The Elbmarsch leukemia cluster: are there conceptual limitations in controlling immission from nuclear establishments in Germany?

The childhood leukemia cluster in the proximity of the German nuclear establishments of Geesthacht is unique in its spatial and temporal concentration. After a steep increase in cases in 1990, the cluster continues to show a significant increase up to the present. Early investigations of blood samples from a casual sample of local residents showed an increase in dicentric chromosomes in lymphocytes, indicating exposure exceeding dose limits. Analyses of the immission data revealed several unexpected deliveries of fission and activation products in the environment but provided no explanation of the source. Because of the observed overdispersion of dicentric chromosomes in cells, the idea of a contribution by densely ionizing emitters was compelling. The routine programs, however, do not include alpha emitters. These were measured in specific studies that proved contamination by transuranic nuclides. As shown in the present investigation, routine environmental surveillance programs support the occurrence of an accidental event near Geesthacht in September 1986. Until now, neither the cause nor the complete scenario of the activity release could be established. The ongoing discussion highlights limitations in the immission-control concept, which is predominantly based on gamma-radiation monitoring.

Structural analysis of a set of proteins resulting from a bacterial genomics project.

The targets of the Structural GenomiX (SGX) bacterial genomics project were proteins conserved in multiple prokaryotic organisms with no obvious sequence homolog in the Protein Data Bank of known structures. The outcome of this work was 80 structures, covering 60 unique sequences and 49 different genes. Experimental phase determination from proteins incorporating Se-Met was carried out for 45 structures with most of the remainder solved by molecular replacement using members of the experimentally phased set as search models. An automated tool was developed to deposit these structures in the Protein Data Bank, along with the associated X-ray diffraction data (including refined experimental phases) and experimentally confirmed sequences. BLAST comparisons of the SGX structures with structures that had appeared in the Protein Data Bank over the intervening 3.5 years since the SGX target list had been compiled identified homologs for 49 of the 60 unique sequences represented by the SGX structures. This result indicates that, for bacterial structures that are relatively easy to express, purify, and crystallize, the structural coverage of gene space is proceeding rapidly. More distant sequence-structure relationships between the SGX and PDB structures were investigated using PDB-BLAST and Combinatorial Extension (CE). Only one structure, SufD, has a truly unique topology compared to all folds in the PDB.

[Mammography screening--neglected aspects of radiation risks]. / Mammographiescreening--Vernachlässigte Aspekte der Strahlenrisikobewertung.

It is generally assumed that the radiation risk from mass screening for breast cancer may be neglected. This is questionable in view of the high biological effectiveness of low energy X-rays used in radiography of the breasts. The hormone replacement therapy for elderly women must be considered as a further cause for unexpected high rates of radiation-induced breast cancer cases. Each normal population of women, moreover, contains a very radiosensitive subgroup: the women bearing a mutation of the gene BRCA 1 or BRCA 2. In these, repeated X-ray use must be definitely avoided.

[Investigation of foodborne outbreak due to Salmonella infantis using epidemiological and microbiological methods]. / Untersuchung einer lebensmittelbedingten Salmonella infantis-Gruppenerkrankung mit Methoden der Epidemiologie und Mikrobiologie.

In foodborne outbreaks, direct microbiological diagnosis is often not possible due to lack of remaining food samples. Therefore, in this investigation of an outbreak of Salmonella infantis at a fair, we chose an epidemiological approach in addition to microbiological testing. In a case control study, fair participants with symptoms of acute gastroenteritis as well as participants showing no signs of disease were interviewed by telephone. Questions concerning what food had been eaten at the fair and the course of disease had priority. Data analysis showed a significantly elevated odds ratio of 144 (p < 0.00001) for the consumption of potato salad. Salmonella infantis was cultured in faeces of symptomatic individuals as well as from left-over potato salad in high concentration. In conclusion, our data show that the cause of a foodborne outbreak can be detected through the application of epidemiologic methods with a high degree of certainty. In order to eliminate memory bias, a structured interview should be carried out as soon as possible after the initial outbreak.

The structure of the signal receiver domain of the Arabidopsis thaliana ethylene receptor ETR1.

