Randomized trial on 14 versus 7 days of esomeprazole, moxifloxacin, and amoxicillin for second-line or rescue treatment of Helicobacter pylori infection

Background: Triple therapy with a proton pump inhibitor, moxifloxacin, and amoxicillin has been proven effective in first‐line treatment of Helicobacter pylori infection. Aim: To explore 1, the value of triple therapy with esomeprazole, moxifloxacin, and amoxicillin in second‐line or rescue treatment of Caucasian patients and 2, the impact of treatment duration on eradication success. Methods: H. pylori‐infected patients with at least one previous treatment failure were randomized to oral esomeprazole 20 mg b.i.d., moxifloxacin 400 mg o.d., and amoxicillin 1000 mg b.i.d. for either 7 (EMA‐7) or 14 days (EMA‐14). Eradication was confirmed by 13C urea breath test. Antimicrobial susceptibility testing was performed in all patients at baseline and in patients who failed treatment. Results: Eighty patients were randomized, and 60% had ≥2 previous treatment failures. Pretreatment resistance against clarithromycin and metronidazole was found in 70.5 and 61.5% of cases, respectively. The intention‐to‐treat eradication rate was significantly higher after EMA‐14 compared with EMA‐7 (95.0 vs 78.9%, p = .036). No independent risk factor for treatment failure could be identified. There were no serious adverse events. Five of the EMA‐14 patients (12.5%) compared with none of the EMA‐7 patients discontinued prematurely because of adverse events (p = .031). Post‐treatment resistance against moxifloxacin was found in one of seven patients with isolated organisms (14.3%). Conclusion: Second‐line/rescue H. pylori eradication therapy with esomeprazole, moxifloxacin, and amoxicillin is very effective and well tolerated. Fourteen days of treatment significantly increase the eradication rate but also the rate of adverse events.     

Untersuchungen zur Veränderung der Unkrautflora bei mehrmaligem Getreidenachbau auf einer Tonschwarzerde des Thüringer Beckens

The latent effects of precocenes I and II (PI and PH) and juvenile hormone I (JHI) when topically applied to the last three instars of Spodoptera littoralis (Boisd.) larvae have been studied. Application of both PI or PII resulted in morphogenetic abnormalities resemble some effects induced by administration of JHI, e.g., larval‐pupal intermediate, partial or severe cases of untanned pupae and imperfect moths. In PII‐treatments, the effect was instar‐dose‐dependent. The intermediate dose (55 μg) was more effective on S. littoralis larvae than other doses. The effectiveness of both doses of 40 or 70 μg in production of deformed larvae and pupae decreased when applied as repeated doses instead of single ones. In Pi‐treatments, the lower dose (25 μg) was more harmful to Spodoptera larvae than the higher dose (70 μg). Repeated application by either lower or higher doses did not enhance the production of imperfect insects. Application of JHI induced symptoms ranging from supernumerary instars, larval‐pupal intermediate, untanned pupae and deformed adults. The effect was dose‐dependent. In all tested compounds, there apparently was a latent or delayed effects. Although the insects were treated while they were larvae the complete effects were not apparent until after the insect had become a pupa or an adult. More efforts will be needed to understand how does precocene interferes with the process of tanning or sclerotization?     

Genome-wide profiling of promoter recognition by the two-component response regulator CpxR-P in Escherichia coli

In Escherichia coli, the two-component Cpx system comprising the CpxA sensor kinase and the CpxR response regulator modulates gene expression in response to a variety of stresses including membrane-protein damage, starvation, and high osmolarity. To date, the few known CpxR-P target operons were mostly identified by genetic screens. To facilitate the discovery of all target operons, we derived a 15-bp weighted matrix for CpxR-P recognition that takes into account the relative base frequency at each nucleotide position. This matrix essentially consists of two tandem 5'-GTAAA-3' motifs separated by a 5-bp linker. All of the 15-bp stretches on both strands of the E. coli MG1655 genome were then scored for their degree of matching with the matrix and classified in statistical deviation groups. The effectiveness of this screening is indicated by the identification of eight new target operons (ung, ompC, psd, mviA, aroK, rpoErseABC, secA, and aer) among eleven candidates tested. Moreover, the matrix score correlates with the likelihood that a site is a true target and with the relative site affinity for CpxR-P in vitro. Our data indicate that some 100 operons are under direct CpxR-P control and that the signal transduction pathway interacts with several other control circuits in manners hitherto unanticipated.     

Human GluR6 Kainate Receptor (GRIK2): Molecular Cloning, Expression, Polymorphism, and Chromosomal Assignment

Glutamate receptors mediate the majority of excitatory neurotransmission in the brain, and molecular cloning studies have revealed several distinct families. Because neuropathological states and possibly human disorders may involve kainate-preferring glutamate receptors, we have isolated a cDNA clone for the human GluR6 kainate-preferring receptor. This clone shows a very high sequence similarity with that of the rat, except for a part of the 3′ untranslated region in which there is a TAA triplet repeat. When the protein was overexpressed in human embryonic kidney 293 cells, it had a molecular weight, an antibody recognition, and a glutamate ligand-binding profile similar to those of the rat GluR6 receptor. Northern analysis showed expression in both human cerebral and cerebellar cortices. By PCR analysis of rodent-human monochromosomal cell lines, the human GluR6 could be assigned to chromosome 6. The length of the TAA triplet repeat was polymorphic in the normal population, with at least four alleles and an observed heterozygosity of about 45%. These studies should provide the basis for expression or linkage studies of the GluR6 kainate receptor in human disease or neuropathologic states.     

