Suboptimal sleep and incident cardiovascular disease among African Americans in the Jackson Heart Study (JHS).

BACKGROUND: Suboptimal sleep, including insufficient/long sleep duration and poor sleep quality, is a risk factor for cardiovascular disease (CVD) common but there is little information among African Americans, a group with a disproportionate CVD burden. The current study examined the association between suboptimal sleep and incident CVD among African Americans. METHODS: This study included 4,522 African Americans without CVD at baseline (2000-2004) of the Jackson Heart Study (JHS). Self-reported sleep duration was defined as very short (<6 h/night), short (6 h/night), recommended (7-8 h/night), and long (≥9 h/night). Participants' self-reported sleep quality was defined as "high" and "low" quality. Suboptimal sleep was defined by low quality sleep and/or insufficient/long sleep duration. Incident CVD was a composite of incident coronary heart disease and stroke. Associations between suboptimal sleep and incident CVD were examined using Cox proportional hazards models over 15 follow-up years with adjustment for predictors of CVD risk and obstructive sleep apnea. RESULTS: Sample mean age was 54 years (SD = 13), 64% female and 66% reported suboptimal sleep. Suboptimal sleep was not associated with incident CVD after covariate adjustment [HR(95% CI) = 1.18(0.97-1.46)]. Long [HR(95%CI) = 1.32(1.02-1.70)] and very short [HR(95% CI) = 1.56(1.06-2.30)] sleep duration were associated with incident CVD relative to recommended sleep duration. Low quality sleep was not associated with incident CVD (p = 0.413). CONCLUSIONS: Long and very short self-reported sleep duration but not self-reported sleep quality were associated with increased hazard of incident CVD.

Susceptibility of Weedy Hosts from Pacific Northwest Potato Production Systems to Crop-Aggressive Isolates of Verticillium dahliae.

Verticillium wilt, caused by Verticillium dahliae, is a disease of dicotyledonous crops such as potato and has a wide host range and persistent, long-term survival structures called microsclerotia that can persist in soil for up to 14 years. Some V. dahliae isolates are particularly aggressive on a specific plant host while retaining the ability to infect a wide range of other hosts. Weeds can serve as hosts for V. dahliae but whether they serve as sources of inoculum for aggressive isolates of V. dahliae to crop hosts is unknown. The goal of this research was to quantify V. dahliae microsclerotia obtained from 16 weeds which were grown in the greenhouse. Potting medium was infested with one of eight V. dahliae isolates from potato, mint, sugar beet, sunflower, tomato, and watermelon. The isolates from mint and potato were aggressive on the host from which they were originally isolated. All 16 weeds were infected by at least one V. dahliae isolate, although the number of microsclerotia produced from some infections was relatively low (≤5 microsclerotia/g of dry plant). Black nightshade yielded greater numbers of microsclerotia of the V. dahliae potato isolate than any other isolate in three of four trials in the greenhouse (second trial false discovery rate, adjusted P ≤ 0.0158; third trial, P ≤ 0.0264; and fourth trial, P ≤ 0.0193). Litchi tomato yielded greater numbers of microsclerotia of the V. dahliae potato isolate than any other isolate in one of four trials (first trial, P ≤ 0.0149). A V. dahliae isolate from tomato yielded greater numbers of microsclerotia in large crabgrass and wild oat in a second trial (P ≤ 0.0158). Weeds, depending on the species, grown during and between potato crop rotations may increase the number of microsclerotia of the potato-aggressive isolates of V. dahliae.

Evaluation of Solanum sisymbriifolium as a Potential Inoculum Source of Verticillium dahliae and Colletotrichum coccodes.

