The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage

NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks.     

The use of H2 antagonists in treating and preventing NSAID-induced mucosal damage

Pain affects the quality of life for millions of individuals and is a major reason for healthcare utilization. As populations age, medical personnel will need to manage more and more patients suffering from pain associated with degenerative and inflammatory musculoskeletal disorders. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective treatment for both acute and chronic musculoskeletal pain; however, their use is associated with potentially significant gastrointestinal (GI) toxicity. Guidelines suggest various strategies to prevent problems in those at risk for NSAID-associated GI complications. In this article, we review the data supporting one such strategy - the use of histamine type-2 receptor antagonists (H2RAs) - for the prevention of GI adverse events in NSAID users. Older studies suggest that high-dose H2RAs are effective in preventing upper GI ulcers and dyspepsia. This suggestion was recently confirmed during clinical trials with a new ibuprofen/famotidine combination that reduced the risk of ulcers by 50% compared with ibuprofen alone.     

Efficient Synthesis of 2′-Deoxynucleoside 3′-C-Phosphonates: Reactivity of Geminal Hydroxyphosphonate Moiety

Abstract

In this report we present a novel, simple way for the synthesis of 3′-C-phosphonate derivatives of all four basic 2′-deoxynucleosides in both fully protected and deprotected forms. The reactivity of the geminal hydroxy phosphonate moiety located at the 3′-carbon atom of the nucleoside was studied with respect to the use of this type of nucleoside phosphonic acid for the preparation of short oligonucleotides, namely, dinucleoside monophosphate analogues.     

Persistent versus transient tree encroachment of temperate peat bogs: effects of climate warming and drought events

Peatlands store approximately 30% of global soil carbon, most in moss‐dominated bogs. Future climatic changes, such as changes in precipitation patterns and warming, are expected to affect peat bog vegetation composition and thereby its long‐term carbon sequestration capacity. Theoretical work suggests that an episode of rapid environmental change is more likely to trigger transitions to alternative ecosystem states than a gradual, but equally large, change in conditions. We used a dynamic vegetation model to explore the impacts of drought events and increased temperature on vegetation composition of temperate peat bogs. We analyzed the consequences of six patterns of summer drought events combined with five temperature scenarios to test whether an open peat bog dominated by moss (Sphagnum) could shift to a tree‐dominated state. Unexpectedly, neither a gradual decrease in the amount of summer precipitation nor the occurrence of a number of extremely dry summers in a row could shift the moss‐dominated peat bog permanently into a tree‐dominated peat bog. The increase in tree biomass during drought events was unable to trigger positive feedbacks that keep the ecosystem in a tree‐dominated state after a return to previous ‘normal’ rainfall conditions. In contrast, temperature increases from 1 °C onward already shifted peat bogs into tree‐dominated ecosystems. In our simulations, drought events facilitated tree establishment, but temperature determined how much tree biomass could develop. Our results suggest that under current climatic conditions, peat bog vegetation is rather resilient to drought events, but very sensitive to temperature increases, indicating that future warming is likely to trigger persistent vegetation shifts.     

Nitrate signals determine the sensing of nitrogen through differential expression of genes involved in nitrogen uptake and assimilation in finger millet

In order to understand the molecular basis of high nitrogen use efficiency of finger millet, five genes (EcHNRT2, EcLNRT1, EcNADH-NR, EcGS, and EcFd-GOGAT) involved in nitrate uptake and assimilation were isolated using conserved primer approaches. Expression profiles of these five genes along with the previously isolated EcDof1 was studied under increased KNO₃ concentrations (0.15 to 1,500 μM) for 2 h as well as at 1.5 μM for 24 h in the roots and shoots of 25 days old nitrogen deprived two contrasting finger millet genotypes (GE-3885 and GE-1437) differing in grain protein content (13.76 and 6.15 %, respectively). Time kinetics experiment revealed that, all the five genes except EcHNRT2 in the leaves of GE-3885 were induced within 30 min of nitrate exposure indicating that there might be a greater nitrogen deficit in leaves and therefore quick transportation of nitrate signals to the leaves. Exposing the plants to increasing nitrate concentrations for 2 h showed that in roots of GE-3885, NR was strongly induced while GS was repressed; however, the pattern was found to be reversed in leaves of GE-1437 indicating that in GE-3885, most of the nitrate might be reduced in the roots but assimilated in leaves and vice-versa. Furthermore, compared with the low-protein genotype, expression of HNRT2 was strongly induced in both roots and shoots of high-protein genotype at the least nitrate concentration supplied. This further indicates that GE-3885 is a quick sensor of nitrogen compared with the low-protein genotype. Furthermore, expression of EcDof1 was also found to overlap the expression of NR, GS, and GOGAT indicating that Dof1 probably regulates the expression of these genes under different conditions by sensing the nitrogen fluctuations around the root zone.     

