Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Time esophageal pH < 4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors

<p>Abstract</p> <p>Background</p> <p>A Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure.</p> <p>Aim</p> <p>We considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4.</p> <p>Methods</p> <p>We calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion.</p> <p>Results</p> <p>The prevalence of pathologic 24-hour esophageal reflux in both studies was significantly higher when measured as time pH < 4 than when measured as integrated acidity. This difference was entirely attributable to a difference between the two measures during the nocturnal period. Nocturnal gastric acid breakthrough was not a useful predictor of pathologic nocturnal esophageal reflux.</p> <p>Conclusion</p> <p>In GERD subjects treated with a PPI, measuring time esophageal pH < 4 will significantly overestimate the prevalence of pathologic esophageal acid exposure over 24 hours and during the nocturnal period.</p

Large-Scale Structures Behind the Milky Way from Near-IR Surveys

About 25% of the optical extragalactic sky is obscured by the dust and stars of our Milky Way. Dynamically important structures might still lie hidden in this zone. Various approaches are presently being employed to uncover the galaxy distribution in the Zone of Avoidance (ZOA) but all suffer from (different) limitations and selection effects. We investigated the potential of using the DENIS NIR survey for studies of galaxies behind the obscuration layer of our Milky Way and for mapping the Galactic extinction. As a pilot study, we recovered DENIS I, J and K band images of heavily obscured but optically still visible galaxies. We determined the I, J and K band luminosity functions of galaxies on three DENIS strips that cross the center of the nearby, low-latitude, rich cluster Abell 3627. The extinction-corrected I-J and J-K colours of these cluster galaxies compare well with that of an unobscured cluster. We searched for and identified galaxies at latitudes where the Milky Way remains fully opaque (|b| 4-5mag) - in a systematic search as well as around positions of galaxies detected with the blind HI survey of the ZOA currently conducted with the Multibeam Receiver of the Parkes Radiotelescope.Comment: 12 pages, including 5 PS figures, LaTeX, uses crckapb.sty and epsf.tex. Better resolved figures available upon request. To appear in proceedings of the 3rd Euroconference (Meudon, France, June 1997) on ``The Impact of Near IR Surveys'', Kluwer 199

CR1 Knops blood group alleles are not associated with severe malaria in the Gambia

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value &lt;0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels

RepSeq-A database of amino acid repeats present in lower eukaryotic pathogens

BACKGROUND Amino acid repeat-containing proteins have a broad range of functions and their identification is of relevance to many experimental biologists. In human-infective protozoan parasites (such as the Kinetoplastid and Plasmodium species), they are implicated in immune evasion and have been shown to influence virulence and pathogenicity. RepSeq http://repseq.gugbe.com is a new database of amino acid repeat-containing proteins found in lower eukaryotic pathogens. The RepSeq database is accessed via a web-based application which also provides links to related online tools and databases for further analyses. RESULTS The RepSeq algorithm typically identifies more than 98% of repeat-containing proteins and is capable of identifying both perfect and mismatch repeats. The proportion of proteins that contain repeat elements varies greatly between different families and even species (3 - 35% of the total protein content). The most common motif type is the Sequence Repeat Region (SRR) - a repeated motif containing multiple different amino acid types. Proteins containing Single Amino Acid Repeats (SAARs) and Di-Peptide Repeats (DPRs) typically account for 0.5 - 1.0% of the total protein number. Notable exceptions are P. falciparum and D. discoideum, in which 33.67% and 34.28% respectively of the predicted proteomes consist of repeat-containing proteins. These numbers are due to large insertions of low complexity single and multi-codon repeat regions. CONCLUSION The RepSeq database provides a repository for repeat-containing proteins found in parasitic protozoa. The database allows for both individual and cross-species proteome analyses and also allows users to upload sequences of interest for analysis by the RepSeq algorithm. Identification of repeat-containing proteins provides researchers with a defined subset of proteins which can be analysed by expression profiling and functional characterisation, thereby facilitating study of pathogenicity and virulence factors in the parasitic protozoa. While primarily designed for kinetoplastid work, the RepSeq algorithm and database retain full functionality when used to analyse other species

Identifying null meta-analyses that are ripe for updating

BACKGROUND: As an increasingly large number of meta-analyses are published, quantitative methods are needed to help clinicians and systematic review teams determine when meta-analyses are not up to date. METHODS: We propose new methods for determining when non-significant meta-analytic results might be overturned, based on a prediction of the number of participants required in new studies. To guide decision making, we introduce the "new participant ratio", the ratio of the actual number of participants in new studies to the predicted number required to obtain statistical significance. A simulation study was conducted to study the performance of our methods and a real meta-analysis provides further evidence. RESULTS: In our three simulation configurations, our diagnostic test for determining whether a meta-analysis is out of date had sensitivity of 55%, 62%, and 49% with corresponding specificity of 85%, 80%, and 90% respectively. CONCLUSIONS: Simulations suggest that our methods are able to detect out-of-date meta-analyses. These quick and approximate methods show promise for use by systematic review teams to help decide whether to commit the considerable resources required to update a meta-analysis. Further investigation and evaluation of the methods is required before they can be recommended for general use