Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1).

In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7-28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.

A model of the physiological and biochemical characteristics of earthworms (Eisenia fetida) in petroleum-contaminated soil.

Current researches found some terrestrial animals absorb petroleum hydrocarbons (PHCs) in oil-polluted soil. However, the absorption behaviour between various biological tissues remains unclear. The aim of our study is to determine the toxic effects and enrichment behaviours of earthworms (Eisenia fetida) in petroleum-contaminated soils and to provide a reasonable dynamics model to explain the migration of PHCs within earthworm tissues. The PHCs are divided into three fractions by equivalent carbon number. An experimental analysis of the PHC concentrations in 3 different earthworm organ systems (body-wall tissue, body fluid and gut tissue) from a contamination exposure experiment at different time intervals was implemented. A dynamics model was built to simulate the absorption mechanism. The model results perform well. The PHC concentrations in the earthworm tissues were gut > body fluid > body wall. The PHCs in the gut reached equilibrium first, and those in the body-wall tissues reached equilibrium last. In the gut tissue, the PHC concentration was different from those in the body-wall tissue and body fluid due to the influence of the feeding rule. In addition, as the length of the carbon chain increases, the molecular size increases, which makes it more difficult for petroleum hydrocarbon fractions to enter an organ system. As a result, the concentration of PHCs in each type of tissue decreases with increasing carbon chain length. This study can provide a theoretical foundation for chemical monitoring in soil.

Angioedema in heart failure patients treated with sacubitril/valsartan (LCZ696) or enalapril in the PARADIGM-HF study.

BACKGROUND: PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest. METHODS: Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg. The study design incorporated two wash-out periods (~36 h each) to minimize any potential risk of angioedema due to overlapping ACE and neprilysin inhibition. Suspected cases of angioedema were reported to, and blindly adjudicated by, an independent angioedema adjudication committee (AAC). RESULTS: Of the 10,513 patients entering the enalapril run-in, 9419 entered the sacubitril/valsartan run-in and 8432 received double-blind treatment. Overall, 148 suspected angioedema events occurring in 144 patients were reported to AAC, with one event reported during screening period. Of the remaining 147 events, 54 were confirmed as angioedema by AAC. A confirmed event was experienced by 15 (0.14%) and 10 (0.11%) patients, during the enalapril and sacubitril/valsartan run-ins, respectively, and by 10 (0.24%) and 19 (0.45%) patients in the corresponding randomized arms during the double-blind phase. The frequency of confirmed angioedema was higher in black patients. Most events were mild. Only five patients required hospitalization and none required mechanical airway support. CONCLUSION: The number of confirmed angioedema events in PARADIGM-HF was low and there was no-marked excess risk of angioedema with sacubitril/valsartan versus enalapril.

Influence of nitrogen fertilization on xylem traits and aquaporin expression in stems of hybrid poplar.

We studied the influence of nitrogen (N) on hydraulic traits and aquaporin (AQP) expression in the stem xylem of hybrid poplar saplings (Populus trichocarpa (Torr. & Gray) x deltoides Bartr. ex Marsh clone H11-11). Plants were grown in a controlled environment and were kept well watered throughout the experiments. Hydraulic measurements were done on basal and distal stem segments of plants receiving high N fertilization (high N plants) versus plants receiving only adequate N fertilization (adequate N plants). High N plants grew faster and exhibited more leaf area than adequate N controls. These morphological differences were paralleled by wider vessels and higher specific conductivities (K(S)) in high N plants. However, stems of high N plants were more vulnerable to xylem cavitation, at least in one of two experiments, and showed lower wood densities than stems of adequate N plants. Leaf area was strongly correlated with cross-sectional xylem area in both plant groups. Since higher K(S) in high N plants was accompanied by concomitant increases in leaf area, leaf-specific conductivities were similar in both plant groups. Influences of N on hydraulic traits were paralleled by changes in AQP expression. Seven AQPs were upregulated in the stem xylem of high N plants, five of which have been identified recently as water transporters. The enhanced growth of secondary xylem of high N plants has been shown to result from both increased cambial activity as well as increased cell size. We suggest that some of these water-transporting AQPs could play a role in xylogenesis, facilitating the influx of water into the zone of differentiating and maturing cells in secondary xylem, including expanding vessels.

One-day famciclovir vs. placebo in patient-initiated episodic treatment of recurrent genital herpes in immunocompetent Black patients.

