Swallowed topical corticosteroids reduce the risk for long-lasting bolus impactions in eosinophilic esophagitis.

BACKGROUND: Long-lasting food impactions requiring endoscopic bolus removal occur frequently in patients with eosinophilic esophagitis (EoE) and harbor a risk for severe esophageal injuries. We evaluated whether treatment with swallowed topical corticosteroids is able to reduce the risk of occurrence of this complication. METHODS: We analyzed data from the Swiss EoE Cohort Study. Patients with yearly clinic visits, during which standardized assessment of symptoms, endoscopic, histologic, and laboratory findings was carried out, were included. RESULTS: A total of 206 patients (157 males) were analyzed. The median follow-up time was 5 years with a total of 703 visits (mean 3.41 visits/patient). During the follow-up period, 33 patients (16 % of the cohort) experienced 42 impactions requiring endoscopic bolus removal. We evaluated the following factors regarding the outcome 'bolus impaction' by univariate logistic regression modeling: swallowed topical corticosteroid therapy (OR 0.503, 95%-CI 0.255-0.993, P = 0.048), presence of EoE symptoms (OR 1.150, 95%-CI 0.4668-2.835, P = 0.761), esophageal stricture (OR 2.832, 95%-CI 1.508-5.321, P = 0.001), peak eosinophil count >10 eosinophils/HPF (OR 0.724, 95%-CI 0.324-1.621, P = 0.433), blood eosinophilia (OR 1.532, 95%-CI 0.569-4.118, P = 0.398), and esophageal dilation (OR 1.852, 95%-CI 1.034-3.755, P = 0.017). In the multivariate model, the following factors were significantly associated with bolus impaction: swallowed topical corticosteroid therapy (OR 0.411, 95%-CI 0.203-0.835, P = 0.014) and esophageal stricture (OR 2.666, 95%-CI 1.259-5.645, P = 0.01). Increasing frequency of use of swallowed topical steroids was associated with a lower risk for bolus impactions. CONCLUSIONS: Treatment of EoE with swallowed topical corticosteroids significantly reduces the risk for long-lasting bolus impactions.

Ataxia and disequilibrium in domestic ducks (Anas platyrhynchos f. dom.) with intracranial lipomas.

Four birds in a flock of 125 purebred Crested ducks (Anas platyrhynchos f. dom.) had cerebellar signs of unknown etiology. They had radiographically evident perforations of various sizes in the parieto-occipital calvaria. Gross necropsy of euthanatized ducks revealed yellow intracranial masses in the brain of each. Histologically, these masses were intracranial lipomas consisting of univacuolated fatty tissue separated into lobules by strands of connective tissue. The masses had caused serious deformation of the rostral part of the cerebellum, leading to a nearly complete flattening of cerebellar folia, and were interpreted as the cause for the central nervous clinical signs observed. These intracranial lipomas were similar to those previously reported in other animals and humans.

Magnetic resonance imaging of intracranial tissue accumulations in domestic ducks (Anas platyrhynchos f. dom.) with feather crests.

The crested breed of domestic duck (Anas platyrhynchos f. dom.) has been described as a variety which has high pre- and postnatal mortalities, malformations in skull and brain anatomy, and several central nervous deficiencies. In addition, intracranial tissue accumulations have been diagnosed in purebred Crested ducks. The incidence, heredity and inheritance of these accumulations as well as their pathogenesis are still generally unknown. The aims of this study were to examine the head of Crested ducks, plain-headed duck breeds, and their crossbreeding relating to the incidence of intracranial alterations. These examinations were performed using magnetic resonance imaging. We found a high incidence of intracranial tissue accumulations in domestic ducks with feather crests. Creasted ducks had more intracranial tissue deposits than plain-headed ducks (p < 0.001). In the present study a correlation between the volume of the crest cushion and the volume of the intracranial tissue deposit could not be found (r = 0.014). Some of the Crested ducks had encephaloceles in addition to the crest cushion.

Osteological investigations of the incidence of cranial alterations in domestic ducks (Anas platyrhynchos f. dom.) with feather crests.