BACKGROUND: In Arabidopsis thaliana, ethylene perception and signal transduction into the cell are carried out by a family of membrane-bound receptors, one of which is ethylene resistant 1 (ETR1). The large cytoplasmic domain of the receptor showed significant sequence homology to the proteins of a common bacterial regulatory pathway, the two-component system. This system consists of a transmitter histidine kinase and a response regulator (or signal receiver). We present the crystal structures of the first plant receiver domain ETRRD (residues 604-738) of ETR1 in two conformations. RESULTS: The monomeric form of ETRRD resembles the known structure of the bacterial receiver domain. ETRRD forms a homodimer in solution and in the crystal, an interaction that has not been described previously. Dimerization is mediated by the C terminus, which forms an extended beta sheet with the dimer-related beta-strand core. Furthermore, the loop immediately following the active site adopts an exceptional conformation. CONCLUSIONS: The three-dimensional structure of ETRRD shows the expected conformational conservation to prokaryotic receiver proteins, such as CheY and CheB, both of which are part of the chemotaxis signaling pathway. ETRRD provides the first detailed example of a dimerized receiver domain. Given that the dimer interface of ETRRD coincides with the phosphorylation-dependent interfaces of CheY and CheB, we suggest that the monomerization of ETRRD is phosphorylation-dependent too. In the Mg(2+)-free form of ETRRD, the gamma-loop conformation does not allow a comparable interaction as observed in the active-site architectures of Mg(2+)-bound CheY from Escherichia coli and Salmonella typhimurium.

Structure-based assignment of the biochemical function of a hypothetical protein: a test case of structural genomics.

Many small bacterial, archaebacterial, and eukaryotic genomes have been sequenced, and the larger eukaryotic genomes are predicted to be completely sequenced within the next decade. In all genomes sequenced to date, a large portion of these organisms' predicted protein coding regions encode polypeptides of unknown biochemical, biophysical, and/or cellular functions. Three-dimensional structures of these proteins may suggest biochemical or biophysical functions. Here we report the crystal structure of one such protein, MJ0577, from a hyperthermophile, Methanococcus jannaschii, at 1.7-A resolution. The structure contains a bound ATP, suggesting MJ0577 is an ATPase or an ATP-mediated molecular switch, which we confirm by biochemical experiments. Furthermore, the structure reveals different ATP binding motifs that are shared among many homologous hypothetical proteins in this family. This result indicates that structure-based assignment of molecular function is a viable approach for the large-scale biochemical assignment of proteins and for discovering new motifs, a basic premise of structural genomics.

Subcloning, crystallization and preliminary X-ray analysis of the signal receiver domain of ETR1, an ethylene receptor from Arabidopsis thaliana.

The signal receiver domain of ETR1, an ethylene receptor from Arabidopsis thaliana, has been subcloned and expressed in E. coli and purified by affinity chromatography. Crystals of both native and a selenomethionine-substituted form of the receiver domain have been obtained. Native crystals grew in 1.6 M Li2SO4 and 0.1 M HEPES pH 7. 5 and once flash-frozen diffract to 2.1 A resolution. They belong to space group P41212 with unit-cell dimensions a = b = 48.4, c = 112.3 A.

A cluster of childhood leukemia near a nuclear reactor in northern Germany.

Between February 1990 and December 1995, professionals diagnosed six cases of childhood leukemia among residents of the small rural community of Elbmarsch in northern Germany. Five of these cases were diagnosed in only a 16-mo period between February 1990 and May 1991. All cases lived in close proximity (i.e., 500-4,500 m) to Germany's largest capacity nuclear boiling-water reactor. We calculated standardized incidence ratios and exact 95% confidence intervals for a 5-km-radius circular area around the plant. The standardized incidence ratio for the time period 1990-1995 was 460 (95% confidence interval: 210, 1,030). The analysis was restricted further to the years 1990 and 1991, and the standardized incidence ratio increased to 1,180 (95% confidence interval: 490, 2,830). Presently, this cluster of childhood leukemia cases cannot be explained in terms of established and putative risk factors--including radiation from medical sources--for childhood leukemia.

Fairy-tales in psychotherapy.