Solanum sisymbriifolium, the litchi tomato, is a perennial herbaceous plant from South America that is used as a trap crop to reduce soilborne populations of the pale cyst nematode Globodera pallida, an important potato pathogen. Possible interactions of soilborne potato pathogens Verticillium dahliae and Colletotrichum coccodes with litchi tomato are unknown, yet important for potato production if litchi tomato is to be planted as a trap crop. The goal of this research was to quantitatively assess if litchi tomato is a potential inoculum source for C. coccodes and V. dahliae by comparing colony forming units (CFU) observed in litchi tomato to susceptible and resistant potato cultivars. The potato cvs. Alturas (P = 0.0003), Ranger Russet (P = 0.0193), and Russet Norkotah (P = 0.0022) produced more CFUs of the potato pathotype of V. dahliae than litchi tomato the first of two years of greenhouse trials. Significantly more CFUs of the potato pathotype of V. dahliae were quantified from stems and roots of only cv. Russet Norkotah compared with litchi tomato (P = 0.0001) in the second year. The CFUs for C. coccodes varied between litchi tomato and the potato cvs., perhaps due to varying levels of resistance since litchi tomato is from a selected intermated seed source. Based on these data, the effect of litchi tomato in rotation with potato is likely to have limited effect on the proliferation of V. dahliae or C. coccodes populations in the soil when compared with a susceptible potato cultivar.

Verticillium dahliae Infects, Alters Plant Biomass, and Produces Inoculum on Rotation Crops.

Verticillium wilt, caused by Verticillium dahliae, reduces yields of potato and mint. Crop rotation is a potential management tactic for Verticillium wilt; however, the wide host range of V. dahliae may limit the effectiveness of this tactic. The hypothesis that rotation crops are infected by V. dahliae inoculum originating from potato and mint was tested by inoculation of mustards, grasses, and Austrian winter pea with eight isolates of V. dahliae. Inoculum density was estimated from plants and soil. Typical wilt symptoms were not observed in any rotation crop but plant biomass of some crops was reduced, not affected, or increased by infection of specific isolates. Each isolate was host-specific and infected a subset of the rotation crops tested but microsclerotia from at least one isolate were observed on each rotation crop. Some isolates were host-adapted and differentially altered plant biomass or produced differential amounts of inoculum on rotation crops like arugula and Austrian winter pea, which supported more inoculum of specific isolates than potato. Evidence of asymptomatic and symptomatic infection and differential inoculum formation of V. dahliae on rotation crops presented here will be useful in designing rotations for management of Verticillium wilt.

Five Reasons to Consider Phytophthora infestans a Reemerging Pathogen.

Phytophthora infestans has been a named pathogen for well over 150 years and yet it continues to "emerge", with thousands of articles published each year on it and the late blight disease that it causes. This review explores five attributes of this oomycete pathogen that maintain this constant attention. First, the historical tragedy associated with this disease (Irish potato famine) causes many people to be fascinated with the pathogen. Current technology now enables investigators to answer some questions of historical significance. Second, the devastation caused by the pathogen continues to appear in surprising new locations or with surprising new intensity. Third, populations of P. infestans worldwide are in flux, with changes that have major implications to disease management. Fourth, the genomics revolution has enabled investigators to make tremendous progress in terms of understanding the molecular biology (especially the pathogenicity) of P. infestans. Fifth, there remain many compelling unanswered questions.

Diversity within the genus Elymus (Poaceae: Triticeae) as investigated by the analysis of the nr5S rDNA variation in species with St and H haplomes.

The genus Elymus ("Ryegrass") is a repository for a range of species with a variety of haplome contents; hence the pejorative name "dustbin" genus. We have analyzed 1,059 sequences from 128 accessions representing 24 species to investigate the relationships among the StH haplomes-containing species described by Yen and Yang (Genus Elymus Beijing 5:58-362, 2013). Sequences were assigned to "unit classes" of orthologous sequences and subjected to a suite of analyses including BLAST (Basic Local Alignment Search Tool) searches, phylogenetic analysis and population genetic analysis to estimate species diversity. Our results support the genome analyses in Yen and Yang (Genus Elymus Beijing 5:58-362, 2013), i.e., genomic constitution StStHH including variants restricted to Elymus. Population genetic analysis of the 5S nrDNA sequence data revealed that the within-species variance component is roughly ±89 %; thus, we were unable to identify molecular markers capable to separate the 24 species analyzed. Separate phylogenetic analyses of the two unit classes and of all the data exhibit a trend only of the species to cluster on the phylograms. Finally, the analysis provides evidence for the multiple origins of American and Eurasian species.