The feather crest of the domestic duck (Anas platyrhynchos f. dom.) represents a peculiar mutation of the integument of the head, which has been known since the 17th century. In literature this is described as a variety with malformations in skull and brain anatomy in which various central nervous deficiencies in affected birds are possible. Our examinations demonstrated several conspicuous anatomical alterations in the skulls of domestic ducks with feather crests. Osteophytes of different size in the hypodermis of the crest integument were found as well as cranial perforations located in the parieto-occipital region. In morphometric studies, a significant increase in the capacity of the cranium was found in Crested ducks compared to other examined breeds (Abacot Ranger, German Pekin ducks). This increase in cranial capacity in Crested ducks results from the occurrence and enlargement of a tentorial fatty depot during craniogenesis. The formation and enlargement of the fat body can influence cranium growth as long as the cranial bones are not entirely fused. Thus, in comparison to other phenotypically similar domesticated birds like the crested chicken, the expression of feather crests in domestic ducks demonstrates symptomatologic differences. In conclusion, our examinations demonstrate that the skulls of Crested ducks show various peculiar morphological alterations whose genesis is up to now not known with satisfactory accuracy. Further investigations are continuing to assertain whether there are linkages between cranial alterations (malformations of the calvaria, osteophytes, increased capacity of the cranium) and the extremely high prenatal and postnatal mortalities and numerous abnormalities described in crested breeds of the domestic duck.

The use of conventional radiography and computer-assisted tomography as instruments for demonstration of gross pathological lesions in the cranium and cerebrum in the crested breed of the domestic duck (Anas platyrhynchos f.dom.).

According to literature reports, the crested breed of the domestic duck (Anas platyrhynchos f. dom.) is described as a variety with high pre- and post-natal mortalities, malformations in skull and brain anatomy, and various central nervous deficiencies in affected birds. A detailed examination as to the cause and pathogenesis of these neurologic disorders has not yet been conducted, nor has an explanation concerning the inheritance of the feather crest been found. By using two non-invasive radiographic techniques, conventional radiography and computer-assisted tomography, living ducks were examined. Our studies have demonstrated that brain and skull anatomy of ducks of various breeds (Crested, Abacot Ranger, and German Pekin) can be well visualized using computer-assisted tomography. The Crested ducks investigated in this study showed abnormal fatty tissue deposits in the tentorium cerebelli, cranial malformations, and variable bone formations in the thickened hypodermis of the crest. In comparison with computer-assisted tomography, only parts of the skull changes were detected with conventional radiography; in no case could fat bodies be seen with this imaging method. An increase of the cranial capacity in the Crested ducks compared with other breeds examined (Abacot Ranger, German Pekin ducks) was found in morphometric studies carried out by computerassisted tomography. This increase of cranial capacity in Crested ducks results from an increase of the tentorial fatty depot during craniogenesis, as an enlargement of the fat body can influence cranium growth as long as the cranial bones are not yet fused. Thus, in comparison with other phenotypically similar domesticated birds like the crested chicken, the expression of the feather crest in domestic ducks demonstrates symptomatologic differences.

Correlating structure and stability of DNA duplexes with incorporated 2'-O-modified RNA analogues.

Chemically modified nucleic acids are currently being evaluated as potential antisense compounds for therapeutic applications. 2'-O-Ethylene glycol substituted oligoribonucleotides are second-generation antisense inhibitors of gene expression with promising features for in vivo use. Relative to DNA, they display improved RNA affinity and higher nuclease resistance. Moreover, chimeric oligonucleotides with 2'-O-methoxyethyl ribonucleoside wings and a central DNA phosphorothioate window have been shown to effectively reduce the growth of tumors in animal models at low doses. Using X-ray crystallography, we have determined the structures of three A-form DNA duplexes containing the following 2'-O-modified ribothymidine building blocks: 2'-O-methoxyethyl ribo-T, 2'-O-methyl[tri(oxyethyl)] ribo-T, and 2'-O-ethoxymethylene ribo-T. In contrast to 2'-O-ethylene glycol substituents, the presence of a 2'-O-ethoxymethylene group leads to slightly reduced RNA affinity of the corresponding oligonucleotides. The three structures allow a qualitative rationalization of the differing stabilities of duplexes between oligonucleotides comprising these types of 2'-O-modified ribonucleotides and complementary RNAs. The stabilizing 2'-O-ethylene glycol substituents are conformationally preorganized for the duplex state. Thus, the presence of one or several ethylene glycol moieties may reduce the conformational space of the substituents in an oligonucleotide single strand. In addition, most of these preferred conformations appear to be compatible with the minor groove topology in an A-type duplex. Factors that contribute to the conformational rigidity of the 2'-O-substituents are anomeric and gauche effects, electrostatic interactions between backbone and substituent, and bound water molecules.

RNA hydration: a detailed look.