Fairy-tales, like mythologies, can be found all over the world containing the same motif and chains of motifs. In this paper I have presented some theories on the occurrence of this archetypal phenomenon ranging from the old migration theory to Sheldrake's theory of morphogenetic fields. I have then tried to show how fairy-tale-motifs can appear in various ways in analytical therapy, often in hidden forms. We find them in patients' dreams as well as in their fantasies and associations. If the therapist is open to them they will also appear in his or her amplifications. He or she might then take note of the fairy-tale or point it out to the patient; in the latter case it might provide better access to the patient's problems and complexes as fairy-tales have an emotional completeness because of their pictorial character. Finally I have described the favourite fairy-tale of one of my patients and related it to his symptoms, his central complex and his personal ways of experiencing and behaving. This survey of how fairy-tales can be used in therapy with children and with adults far from exhaustive.

Pentafluorobenzylation of the fungicide metabolite fenpropimorphic acid for GC/MS investigations of soil samples.

For the determination of fenpropimorphic acid in soil samples, a derivatization step with pentafluorobenzylbromide has been established in order to perform GC/MS with negative chemical ionization. In spite of forming the electrophilic pentafluorobenzyl ester, only the fenpropimophic acid anion was detected. Additional derivatization reactions with diazomethane and 2,2,2-trichloroethanol showed that the formation of this acid anion was depending on the leaving group. In comparison with the determination of the methyl ester with GC/MS and electron impact ionization, the detection limit was however improved from 10 microg/kg to 2 microg/kg dry soil and the analytical quality was ensured due to higher stability of the pentafluorobenzyl ester standards.

Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase.

The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation makes them a promising target for studying inhibitory molecules that can modify the degree of cell proliferation. The discovery of specific inhibitors of CDKs such as polyhydroxylated flavones has opened the way to investigation and design of antimitotic compounds. A novel flavone, (-)-cis-5,7-dihydroxyphenyl-8-[4-(3-hydroxy-1-methyl)piperidinyl] -4H-1-benzopyran-4-one hydrochloride hemihydrate (L868276), is a potent inhibitor of CDKs. A chlorinated form, flavopiridol, is currently in phase I clinical trials as a drug against breast tumors. We determined the crystal structure of a complex between CDK2 and L868276 at 2.33 angstroms resolution and refined to an Rfactor 20.3%. The aromatic portion of the inhibitor binds to the adenine-binding pocket of CDK2, and the position of the phenyl group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP complex structure. The analysis of the position of this phenyl ring not only explains the great differences of kinase inhibition among the flavonoid inhibitors but also explains the specificity of L868276 to inhibit CDK2 and CDC2.

[Cor triatriatum--a rare cause of pulmonary hemosiderosis]. / Cor triatriatum--seltene Ursache einer Lungenhämosiderose.

Pneumological examinations including open lung biopsy performed on a male patient of 30 years of age suffering from severe respiratory distress that disabled him, as well as from massive recurring attacks of hemoptysis, resulted in suspicion of idiopathic pulmonary hemosiderosis (also known as Ceelen-Gellerstedt's syndrome). Diagnosis of cor triatriatum followed by surgery was arrived at only after a pulmonary oedema had developed and after other rare cardiac diseases had been considered. This rare congenital malformation--which occasionally becomes clinically manifest only in the adult--should be suspected in differential diagnosis of respiratory distress and a sometimes also life-threatening hemoptysis. Echocardiography is the diagnostic method of choice in this regard.

Substrate specificity and assembly of the catalytic center derived from two structures of ligated uridylate kinase.

Two crystal structures of ligated uridylate kinase from Saccharomyces cerevisiae were determined by X-ray analyses. The ligands were ADP and AMP. Cocrystallization with ATP yielded crystals with ADP at the ATP site and a mixture of AMP and ADP at the NMP site. Cocrystallization with ADP gave rise to a distinct crystal type with ADP at the ATP site, but only AMP at the NMP site. In both cases, the substrates are kept in place by favorable crystal contacts. The structures have been refined to R-factors of 17.8% and 19.6% at resolutions of 2.1 A and 1.9 A, respectively. A comparison with the related cytosolic adenylate kinase from pig disclosed large induced-fit movements on substrate binding and the disassembly of the catalytic center in the absence of substrates. The relatively high side-activity of uridylate kinase for AMP is explained by the finding that the binding pocket is sized for an AMP, but constructed to bind UMP together with a water molecule.