Inferring outcrossing in the homothallic fungus Sclerotinia sclerotiorum using linkage disequilibrium decay.

The occurrence and frequency of outcrossing in homothallic fungal species in nature is an unresolved question. Here we report detection of frequent outcrossing in the homothallic fungus Sclerotinia sclerotiorum. In using multilocus linkage disequilibrium (LD) to infer recombination among microsatellite alleles, high mutation rates confound the estimates of recombination. To distinguish high mutation rates from recombination to infer outcrossing, 8 population samples comprising 268 S. sclerotiorum isolates from widely distributed agricultural fields were genotyped for 12 microsatellite markers, resulting in multiple polymorphic markers on three chromosomes. Each isolate was homokaryotic for the 12 loci. Pairwise LD was estimated using three methods: Fisher's exact test, index of association (IA) and Hedrick's D'. For most of the populations, pairwise LD decayed with increasing physical distance between loci in two of the three chromosomes. Therefore, the observed recombination of alleles cannot be simply attributed to mutation alone. Different recombination rates in various DNA regions (recombination hot/cold spots) and different evolutionary histories of the populations could explain the observed differences in rates of LD decay among the chromosomes and among populations. The majority of the isolates exhibited mycelial incompatibility, minimizing the possibility of heterokaryon formation and mitotic recombination. Thus, the observed high intrachromosomal recombination is due to meiotic recombination, suggesting frequent outcrossing in these populations, supporting the view that homothallism favors universal compatibility of gametes instead of traditionally believed haploid selfing in S. sclerotiorum. Frequent outcrossing facilitates emergence and spread of new traits such as fungicide resistance, increasing difficulties in managing Sclerotinia diseases.

What does the nr5S DNA multigene family tell us about the genomic relationship between Dasypyrum breviaristatum and D. villosum (Triticeae: Poaceae)?

The genus Dasypyrum contains two species: the annual and widespread D. villosum (2x = 2n = 14) and the perennial and generally rare D. breviaristatum (2x = 2n = 14 and 4x = 2n = 28). The origin of the latter and its genome constitution have been subject of several studies. There is agreement that the genome of the diploid D. villosum (VV) is different from the diploid cytotype of D. breviaristatum (VbVb), but there is no agreement of the constitution of the tetraploid cytotype, specifically whether is it an autotetraploid or an allotetraploid. This is a long-standing disagreement that this study aims to resolve using the 5S nrDNA as a genomic marker. Our studies suggest that the 4x D. breviaristatum is an allotetraploid (VVVbVb).

What does the 5S rRNA multigene family tell us about the origin of the annual Triticeae (Poaceae)?

We have investigated the complex relationships among the annual genera within the tribe Triticeae through phylogenetic analyses of the 5S rRNA multigene family. Cloned sequences were assigned to groups of orthologous sequences, called unit classes, that were subjected to several analyses including BLAST (Basic Local Alignment Search Tool) searches to assess possible ancestral relationships with perennial genera; phylogenetic analyses using parsimony (Pars), maximum likelihood (ML), and Bayesian methods; and minimum reticulation networks from the Pars, ML, and Bayesian trees. In this study, we included genera with both annual and perennial species, such as Dasypyrum, Hordeum, and Secale. BLAST pointed to Pseudoroegneria (carrier of the St genome) and possibly Thinopyrum (carrier of the J genome) as the potential next of kin. However, Thinopyrum and Pseudoroegneria have never fallen together on the individual trees with the former generally associated with Crithopsis, Aegilops, Triticum, and Dasypyrum, while the latter is usually associated with the rest of the genera within Triticeae. The "long" unit classes placed Dasypyrum breviaristatum together with Dasypyrum villosum, whereas the "short" unit classes put them far apart on the trees. None of the gene trees alone was able to summarize the complex relationships among the genera, in line with previous results in the Triticeae. However, the application of tools designed to display phylogenetic networks was able to depict the complex links among the genera based on the short and the long gene trees, including the close link between Thinopyrum and Pseudoroegneria suggested by the phylogenetic analyses. In addition, our analyses provide support for the hypothesis that at least some annual Triticeae taxa are derived from their perennial relatives.