BACKGROUND: There are no known racial differences in genital herpes disease pathogenesis or response to therapy. Despite high herpes simplex virus (HSV) seroprevalence in Black persons, clinical trials investigating the treatment of recurrent genital herpes (RGH) have typically enrolled a small proportion of Black patients. METHODS: This multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of patient-initiated, 1-day famciclovir 1000 mg twice-daily in immunocompetent Black adults (USA and South Africa) with RGH. Eligible patients were randomized (2:1) to famciclovir or placebo. The primary endpoint was time to healing of non-aborted genital herpes lesions (i.e., lesions that progressed beyond papule stage). Secondary endpoints included proportion of patients with aborted genital herpes lesions, time to resolution of associated symptoms, and safety. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov ; trial identifier NCT00477334. RESULTS: A total of 299 patients with RGH (66% female, median age = 37 years) received either 1-day famciclovir 1000 mg twice-daily (n = 201) or placebo (n = 98). In the modified intent-to-treat population, the estimated median time to healing of non-aborted genital herpes lesions was 5.38 days for famciclovir and 4.79 days for placebo (median of treatment differences = 0.26 days; 95% CI [-0.40, 0.98]; p = 0.416). Consistent findings were reported in the completer and per-protocol populations. No significant differences were reported for all secondary analyses. Adverse events (AEs) were consistent with the established safety profile of famciclovir: 18 (6%) patients had drug-related AEs (16 [8%] famciclovir; 2 [2%] placebo), none of which were serious or led to discontinuation or dose adjustment/interruption. There are some limitations of this research: many study sites either lacked prior experience in conducting clinical studies in patients with HSV infection or enrolled small numbers of patients, which may have compromised efficacy outcomes. Also, HIV antibody testing was not mandated at enrollment. CONCLUSION: This study showed similar efficacy and tolerability of 1-day treatment with famciclovir 1000 mg twice-daily compared to placebo in immunocompetent Black adults with RGH. Famciclovir has proven efficacy and safety in the overall RGH population. Further understanding of the efficacy of antiherpes therapy in Black patients with recurrent genital herpes may be warranted.

Efficacy and tolerability of lumiracoxib 200 mg once daily for treatment of primary dysmenorrhea: results from two randomized controlled trials.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are established as treatment for managing pain associated with primary dysmenorrhea. However, the efficacy and tolerability of lumiracoxib 200 mg once daily (q.d.) has not previously been examined in primary dysmenorrhea. METHODS: Two randomized, multicenter, double-blind, placebo-controlled, crossover studies of similar design have assessed the efficacy and tolerability of two regimens of lumiracoxib compared with placebo (Study 1) or naproxen and placebo (Study 2) in women (aged 18-45 years) with moderate to severe primary dysmenorrhea. In Study 1 (n = 132), patients received lumiracoxib 200 mg q.d., lumiracoxib 200 mg with a 200 mg redose (p.r.n.) on day 1, or placebo. In Study 2 (n = 144), patients received lumiracoxib 200 mg q.d., lumiracoxib 200 mg with a 200 mg redose p.r.n. on day 1, naproxen 500 mg twice daily (b.i.d.), or placebo. Patients recorded study medication use, efficacy assessments, and rescue medication use. RESULTS: The primary efficacy variable, summed (time-weighted) pain intensity difference (categorical scale) over the first 8 hours (SPID-8), was similar between all active treatments (e.g., p = 0.939 for naproxen 500 mg b.i.d. vs. lumiracoxib 200 mg q.d. in Study 2), and all active treatments were superior to placebo (p < 0.001). Median time-to-onset of analgesia was similar between lumiracoxib 200 mg q.d. and naproxen 500 mg b.i.d. Similar trends were observed for all other secondary efficacy variables. All treatments were well tolerated. CONCLUSIONS: Short-term administration of lumiracoxib 200 mg q.d. is effective and well tolerated and provides an alternative treatment option for the management of moderate to severe pain associated with primary dysmenorrhea.

Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate.

