Wheat blast is a serious disease caused by the fungus Magnaporthe oryzae (Triticum pathotype) (MoT). The objective of this study was to determine the effect of the 2NS translocation from Aegilops ventricosa (Zhuk.) Chennav on wheat head and leaf blast resistance. Disease phenotyping experiments were conducted in growth chamber, greenhouse, and field environments. Among 418 cultivars of wheat (Triticum aestivum L.), those with 2NS had 50.4 to 72.3% less head blast than those without 2NS when inoculated with an older MoT isolate under growth chamber conditions. When inoculated with recently collected isolates, cultivars with 2NS had 64.0 to 80.5% less head blast. Under greenhouse conditions when lines were inoculated with an older MoT isolate, those with 2NS had a significant head blast reduction. With newer isolates, not all lines with 2NS showed a significant reduction in head blast, suggesting that the genetic background and/or environment may influence the expression of any resistance conferred by 2NS. However, when near-isogenic lines (NILs) with and without 2NS were planted in the field, there was strong evidence that 2NS conferred resistance to head blast. Results from foliar inoculations suggest that the resistance to head infection that is imparted by the 2NS translocation does not confer resistance to foliar disease. In conclusion, the 2NS translocation was associated with significant reductions in head blast in both spring and winter wheat.
Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log10 PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases.
Cowpox; Orthopoxvirus; Animal model; Computed tomography; CT; Pathogenesis; Aerosol inoculation
CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Δ7steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage. Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1. Finally, CYP11A1-derived secosteroidal hydroxy-derivatives and Δ7steroids are biologically active when administered in vitro in a manner dependent on the structure of the compound and the lineage of the target cells, suggesting physiological roles for these metabolites. This article is part of a special issue entitled ‘SI: Steroid/Sterol signaling’.
CYP11A1; Cholesterol; Plant sterols; Vitamin D; 7-Dehydrocholesterol; Ergosterol
Clinicians may record patients presenting with osteoarthritis (OA) symptoms with joint pain rather than an OA diagnosis. This may have implications for OA research studies and patient care. The objective was to assess whether older adults recorded with joint pain are similar to those with a recorded OA diagnosis.
A study of adults aged ≥50 years in eight United Kingdom general practices, with electronic health records linked to survey data. Patients with a recorded regional OA diagnosis were compared to those with a recorded joint pain symptom on socio-demographics, risk factors, body region, pain severity, prescribed analgesia, and potential differential diagnoses. A sub-group was compared on radiographic knee OA.
Thirteen thousand eight hundred and thirty-one survey responders consented to record review. One thousand four hundred and twenty-seven (10%) received an OA (n = 616) or joint pain (n = 811) code with wide practice variation. Receiving an OA diagnosis was associated with age (75+ compared to 50–64 OR 3.25; 95% Credible intervals (CrI) 2.36, 4.53), obesity (1.72; 1.22, 2.33), and pain interference (1.45; 1.09, 1.92). Analgesia management was similar. Radiographic OA was common in both groups. A quarter of those with a joint pain record received an OA diagnosis in the following 6 years.
Recording OA diagnoses are less common than recording a joint pain symptom and associated with risk factors and severity. OA studies in primary care need to consider joint pain symptoms to understand the burden and quality of care across the spectrum of OA. Patients recorded with joint pain may represent early cases of OA with need for early intervention.
Osteoarthritis; Computerized patient medical records; Primary health care
Musculoskeletal pain conditions are common and create substantial burden for the individual and society. While research has shown concordance between couples for risk of some diseases, e.g. heart disease or diabetes, little information is available on such effects for musculoskeletal pain conditions. Our aims were to investigate the presence of concordance between couples for consultations about pain, and to examine theoretical influences on such concordance.
This was a 1‐year cross‐sectional study of musculoskeletal pain consultations in a UK primary care database. In total 27,014 patients (13,507 couples) aged between 30 and 74 years were included. The main outcome measure was the presence of a musculoskeletal morbidity read code indicating a consultation for musculoskeletal conditions (any, back, neck, knee, shoulder, foot, osteoarthritis). Logistic regression was used to test associations with odds ratios (OR) and 95% confidence intervals (95% CI).
Patients whose partner had a musculoskeletal pain consultation were also more likely to consult for a musculoskeletal condition (OR 1.22, 95% CI 1.12–1.32). This association was found to be strongest for shoulder disorders (OR 1.91, 95% CI 1.06–3.47). No significant associations were found for other pain conditions.
Results show that partner concordance is present for consultations for some musculoskeletal conditions but not others. Possible explanations for concordance include the shared health behaviours between couples leading to potential heightened awareness of symptoms. Given the high prevalence of musculoskeletal pain within populations, it may be worth considering further the mechanisms that explain partner concordance.