First Report of Blackleg Caused by Leptosphaeria maculans on Canola in Idaho.

Canola (Brassica napus L.) is produced in the dryland agriculture areas of eastern Washington State and northern Idaho, often in rotation with cereal cropping systems. Canola is also used as a rotation crop in irrigated circles in the Columbia Basin of Washington and southern Idaho, where potato is the main cash crop. In 2011, 7,700 ha of canola were harvested in Idaho and 4,200 ha in Washington. One of the major diseases of canola around the world is blackleg, caused by Leptosphaeria maculans (aggressive) and L. biglobosa (non-aggressive). Both Washington and Idaho have been considered blackleg-free, and production of canola in Idaho is subject to government regulations. Canola seed originating from outside of Washington and Idaho should have a phytosanitary certificate. This disease is widespread in Canada and the U.S. Northern Plains, Midwest, and South, and is the major disease of canola in these areas. In August 2011, a sample from a canola field in Bonners Ferry, Idaho, was brought for diagnosis to Washington State University. The canola stems showed the typical gray to dark grey lesions with black pycnidia. The pycnidia and conidia were examined microscopically, and found to be similar to descriptions of Phoma lingam, the anamorph of L. maculans (2). Samples were sent to the University of Manitoba for confirmation with PCR. The pathogen was cultured out of stems on V8 juice agar amended with streptomycin and 22 single pynidiospore isolates were made from the cultures. DNA was extracted from the cultures using methods described in Fernando et al. (1) and a multiplex PCR was performed with species-specific primers for L. maculans and L. biglobosa. The reaction should produce a 330-bp amplicon for L. maculans and a 440-bp amplicon for L. biglobosa. Based on this, all 22 isolates were identified as L. maculans. The susceptible cultivar Westar was inoculated with the isolates, by wound inoculating 7-day-old cotyledons with a concentration of 107 spores/ml. Plants were kept in a moist chamber at 23°C. After 14 days, plants were rated for disease with a 0 to 9 scale, where 0 = no infection and 9 = tissue collapse and appearance of pycnidiospores. Isolates with rating ≥5 are considered virulent. All isolates produced a rating of 7 to 9, indicating a high level of virulence. The source of the seed used in the infested fields is not known at this time. This disease is seedborne, and may pose a threat to the two major vegetable and oilseed brassica seed production areas of Washington: the Skagit River valley of western Washington and the Columbia Basin area of central Washington. In addition, the susceptibility of Pacific Northwest varieties of canola and other brassica oilseeds is largely unknown. References: (1) W. G. D. Fernando et al. Plant Dis. 90:1337, 2006. (2) S. Roger Rimmer et al. Compendium of Brassica Diseases, APS Press, 2007.

The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal-hippocampal cholinergic tract.

Dehydroepiandrosterone sulfate (DHEAS), is an excitatory neurosteroid synthesized within the CNS that modulates brain function. Effects associated with augmented DHEAS include learning and memory enhancement. Inhibitors of the steroid sulfatase enzyme increase brain DHEAS levels and can also facilitate learning and memory. This study investigated the effect of steroid sulfatase inhibition on learning and memory in rats with selective cholinergic lesion of the septo-hippocampal tract using passive avoidance and delayed matching to position T-maze (DMP) paradigms. The selective cholinergic immunotoxin 192 IgG-saporin (SAP) was infused into the medial septum of animals and then tested using a step-through passive avoidance paradigm or DMP paradigm. Peripheral administration of the steroid sulfatase inhibitor, DU-14, increased step-through latency following footshock in rats with SAP lesion compared to both vehicle treated control and lesioned animals (p<0.05). However, in the DMP task, steroid sulfatase inhibition impaired acquisition in lesioned rats while having no effect on intact animals. These results suggest that steroid sulfatase inhibition facilitates memory associated with contextual fear, but impairs acquisition of spatial memory tasks in rats with selective lesion of the septo-hippocampal tract.