This randomized, double-blind, double-dummy, multicenter trial assessed safety and efficacy of a single dose of IV zoledronic acid (ZOL) 5 mg vs. oral alendronate (ALN) 70 mg weekly in postmenopausal women with low bone mineral density (BMD) who had previously been treated with ALN. Postmenopausal women who were receiving oral ALN for at least 1 year immediately prior to randomization and with lumbar spine or femoral neck BMD T-score values < or = -2.0 prior to initiation of ALN were randomized to one 15-min IV infusion of ZOL 5 mg plus 52 weeks of oral placebo (n=113) or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg (n=112). End points included percent change in lumbar spine BMD from baseline to month 12 and relative change from baseline in urine N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen (CTX), amino terminal propeptides of type I collagen (PINP), and bone-specific alkaline phosphatase (bone ALP) over 12 months. Adverse events, bone histomorphometry and microscopic appearance, and patient preference for the 2 treatment regimens were also assessed. In this study, a single infusion of ZOL 5 mg maintained BMD 12 months following the switch from oral ALN in women with osteoporosis. The mean duration of prior ALN therapy at baseline was 4 years. Mean biomarker levels in the ALN 70-mg group remained at or close to baseline levels for the duration of the study. In the ZOL 5-mg group, mean biomarker levels were reduced from baseline after 3 months, returned to baseline after 6 months, and increased thereafter but remained within the premenopausal range. The overall rates of adverse events were comparable in the 2 groups (ZOL 5 mg, 86.7%; ALN 70 mg, 80.4%). Headache occurred more commonly within the first 3 days after infusion with ZOL 5 mg (12.4%) than with ALN 70 mg (6.3%). Bone biopsies indicate that both treatments decrease excessive remodeling seen in osteoporosis. The majority (78.7%) of patients expressed preference for once yearly infusion over weekly oral therapy. We conclude that patients can be switched from oral ALN to ZOL 5 mg infusion with maintenance of therapeutic effect for at least 12 months and that patients prefer a once yearly infusion to weekly oral therapy.

A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density.

Early data suggest that an annual i.v. infusion of zoledronic acid (ZOL) might have therapeutic use in women with osteoporosis. In this randomized, double-blind, double-dummy, multicenter, 24-week trial, we evaluated the onset of action of a single infusion of ZOL 5 mg (n=69) compared with weekly oral alendronate (ALN) 70 mg (n=59) in postmenopausal women with low bone mineral density (T score< or =-2 by DXA) as assessed by reductions in urine N-telopeptide of type I collagen (NTX) at week 1. The effects of these therapies on other markers of bone turnover, patient preference for once yearly i.v. vs. oral weekly treatment, and adverse events were also assessed. At week 1, ZOL 5 mg resulted in a significantly greater reduction in mean urine NTX from baseline than ALN 70 mg (P<0.0001). Significantly greater reduction in urine NTX and serum beta-C-telopeptide of type I collagen (beta-CTX) were also observed in the ZOL 5 mg group at all post-baseline time points. Bone-specific alkaline phosphatase (BSAP) levels showed a more gradual reduction in both the ZOL 5 mg and ALN 70 mg groups, reaching premenopausal range by week 12. A comparable proportion of patients reported adverse events in each treatment group (ZOL 5 mg, 91.3%; ALN 70 mg, 86.4%). Transient, flu-like symptoms were the most common adverse events in the ZOL 5 mg group and resulted in a higher frequency of adverse events in this group during the first 3 days of treatment. After 3 days, adverse event rates were similar in the 2 groups. The majority of patients, including those experiencing flu-like symptoms, expressed a preference for annual i.v. therapy (66.4%) compared with weekly oral therapy (19.7%). We conclude that a single i.v. infusion of ZOL 5 mg reduced urine NTX levels more rapidly than weekly oral ALN 70 mg. The majority of study patients preferred an i.v. treatment regimen of ZOL 5 mg over weekly osteoporosis therapy with ALN 70 mg.

Identification of differentially regulated proteins in response to a compatible interaction between the pathogen Fusarium graminearum and its host, Triticum aestivum.

Using proteomic analyses, a study was carried out aimed at understanding the molecular mechanism of interaction between Fusarium graminearum and Triticum aestivum. Wheat spikelets were inoculated with H2O and conidia spores of F. graminearum. Proteins were extracted from spikelets harvested at three time points: 1, 2 and 3 days post inoculation. About 1380 protein spots were displayed on 2-D gels stained with Sypro Ruby. In total, 41 proteins were detected to be differentially regulated due to F. graminearum infection, and were analyzed with LC-MS/MS for their identification. The proteins involved in the antioxidant and jasmonic acid signaling pathways, pathogenesis-related response, amino acid synthesis and nitrogen metabolism were up-regulated, while those related to photosynthesis were less abundant following F. graminearum infection. The DNA-damage inducible protein was found to be induced and glycosylated in F. graminearum-infected spikelets. Using TargetP program, seven of the identified wheat proteins were predicted to be located in the chloroplast, implying that the chloroplast is the organelle mostly affected by F. graminearum infection. Eight identified fungal proteins possess possible functions such as antioxidant and acquiring carbon from wheat through glycolysis in a compatible interaction between F. graminearum and wheat.