Assessing Human Genome-wide Variation in the Massim Region of Papua New Guinea and Implications for the Kula Trading Tradition

The Massim, a cultural region that includes the southeastern tip of mainland Papua New Guinea (PNG) and nearby PNG offshore islands, is renowned for a trading network called Kula, in which different valuable items circulate in different directions among some of the islands. Although the Massim has been a focus of anthropological investigation since the pioneering work of Malinowski in 1922, the genetic background of its inhabitants remains relatively unexplored. To characterize the Massim genomically, we generated genome-wide SNP data from 192 individuals from 15 groups spanning the entire region. Analyzing these together with comparative data, we found that all Massim individuals have variable Papuan-related (indigenous) and Austronesian-related (arriving ∼3,000 years ago) ancestries. Individuals from Rossel Island in southern Massim, speaking an isolate Papuan language, have the highest amount of a distinct Papuan ancestry. We also investigated the recent contact via sharing of identical by descent (IBD) genomic segments and found that Austronesian-related IBD tracts are widely distributed geographically, but Papuan-related tracts are shared exclusively between the PNG mainland and Massim, and between the Bismarck and Solomon Archipelagoes. Moreover, the Kula-practicing groups of the Massim show higher IBD sharing among themselves than do groups that do not participate in Kula. This higher sharing predates the formation of Kula, suggesting that extensive contact between these groups since the Austronesian settlement may have facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.     

Variation on a theme of SDR. dTDP-6-deoxy-L- lyxo-4-hexulose reductase (RmlD) shows a new Mg2+-dependent dimerization mode

dTDP-6-deoxy-L-lyxo-4-hexulose reductase (RmlD) catalyzes the final step in the conversion of dTDP-D-glucose to dTDP-L-rhamnose in an NAD(P)H- and Mg2+-dependent reaction. L-rhamnose biosynthesis is an antibacterial target. The structure of RmlD from Salmonella enterica serovar Typhimurium has been determined, and complexes with NADH, NADPH, and dTDP-L-rhamnose are reported. RmlD differs from other short chain dehydrogenases in that it has a novel dimer interface that contains Mg2+. Enzyme catalysis involves hydride transfer from the nicotinamide ring of the cofactor to the C4'-carbonyl group of the substrate. The substrate is activated through protonation by a conserved tyrosine. NAD(P)H is bound in a solvent-exposed cleft, allowing facile replacement. We suggest a novel role for the conserved serine/threonine residue of the catalytic triad of SDR enzymes.     

Sunless skin tanning with dihydroxyacetone delays broad-spectrum ultraviolet photocarcinogenesis in hairless mice

Sunless tanning with dihydroxyacetone (DHA) is not considered to be a sunscreen although it does absorb parts of the ultraviolet (UV) spectrum. We investigated the protection with topical application of DHA against solar UV-induced skin carcinogenesis in lightly pigmented hairless hr/hr C3H/Tif mice. Broad-spectrum UV radiation, simulating the UV part of the solar spectrum was obtained from one Philips TL12 and five Bellarium-S SA-1-12 tubes. Three groups of mice were UV-exposed four times a week to a dose-equivalent of four times the standard erythema dose (SED), without or with application of 5 or 20% DHA only twice a week. Similarly, three groups of mice were treated with DHA and irradiated with a high UV dose (8 SED), simulating a skin burn. Two groups (controls) were not irradiated, but either left untreated or treated with 20% DHA alone. The UV-induced skin pigmentation by melanogenesis could easily be distinguished from DHA-induced browning and was measured by a non-invasive, semi-quantitative method. Application of 20% DHA reduced by 63% the pigmentation produced by 4 SED, however, only by 28% the pigmentation produced by 8 SED. Furthermore, topical application of 20% DHA significantly delayed the time to appearance of the first tumor ≥1 mm (P=0.0012) and the time to appearance of the third tumor (P=2×10⁻⁶) in mice irradiated with 4 SED. However, 20% DHA did not delay tumor development in mice irradiated with 8 SED. Application of 5% DHA did not influence pigmentation or photocarcinogenesis.In conclusion, this is the first study to show that the superficial skin coloring generated by frequent topical application of DHA in high concentrations may delay skin cancer development in hairless mice irradiated with moderate UV doses.     

High‐affinity binding of phosphatidylinositol 4‐phosphate by Legionella pneumophila DrrA

The DrrA protein of Legionella pneumophila is involved in mistargeting of endoplasmic reticulum‐derived vesicles to Legionella‐containing vacuoles through recruitment of the small GTPase Rab1. To this effect, DrrA binds specifically to phosphatidylinositol 4‐phosphate (PtdIns(4)P) lipids on the cytosolic surface of the phagosomal membrane shortly after infection. In this study, we present the atomic structure of the PtdIns(4)P‐binding domain of a protein (DrrA) from a human pathogen. A detailed kinetic investigation of its interaction with PtdIns(4)P reveals that DrrA binds to this phospholipid with, as yet unprecedented, high affinity, suggesting that DrrA can sense a very low abundance of the lipid.