Genetic identification of a high-affinity Ni transporter and the transcriptional response to Ni deprivation in Synechococcus sp. strain WH8102.

One biological need for Ni in marine cyanobacteria stems from the utilization of the Ni metalloenzyme urease for the assimilation of urea as a nitrogen source. In many of the same cyanobacteria, including Synechococcus sp. strain WH8102, an additional and obligate nutrient requirement for Ni results from usage of a Ni superoxide dismutase (Ni-SOD), which is encoded by sodN. To better understand the effects of Ni deprivation on WH8102, parallel microarray-based analysis of gene expression and gene knockout experiments were conducted. The global transcriptional response to Ni deprivation depends upon the nitrogen source provided for growth; fewer than 1% of differentially expressed genes for Ni deprivation on ammonium or urea were concordantly expressed. Surprisingly, genes for putative Ni transporters, including one colocalized on the genome with sodN, sodT, were not induced despite an increase in Ni transport. Knockouts of the putative Ni transporter gene sodT appeared to be lethal in WH8102, so the genes for sodT and sodN in WH8102 were interrupted with the gene for Fe-SOD, sodB, and its promoter from Synechococcus sp. strain WH7803. The sodT::sodB exconjugants were unable to grow at low Ni concentrations, confirming that SodT is a Ni transporter. The sodN::sodB exconjugants displayed higher growth rates at low Ni concentrations than did the wild type, presumably due to a relaxed competition between urease and Ni-SOD for Ni. Both sodT::sodB and sodN::sodB lines exhibited an impaired ability to grow at low Fe concentrations. We propose a posttranslational allosteric SodT regulation involving the binding of Ni to a histidine-rich intracellular protein loop.

Systematic review: the burden of disruptive gastro-oesophageal reflux disease on health-related quality of life.

BACKGROUND: About one-third of patients with gastro-oesophageal reflux disease (GERD) have frequent and/or severe reflux symptoms ('disruptive GERD'). The relative burden of disruptive GERD on health-related quality of life (HRQL) has not been systematically investigated. AIM: To assess the burden of disruptive vs. nondisruptive GERD on HRQL. METHODS: Systematic searches were conducted in PubMed and Embase. To be included, studies had to have used validated questionnaires to assess HRQL. RESULTS: Nineteen studies were included. Data on the comparative burden of frequent (ranging from daily to ≥weekly) and severe reflux symptoms were provided in eight and 13 studies respectively; six reported on the additional burden of nocturnal symptoms. Compared with individuals with nondisruptive GERD, those with disruptive GERD had 2.4-times and 1.5-times higher mean rates of absenteeism and presenteeism respectively (five studies), 1.5-times lower sleep quality scores (three studies), 1.1-times lower mean summary scores for physical and mental health (five studies) and 1.3-times lower mean scores for psychological and general well-being (four studies). Increasing symptom frequency and severity both increased the burden of disease to a similar extent. The presence of nocturnal symptoms in addition to daytime symptoms led to worsening of physical health, but their effect on mental health and work productivity was less clear. CONCLUSIONS: Disruptive GERD is associated with a high burden of disease compared with occasional or mild reflux symptoms. Disease management needs to vary across the GERD spectrum and should be tailored to patients' requirements for optimal therapeutic outcomes.

Phylogenetic relationships among the polyploid and diploid Aegilops species inferred from the nuclear 5S rDNA sequences (Poaceae: Triticeae).