The novel oral anticoagulants or direct oral anticoagulants (DOAC) are becoming more common in clinical practice for the prevention of stroke in non-valvular atrial fibrillation (NVAF). The availability of several agents with similar efficacy and safety for stroke prevention in NVAF patients offers more selection, but at the same time requires certain knowledge to make a good choice. This comparative analysis provides an appraisal of the respective clinical trials and highlights much of what remains unknown about four FDA-approved agents: dabigatran, apixaban, rivaroxaban, and edoxaban. It details how the DOACs compare to warfarin and to one another summarizes pharmacologic and pharmacodynamic properties, and drug interactions from the stand point of practical consequences of these findings. Common misconceptions and reservations are addressed. The practical application of this data is intended to help choosing the most appropriate agent for individual NVAF patient.
Direct thrombin inhibitors; Factor Xa inhibitors; Rivaroxaban; Dabigatran; Apixaban; Warfarin; Nonvalvular atrial fibrillation
Data on immune mediators in the genital tract and the factors that modulate them in sub-Saharan women are limited. Cervicovaginal lavage (CVL) samples from 430 sexually active women from Kenya, South Africa, and Rwanda were analyzed for 12 soluble immune mediators using Bio-Plex and Meso Scale Discovery multiplex platforms, as well as single enzyme-linked immunosorbent assays. Ten bacterial species were quantified in vaginal swab samples. Bacterial vaginosis (BV) was defined by Nugent scoring. CVL samples from HIV-infected women showed a clear-cut proinflammatory profile. Pregnant women, adolescents, and women engaging in traditional vaginal practices differed in specific soluble markers compared to reference groups of adult HIV-negative women. Cervical mucus, cervical ectopy, abnormal vaginal discharge, and having multiple sex partners were each associated with an increase in inflammatory mediators. The levels of interleukin-1α (IL-1α), IL-1β, IL-6, IL-12(p70), and IL-8 were elevated, whereas the IL-1RA/IL-1(α+β) ratio decreased in women with BV. The level of gamma interferon-induced protein 10 was lower in BV-positive than in BV-negative women, suggesting its suppression as a potential immune evasion mechanism by BV-associated bacteria. Lactobacillus crispatus and Lactobacillus vaginalis were associated with decreased proinflammatory cytokines and each BV-associated species with increased proinflammatory cytokines. Remarkably, the in vitro anti-HIV activity of CVL samples from BV-positive women was stronger than that of BV-negative women. In conclusion, we found significant associations of factors, including vaginal microbiota, which can influence immune mediators in the vaginal environment in sexually active women. These factors need to be considered when establishing normative levels or pathogenic cutoffs of biomarkers of inflammation and associated risks in African women.
To assess and compare patient perceived quality of osteoarthritis (OA) management in primary healthcare in Denmark, Norway, Portugal and the UK.
Participants consulting with clinical signs and symptoms of knee OA were identified in 30 general practices and invited to complete a cross-sectional survey including quality indicators (QI) for OA care. A QI was considered as eligible if the participant had checked ‘Yes’ or ‘No’, and as achieved if the participant had checked ‘Yes’ to the indicator. The median percentage (with IQR and range) of eligible QIs achieved by country was determined and compared in negative binominal regression analysis. Achievement of individual QIs by country was determined and compared using logistic regression analyses.
A total of 354 participants self-reported QI achievement. The median percentage of eligible QIs achieved (checked ‘Yes’) was 48% (IQR 28%, 64%; range 0–100%) for the total sample with relatively similar medians across three of four countries. Achievement rates on individual QIs showed a large variation ranging from 11% (referral to services for losing weight) to 67% (information about the importance of exercise) with significant differences in achievement rates between the countries.
The results indicated a potential for improvement in OA care in all four countries, but for somewhat different aspects of OA care. By exploring these differences and comparing healthcare services, ideas may be generated on how the quality might be improved across nations. Larger studies are needed to confirm and further explore the findings.
Osteoarthritis; Quality Indicators; Health services research; Patient perspective
This phase III trial demonstrated that adding a single dose of fosaprepitant to a 5-HT3 receptor antagonist and corticosteroid in a nonanthracycline and cyclophosphamide-based moderately emetogenic chemotherapy population significantly improved the prevention of chemotherapy-induced nausea and vomiting. The use of this regimen may eliminate the need for multiday antiemetic therapy in such patients.
To establish the role of antiemetic therapy with neurokinin-1 (NK1) receptor antagonists (RAs) in nonanthracycline and cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) regimens, this study evaluated single-dose intravenous (i.v.) fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with non-AC MEC.
Patients and methods
In this international, phase III, double-blind trial, adult cancer subjects scheduled to receive ≥1 non-AC MEC on day 1 were randomized to a regimen comprising single-dose i.v. fosaprepitant 150 mg or placebo along with ondansetron and dexamethasone on day 1; control regimen recipients received ondansetron on days 2 and 3. Primary end points were the proportion of subjects achieving a complete response (CR; no vomiting and no use of rescue medication) in the delayed phase (25–120 h after MEC initiation) and safety. Secondary end points included CR in the overall and acute phases (0–120 and 0–24 h after MEC initiation, respectively) and no vomiting in the overall phase. Nausea and the Functional Living Index-Emesis were assessed as exploratory end points.
