework is readily available. I call it exploratory experimentation and I explicate its systematic guidelines. From the historical examples I argue furthermore that exploratory experimentation may have an immense, but hitherto widely neglected, epistemic significance.

Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis Evidence from paired transcranial magnetic stimulation

Abstract: We investigated 14 patients with amyotrophic lateral sclerosis (ALS) by paired conditioning-test transcranial magnetic stimulation to test the hypothesis that the motor cortex is hyperexcitable in ALS. Intracortical (corticocortical) inhibition was significantly less in the ALS group than in an age-matched healthy control group (85.3 +/- 27.0% versus 45.2 +/- 15.5%, respectively; p < 0.0001). In contrast, intracortical facilitation, motor threshold, and cortical silent period duration in the ALS patients were not different from the control group. We suggest that the selective abnormality of intracortical inhibition is best compatible with an impaired function of inhibitory interneuronal circuits in the motor cortex that in turn renders the corticomotoneuron hyperexcitable.