Phylogenetic inferences of the polyploid Aegilops taxa were drawn based upon the analysis of 909 nuclear 5S rDNA sequences obtained from 15 Aegilops polyploid taxa (531 sequences new to this paper) and 378 sequences from our previous study on the diploid taxa. The 531 sequences can be split into two orthologous groups (unit classes), the long AE1 and short AE1 previously identified in the diploid set. An examination of the relationships between unit classes and their associated haplomes suggests that U haplome sequences found in Ae. umbellulata are the closest to the T sequences found in Amblyopyrum muticum and that sequences of the polyploid species expected to be the M type found in Ae. comos are more similar to the T haplome sequences, except in the three hexaploids Ae. glumiaristata, Ae. juvenalis, and Ae. vavilovii and the tetraploid Ae. crassa where they are found to be similar to the M haplome sequences. These three hexaploid taxa likely originated from the tetraploid Ae. crassa (DM), while the closest taxon to the fourth hexaploid, Ae. recta, is the tetraploid Ae. neglecta (UM). Based upon the distribution of the unit classes, several reticulate phylogenies depicting evolutionary relationships among diploid, tetraploid, and hexaploid taxa were constructed; however, none of these widely used methods could depict the expected reticulate relationship as previously drawn from cytogenetic analyses in this group of allopolyploid species. These results suggest that evolutionary relationships derived from models based upon the assumption of bifurcating species require careful interpretation when these same models are applied to species with reticulate evolution.

Expression of polyhydroxybutyric acid as a model for metabolic engineering of soybean seed coats.

The feasibility of genetically engineering soybean seed coats to divert metabolism towards the production of novel biochemicals was tested. The genes phbA, phbB, phbC from Ralstonia eutropha each under the control of the seed coat peroxidase promoter were introduced into soybean and the production of polyhydroxybutyrate (PHB) was assayed. The analysis of seed coats arising from 4 independent transformation events demonstrated that PHB was produced at a mean of 0.12% seed coat dried weight with individual values up to 0.36%. These values demonstrate that it is possible to metabolically engineer soybean seed coats.

First Report of Pectobacterium wasabiae Causing Aerial Stem Rot of Potato in Washington State.

Aerial stem rot of potato (Solanum tuberosum), also known as bacterial stem rot, is often caused by the pectolytic bacteria Pectobacterium (Erwinia) carotovorum subsp. carotovorum, P. atrosepticum, or Dickeya spp. (3). A survey was carried out in August 2008 in 'Russet Burbank' potato fields exhibiting aerial stem rot symptoms in the Columbia Basin of Washington State. One bacterial strain isolated during the survey, PwO405, exhibited pectolytic ability on crystal violet pectate (CVP) agar and potato slices and failed to grow at 37°C, but physiological tests did not conclusively distinguish the bacterium as P. atrosepticum (1). The bacterium was positive for ONPG, N-acetylglucosaminyl transferase, gelatin liquefaction, and acid production from D-galactose, lactose, melibiose, raffinose, citrate, and trehalose. The bacterium was negative for indole production and acid production from maltose, α-methyl-D-glucoside, sorbitol, D-arabitol, inositol, inulin, and melezitose. Molecular identification of the bacterium was performed with 16S rRNA, aconitase (acnA), and malate dehydrogenase (mdh) coding sequences as previously described (2,4). Partial sequences of 16S rRNA (1,408 bp) and acnA (412 bp) genes (GenBank Accession Nos. JQ723958 and JQ723959, respectively) exhibited 99% shared identities with P. wasabiae strain WPP163, while the mdh sequence (435 bp) (GenBank Accession No. JQ723960) exhibited 100% shared identity with mdh sequences from three P. wasabiae strains (NZEC9, NZEC10, and NZEC8974). Maximum parsimony analysis using concatenated acnA and mdh sequences from this study and Pectobacterium sequences previously deposited in GenBank (2,4) clustered strain PwO405 with other P. wasabiae strains. Three 7-week-old 'Russet Norkotah' potato plants were wound-inoculated by inserting a sterile 23 gauge needle just above a central leaf axil at a depth of 1 mm. A 10-µl drop of inoculum (104 CFU) was placed on the wound. Plants were exposed to a 24-h leaf wetness period (90 to 100% RH in a mist chamber) and lesions were measured. All three inoculated plants exhibited aerial stem rot symptoms similar to those observed in the field, including brown water-soaked lesions that spread acropetally and basipetally. Upon drying, the lesions became shriveled and turned dark brown to black. Some plants exhibited hollowing of the stems and unilateral wilt on the side of the lesion. Symptoms were not observed on water-inoculated controls. The bacteria that were reisolated into pure culture from all three inoculated stems caused pitting on CVP and exhibited the same morphology as the original culture and were confirmed as P. wasabiae using 16S rRNA, acnA, and mdh coding sequences, fulfilling Koch's postulates. Stem rot ability of the bacterium was also confirmed on four potato cultivars: 'Ranger Russet,' 'Russet Burbank,' 'Russet Norkotah,' and 'Umatilla Russet' by wound-inoculating six single-stem plants of each cultivar as described above. To our knowledge, this is the first report of aerial stem rot of potato caused by P. wasabiae in Washington State. References: (1) S. De Boer and A. Kelman. Page 56 in: Laboratory Guide for Identification of Plant Pathogenic Bacteria, 3rd ed. N. Schaad et al., ed. APS Press, St. Paul, 2001. (2) A. Pitman et al. Eur. J. Plant Pathol. 32:211, 2010. (3) M. Powelson and G. Franc. Page 10 in: Compendium of Potato Diseases. W. Stevenson et al., ed. APS Press, St. Paul, 2002. (4) M. Yap et al. Appl. Environ. Microbiol. 70:3013, 2004.