The structure of uridylate kinase with its substrates, showing the transition state geometry.

Uridylate kinase from Saccharomyces cerevisiae is a member of the nucleoside monophosphate (NMP) kinase family and catalyzes the reaction ATP+NMP<==>ADP+NDP with moderate specificity for UMP. The recombinant enzyme crystallized together with two substrate molecules. The structure was solved, by multiple isomorphous replacement and solvent flattening, at 3.0 A and then refined at 2.13 A resolution. The present R-factor is 19%. Superposition onto the structure of a substrate-free adenylate kinase revealed the motions induced by substrate binding. A further superposition onto an adenylate kinase with bound P1,P5-bis(5'-adenosyl)pentaphosphate (Ap5A), a two-substrate-mimicking inhibitor, failed to explain the UMP preference of the uridylate kinase, but superimposed the nucleosides and in particular the non-transferred phosphates at the ATP- and NMP-site rather well. The coincidence of the phosphates indicate strongly that these groups assume their final positions during catalysis. This locates the transition state, which can be modeled with reasonable geometry in agreement with an in-line associative SN2 mechanism.

[Incidence of leukemia in the Elbmarsch area]. / Häufung von Leukämieerkrankungen in der Elbmarsch.

The extremely conspicuous excess of leukaemia in the immediate neighbourhood of the world's largest boiling water reactor Krümmel is shown in its temporal and spatial context. An early extensive Lower Saxony state research programme gives no hint what so ever for a cause beyond three known risks of the region: 1. the main point is that the radiation exposure is well-known for causing leukaemia; 2. contamination of drinking water with an unknown substance containing nitrogen; 3. emissions from a chemical factory (according to a brief toxicological report, however, without potential for causing leukaemia). The leukaemia cluster is discussed against the background of a new valuation of radiation risk derived from recent Hiroshima data and the Mainz Leukaemia Study published in February, which points out in analogy to late British studies a significant increase in the leukaemia risk for the most radiation-sensitive group of infants and young children (aged 0-4) in the proximity of nuclear power plants.

Postmortem angiographic and pathologic-anatomic findings in coronary heart disease: a comparative study using planimetry.

Comparisons of the results of angiographic and pathologic-anatomic estimations of the degree of coronary artery stenosis are rare and the findings contradictory. In the present study, postmortem examinations were carried out on 26 hearts with coronary artery disease. Quantitative planimetric measurements of 203 coronary artery cross-sections were performed and compared with the results of postmortem coronary angiograms. Using a score rating scale, a highly significant difference (P < 0.001) between the angiographic and morphologic findings was detected, with the degree of stenosis and underestimated angiographically in 96 of the 203 sections (47%), overestimated in 18 (9%), and correctly estimated in 89 (44%). The tendency to underestimation was equal in all of the coronary arteries (left anterior descending, circumflex, and right coronary arteries); there were no statistically significant differences (P < 0.20, P < 0.30, P < 0.10). The frequency of angiographic underestimation of the degree of morphologic stenosis--especially in critical stenoses of more than 60%)--has important implications in the assessment of whether coronary artery surgery is warranted.

[Trigeminal neuralgia and its differential diagnosis (author's transl)]. / Die Trigeminus- neuralgien und ihre Differentialdiagnose.

Trigeminal neuralgia (Tr. N.) occurring as tic douloureux usually proves to be senile neuralgia without any etiological background. On the other hand, isolated Tr. N. of the first ramus suggests the process. Bilateral Tr. N. are rare yet most frequently an expression of a multiple sclerosis with attacks first on one side and then on the other. Symptomatic Tr. N. occurs seldom as perhaps in M.S., only as tic douloureux, usually as a continuous pain with more or less acute exacerbations. Tr. N. are therapeutically problematic after operative treatment of the maxillary sinuses, still more so after herpes zoster. Other neuralgias and facial neuralgias (e.g. a glossopharyngeal neuralgia, nasociliary neuralgia, Sluder's neuralgia, Costen's syndrome, Horton's syndrome etc.) must be diagnostically differentiated from Tr. N.