Transfer of the Nonmatch-to-Goal rule in Monkeys across Cognitive Domains

To solve novel problems, it is advantageous to abstract relevant information from past experience to transfer on related problems. To study whether macaque monkeys were able to transfer an abstract rule across cognitive domains, we trained two monkeys on a nonmatch-to-goal (NMTG) task. In the object version of the task (O-NMTG), the monkeys were required to choose between two object-like stimuli, which differed either only in shape or in shape and color. For each choice, they were required to switch from their previously chosen object-goal to a different one. After they reached a performance level of over 90% correct on the O-NMTG task, the monkeys were tested for rule transfer on a spatial version of the task (S-NMTG). To receive a reward, the monkeys had to switch from their previously chosen location to a different one. In both the O-NMTG and S-NMTG tasks, there were four potential choices, presented in pairs from trial-to-trial. We found that both monkeys transferred successfully the NMTG rule within the first testing session, showing effective transfer of the learned rule between two cognitive domains.     

Mapping the Genes for Susceptibility and Response to Leishmania tropica in Mouse

Background

L. tropica can cause both cutaneous and visceral leishmaniasis in humans. Although the L. tropica-induced cutaneous disease has been long known, its potential to visceralize in humans was recognized only recently. As nothing is known about the genetics of host responses to this infection and their clinical impact, we developed an informative animal model. We described previously that the recombinant congenic strain CcS-16 carrying 12.5% genes from the resistant parental strain STS/A and 87.5% genes from the susceptible strain BALB/c is more susceptible to L. tropica than BALB/c. We used these strains to map and functionally characterize the gene-loci regulating the immune responses and pathology.

Methods

We analyzed genetics of response to L. tropica in infected F₂ hybrids between BALB/c×CcS-16. CcS-16 strain carries STS-derived segments on nine chromosomes. We genotyped these segments in the F₂ hybrid mice and tested their linkage with pathological changes and systemic immune responses.

Principal Findings

We mapped 8 Ltr (Leishmania tropica response) loci. Four loci (Ltr2, Ltr3, Ltr6 and Ltr8) exhibit independent responses to L. tropica, while Ltr1, Ltr4, Ltr5 and Ltr7 were detected only in gene-gene interactions with other Ltr loci. Ltr3 exhibits the recently discovered phenomenon of transgenerational parental effect on parasite numbers in spleen. The most precise mapping (4.07 Mb) was achieved for Ltr1 (chr.2), which controls parasite numbers in lymph nodes. Five Ltr loci co-localize with loci controlling susceptibility to L. major, three are likely L. tropica specific. Individual Ltr loci affect different subsets of responses, exhibit organ specific effects and a separate control of parasite load and organ pathology.

Conclusion

We present the first identification of genetic loci controlling susceptibility to L. tropica. The different combinations of alleles controlling various symptoms of the disease likely co-determine different manifestations of disease induced by the same pathogen in individual mice.     

Evaluation of the performance and accuracy of Global Positioning System bug transmitters deployed on a small mammal

Recent technological advances in Global Positioning System (GPS) telemetry have allowed the production of lightweight devices suitable for use on small mammals. We evaluated the use of GPS bugs on the European hedgehog (Erinaceus europaeus) in a series of static and field tests. Static tests were conducted in five different rural habitats, affording different degrees of obstruction to satellites. GPS bug performance was good in all habitats (fix success rate (FSR): median ≥?66.8 %; location error (LE): mean ≤?13.5 m), except woodland (FSR?=?37.7 %; LE?=?15.6 m), with performance highest in the open pasture habitat (FSR?=?100 %; LE?=?6.4 m). Field tests revealed mean FSR was high (84.6 %), with the use of nesting habitats, the probable cause of most failed fixes. Despite being more expensive, GPS bugs require less survey effort and substantially lower labour costs with unlimited longevity permitting re-use in multiple seasons. We recommend the use of GPS bugs in the spatial ecological study of any small mammal in a rural environment, providing accurate and unbiased movement data. Further performance testing is recommended before deployment on species inhabiting forested habitats where reduced FSR and high LE support the alternative use of very high frequency tracking.