Race affects healing of erosive oesophagitis in patients treated with proton pump inhibitors.

BACKGROUND: Erosive oesophagitis appears to be more common in white vs. nonwhite patients with gastro-oesophageal reflux disease (GERD). AIM: To evaluate the association between race and erosive oesophagitis healing in patients with GERD treated with once-daily proton pump inhibitors (PPIs). METHODS: Data from five double-blind trials of once-daily treatment with esomeprazole 40mg vs. omeprazole 20mg or lansoprazole 30mg for erosive oesophagitis healing (evaluated at weeks 4 and 8 by endoscopy) were pooled and stratified by baseline race and Los Angeles (LA) severity grade. Multiple logistic regression models were fit with erosive oesophagitis healing (dependent variable) and race (independent variable), with adjustments for treatment, study, baseline LA grade, age, gender, BMI, Helicobacter pylori status, hiatal hernia and interactions of these factors with race. RESULTS: Of 11,027 patients, 91% were white. Nonwhite (n=978) and black (n=613) patients were less likely to have severe baseline erosive oesophagitis (LA grade C or D) than white patients [adjusted OR: 0.69 (95% CI, 0.61-0.79) and 0.67 (0.57-0.78), respectively; P<0.0001]. At week 8, nonwhite and black patients had lower healing rates than white patients [OR: 0.75 (0.63-0.89) and 0.67 (0.54-0.83), respectively; P≤0.001]. Greater odds of healing were associated with less severe baseline LA grade, increasing age, hiatal hernia, esomeprazole treatment (vs. lansoprazole or omeprazole) and lansoprazole treatment (vs. omeprazole) (all P≤0.0009); no factor interacted significantly with race. CONCLUSIONS: Nonwhite patients with GERD had less severe baseline erosive oesophagitis, but were less likely than white patients to have erosive oesophagitis healing after 8-week PPI therapy.

Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354 in healthy human subjects: implications for selection of clinical dose.