The crystal structure of the RNA duplex [r(CCCCGGGG)]2 has been refined to 1.46 A resolution with room temperature synchrotron diffraction data. This represents the highest resolution reported to date for an all-RNA oligonucleotide and is well beyond the best resolution ever achieved with an A-form DNA duplex. The analysis of the ordered hydration around the octamer duplex reveals conserved regular arrangements of water molecules in both grooves. In the major groove, all located first shell water molecules can be fitted into a pattern that is repeated through all eight base pairs, involves half the phosphate oxygens, and joins the two strands. In the minor groove, roughly across its narrowest dimension, tandem water molecules link the 2'-hydroxyl groups of adjacent nucleotides in base-pair steps in a similarly regular fashion. The structure provides evidence for an important role of the 2'-hydroxyl groups in the thermodynamic stabilization of RNA, beyond their known functions of locking the sugar pucker and mediating 3' --> 5' intrastrand O2'...O4' hydrogen bonds. The ribose 2'-hydroxyls lay the foundation for the enthalpic stability of the RNA relative to the DNA duplex, both as a scaffold for the water network in the minor groove and through their extensive individual hydration.

Crystal structures of an A-form duplex with single-adenosine bulges and a conformational basis for site-specific RNA self-cleavage.

BACKGROUND: Bulged nucleotides are common secondary structural motifs in RNA molecules and are often involved in RNA-RNA and RNA-protein interactions. RNA is selectively cleaved at bulge sites (when compared to other sites within stems) in the presence of divalent metal cations. The effects of bulge nucleotides on duplex stability and topology have been extensively investigated, but no detailed X-ray structures of bulge-containing RNA fragments have been available. RESULTS: We have crystallized a self-complementary RNA-DNA chimeric 11-nucleotide sequence containing single-adenosine bulges under two different conditions, giving two distinct crystal forms. In both lattices the adenosines are looped out, leaving the stacking interactions in the duplex virtually unaffected. The bulges cause the duplex to kink in both cases. In one of the structures, the conformation of the bulged nucleotide places its modeled 2'-oxygen in line with the adjacent phosphate on the 3' side, where it is poised for nucleophilic attack. CONCLUSIONS: Single adenosine bulges cause a marked opening of the normally narrow RNA major groove in both crystal structures, rendering the bases more accessible to interacting molecules compared with an intact stem. The geometries around the looped-out adenosines are different in the two crystal forms, indicating that bulges can confer considerable local plasticity on the usually rigid RNA double helix. The results provide a conformational basis for the preferential, metal-assisted self-cleavage of RNA at bulged sites.

Crystallization and preliminary X-ray diffraction analysis of double-helical RNA octamers.

Single crystals of a chemically synthesized self-complementary RNA octamer with sequence r(CCCCGGGG) have been obtained by screening 50 different conditions at room temperature using a standard sparse-matrix sampling method. Two crystal forms with different morphologies grew under diverse crystallization conditions within days by hanging-drop vapor diffusion. Hexagonal crystals with space group P6(1)22 (one strand per asymmetric unit) and unit-cell dimensions a = b = 39.73 and c = 58.55 A, diffracted to 2.6 A. Rhombohedral crystals with space group R32 (one duplex per asymmetric unit) and unit-cell dimensions a = b = 42.38 and c = 131.70 A, (hexagonal setting) diffracted beyond 1.5 A. Data sets for both crystal forms were collected on image-plate/rotating-anode generator equipment and structure determinations and refinements are under way.

The crystal structure of r(CCCCGGGG) in two distinct lattices.

The structure of the RNA octamer r(C4G4) has been determined in two different crystal forms. The conformations of the RNA duplex in the rhombohedral and hexagonal lattices display only minimal deviations, demonstrating that the RNA double helix is considerably less deformable than the DNA double helix. For the first time the crystal structures of an A-RNA and an A-DNA with identical sequence can now be compared. The large number of ordered water molecules observed in the minor groove of the RNA duplex suggests that an important contribution to its higher rigidity derives from the improved hydration due to the presence of the 2'-hydroxyl groups. Our finding that the conformation of the RNA double helix is virtually unaffected by different crystal packing modes provides evidence that proteins may not alter the conformation of RNA stem regions in a significant way.

[Preclinical management of accident patients]. / Präklinische Betreuung von Unfallpatienten.

We are reporting on the preclinical care of our patients taking the conditions of Davos into account. We present the manifold and exact work of the different rescue services, which goes on according the "rescue chain" and international standards. Measures of the prevention of accidents as well as the legal basis are presented. Finally we refer to the development during of rescue activities the past years.