Identification of proteins induced or upregulated by Fusarium head blight infection in the spikes of hexaploid wheat (Triticum aestivum).

Fusarium head blight (FHB) caused by Fusarium graminearum is a destructive disease of wheat and barley. It causes economic losses due to reduction in both yield and quality. Although FHB resistance has been well documented and resistant cultivars have been developed to reduce incidence and severity of FHB, there is a limited understanding of the molecular mechanisms involved in plant resistance against the infection and spread of F. graminearum. In the current study, 2-dimensional displays of proteins extracted from wheat spikelets infected with F. graminearum were compared with those from spikelets inoculated with sterile H2O. Fifteen protein spots were detected that were either induced (qualitatively different) or upregulated (quantitatively increased) following F. graminearum infection of spikelets of 'Ning7840', a resistant cultivar. These proteins were identified by LC-MS/MS analysis. Proteins with an antioxidant function such as superoxide dismutase, dehydroascorbate reductase, and glutathione S-transferases (GSTs) were upregulated or induced 5 d after inoculation with F. graminearum, indicating an oxidative burst of H2O2 inside the tissues infected by FHB. An ascorbate-glutathione cycle is likely involved in reduction of H2O2. Expression of proteins with highest similarity to dehydroascorbate reductase and TaGSTF5 (a glutathione S-transferase) differed following FHB infection in susceptible and resistant cultivars. A 14-3-3 protein homolog was also upregulated in FHB-infected spikelets. In addition, a PR-2 protein (beta-1, 3 glucanase) was upregulated in FHB-infected spikes, which is in accord with a previous study that analyzed transcript accumulation.

Molecular characterization of Fusarium head blight resistance in Wangshuibai with simple sequence repeat and amplified fragment length polymorphism markers.

Molecular mapping of Fusarium head blight (FHB) resistance quantitative trait loci (QTL) and marker-assisted selection of these QTL will aid in the development of resistant cultivars. Most reported FHB resistance QTL are from 'Sumai 3' and its derivatives. 'Wangshuibai' is a FHB-resistant landrace that originated from China and is not known to be related to 'Sumai 3'. A mapping population of 139 F(5:6) recombinant inbred lines was developed from a cross of 'Wangshuibai' and 'Wheaton'. This population was developed to map the FHB-resistant QTL in 'Wangshuibai' and was evaluated twice for Type II FHB resistance. A total of 1196 simple sequence repeat and amplified fragment length polymorphism markers were screened on this population, and four FHB resistance QTL were detected. A major QTL near the end of 3BS explained 37.3% of the phenotypic variation. Another QTL on 3BS, located close to the centromere, explained 7.4% of the phenotypic variation. Two additional QTL on 7AL and 1BL explained 9.8% and 11.9% of the phenotypic variation, respectively. The simple sequence repeat and amplified fragment length polymorphism markers closely linked to these QTL may be useful for stacking QTL from 'Wangshuibai' and other sources to develop cultivars with transgressive FHB resistance.

Genetic analysis of scab resistance QTL in wheat with microsatellite and AFLP markers.

Three chromosomal regions associated with scab resistance were detected in a common cultivar, Ning7840, by microsatellite and AFLP analysis. Six microsatellites on chromosome 3BS, Xgwm389, Xgwm533, Xbarc147, Xgwm493, Xbarc102, and Xbarc131, were integrated into an amplified fragment length polymorphism (AFLP) linkage group containing a major quantitative trait locus (QTL) for scab resistance in a mapping population of 133 recombinant inbred lines (RILs) derived from 'Ning7840' x 'Clark'. Based on single-factor analysis of variance of scab infection data from four experiments, Xgwm533 and Xbarc147 were the two microsatellite markers most tightly associated with the major scab resistance QTL. Interval analysis based on the integrated map of AFLP and microsatellite markers showed that the major QTL was located in a chromosome region about 8 cM in length around Xgwm533 and Xbarc147. Based on mapping of six microsatellite markers on eight 3BS deletion lines, the major QTL was located distal to breakage point 3BS-8. In total, 18 microsatellites were physically located on different subarm regions on 3BS. Two microsatellites, Xgwm120 and Xgwm614, were significantly associated with QTL for scab resistance on chromosome 2BL and 2AS, respectively. The resistance alleles on 3BS, 2BL, and 2AS were all derived from 'Ning7840'. Significant interaction between the major QTL on 3BS and the QTL on 2BL was detected based on microsatellite markers linked to them. Using these microsatellite markers would facilitate marker-assisted selection to improve scab resistance in wheat.