The safety and pharmacokinetic (PK)/pharmacodynamic (PD) profile of the novel CCR1 antagonist CCX354 was evaluated in double-blind, placebo-controlled, single- and multiple-dose phase I studies (1-300 mg/day oral doses). CCX354 was well tolerated and displayed a linear dose-exposure profile, with half-life approaching 7 h at the 300-mg dose. The extent of CCR1 receptor blockade on blood monocytes, which correlated well with plasma concentrations of the drug, was assessed using fluorescently labeled CCL3 binding in whole blood from phase I subjects. High levels of receptor coverage at the 12-h time point were achieved after a single dose of 100 mg CCX354. Preclinical studies indicate that effective blockade of inflammatory cell infiltration into tissues requires ≥90% CCR1 inhibition on blood leukocytes at all times. The comparison of the properties of CCX354 with those published for other CCR1 antagonists has informed the dose selection for ongoing clinical development of CCX354 in rheumatoid arthritis (RA).

Randomised clinical trial: a novel rabeprazole extended release 50 mg formulation vs. esomeprazole 40 mg in healing of moderate-to-severe erosive oesophagitis - the results of two double-blind studies.

BACKGROUND: Current PPIs may not achieve desired outcomes in some GERD patients due to limited duration of acid inhibition. AIM: To evaluate a novel rabeprazole extended release (ER), which provides longer duration of drug exposure and acid suppression, in healing and symptomatic resolution of moderate-severe erosive oesophagitis. METHODS: Patients with LA grade C or D oesophagitis were randomised to rabeprazole-ER 50 mg or esomeprazole 40 mg once daily in two identical 8-week double-blind trials (N = 2130). Two primary endpoints were tested sequentially: (1) healing by 8 weeks [hypothesis: rabeprazole-ER non-inferior to esomeprazole (non-inferiority margin = 8%)], (2) healing by 4 weeks [hypothesis: rabeprazole-ER superior to esomeprazole (P < 0.05)]. The secondary endpoint was sustained heartburn resolution at 4 weeks. RESULTS: Rabeprazole-ER was non-inferior to esomeprazole in week-8 healing (80.0% vs. 75.0%; 77.5% vs. 78.4%). Week-4 healing (54.8% vs. 50.3%; 50.9% vs. 50.7%) and sustained heartburn resolution (48.3% vs. 48.2%; 53.2% vs. 52.5%) were not significantly different. Post hoc combined results for grade D revealed rabeprazole-ER vs. esomeprazole differences in week-8 healing = 10.4% (95% CI: -1.4%, 22.2%) and week-4 healing = 12.0% (P = 0.048). CONCLUSIONS: Rabeprazole-ER is as effective as esomeprazole in healing moderate-severe oesophagitis and achieves similar rates of heartburn resolution. Subgroup analysis suggests the possibility of benefit in severe oesophagitis, but this requires further evaluation (ClinicalTrials.gov: NCT00658528 and NCT00658775).

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome.

Tumor growth factor-ß (TGF-ß) signaling in cancer has been implicated in growth suppression of early lesions and enhancing tumor cell invasion and metastasis. However, the cellular mechanisms that determine this signaling output in individual tumors are still largely unknown. In endothelial cells, TGF-ß signaling is modulated by the TGF-ß co-receptor endoglin (CD105). Here we demonstrate that endoglin is expressed in a subset of invasive breast cancers and cell lines and is subject to epigenetic silencing by gene methylation. Endoglin downregulation in non-tumorigenic MCF10A breast cells leads to the formation of abnormal acini in 3D culture, but does not promote cell migration or transformation. In contrast, in the presence of activated ErbB2, endoglin downregulation in MCF10A cells leads to enhanced invasion into a 3D matrix. Consistent with these data, ectopic expression of endoglin in MDA-MB-231 cells blocks TGF-ß-enhanced cell motility and invasion and reduces lung colonization in an in vivo metastasis model. Unlike endothelial cells, endoglin does not modulate Smad-mediated TGF-ß signaling in breast cells but attenuates the cytoskeletal remodeling to impair cell migration and invasion. Importantly, in a large cohort of invasive breast cancers, lack of endoglin expression in the tumor cell compartment correlates with ENG gene methylation and poor clinical outcome.