The fosaprepitant regimen improved CR significantly in the delayed (78.9% versus 68.5%; P < 0.001) and overall (77.1% versus 66.9%; P < 0.001) phases, but not in the acute phase (93.2% versus 91.0%; P = 0.184), versus control. In the overall phase, the proportion of subjects with no vomiting (82.7% versus 72.9%; P < 0.001) and no significant nausea (83.2% versus 77.9%; P = 0.030) was also significantly improved with the fosaprepitant regimen. The fosaprepitant regimen was generally well tolerated.
Single-dose fosaprepitant added to a 5-HT3 RA and dexamethasone was well tolerated and demonstrated superior control of CINV (primary end point achieved) associated with non-AC MEC. This is the first study to evaluate NK1 RA therapy as an i.v. formulation in a well-defined non-AC MEC population.
fosaprepitant dimeglumine; neurokinin-1 receptor antagonists; vomiting; nausea; moderately emetogenic chemotherapy
The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.
Salvinorin A and B; Michael acceptor-type ligands; kappa; delta; mu opioid receptors; molecular modeling
Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100 000 births.
To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments.
Epidemiological and retrospective observational study.
Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3 030 083 newborns screened with a TREC test.
MAIN OUTCOMES AND MEASURES
Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked.
Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58 000 infants (95%CI, 1/46 000-1/80 000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87%(45/52), 92%(45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia.
CONCLUSIONS AND RELEVANCE
Newborn screening in 11 programs in the United States identified SCID in 1 in 58 000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.
The development of new drugs for the treatment of depression is strategic to achieving clinical needs of patients. This study evaluates antidepressant-like effect and neural mechanisms of four oleanolic acid derivatives i.e. acrylate (D1), methacrylate (D2), methyl fumarate (D3) and ethyl fumarate (D4). All derivatives were obtained by simple one-step esterification of oleanolic acid prior to pharmacological screening in the forced swimming (FS) and open field (OF) tests. Pharmacological tools like α-methyl-p-tyrosine (AMPT, catecholamine depletor), p-chlorophenylalanine (serotonin depletor), prazosin (PRAZ, selective α1-receptor antagonist), WAY-100635 (selective serotonin 5-HT1A receptor antagonist) as well as monoamine oxidase (MAO) and functional binding assays were conducted to investigate possible neural mechanisms. In the FS test, D1 showed the most promising antidepressant-like effect without eliciting locomotor incoordination. Unlike group of mice pretreated with AMPT 100 mg/kg, PCPA 100 mg/kg or PRAZ 1 mg/kg, the effect of D1 was attenuated by WAY-100635 0.3 mg/kg pretreatment. D1 demonstrated moderate inhibition of MAO-A (IC50 = 48.848 ± 1.935 μM), potency (pEC50 = 6.1 ± 0.1) and intrinsic activity (Emax = 26 ± 2.0%) on 5-HT1A receptor. In conclusion, our findings showed antidepressant-like effect of D1 and possible involvement of 5-HT1A receptor.
DOCK8; atopy; CNS vasculopathy; varicella zoster
To identify valid and feasible quality indicators for the primary care of osteoarthritis (OA).
Systematic review and narrative synthesis.
Electronic reference databases (MEDLINE, EMBASE, CINAHL, HMIC, PsychINFO), quality indicator repositories, subject experts.
Eligible articles referred to adults with OA, focused on development or implementation of quality indicators, and relevant to UK primary care. An English language restriction was used. The date range for the search was January 2000 to August 2013. The majority of OA management guidance has been published within this time frame.
Relevant studies were quality assessed using previous quality indicator methodology. Two reviewers independently extracted data. Articles were assessed through the Outcome Measures in Rheumatology filter; indicators were mapped to management guidance for OA in adults. A narrative synthesis was used to combine the indicators within themes.
10 853 articles were identified from the search; 32 were included in the review. Fifteen indicators were considered valid and feasible for implementation in primary care; these related to assessment non-pharmacological and pharmacological management. Another 10 indicators were considered less feasible, in various aspects of assessment and management. A small number of recommendations had no published corresponding quality indicator, such as use of topical non-steroidal anti-inflammatory drugs. No negative (‘do not do’) indicators were identified.
Conclusions and implications of key findings
There are well-developed, feasible indicators of quality of care for OA which could be implemented in primary care. Their use would assist the audit and quality improvement for this common and frequently disabling condition.
Osteoarthritis; Quality Indicators; Analgesics; NSAIDs
Sociodemographic, behavioral and clinical correlates of the vaginal microbiome (VMB) as characterized by molecular methods have not been adequately studied. VMB dominated by bacteria other than lactobacilli may cause inflammation, which may facilitate HIV acquisition and other adverse reproductive health outcomes.
We characterized the VMB of women in Kenya, Rwanda, South Africa and Tanzania (KRST) using a 16S rDNA phylogenetic microarray. Cytokines were quantified in cervicovaginal lavages. Potential sociodemographic, behavioral, and clinical correlates were also evaluated.
Three hundred thirteen samples from 230 women were available for analysis. Five VMB clusters were identified: one cluster each dominated by Lactobacillus crispatus (KRST-I) and L. iners (KRST-II), and three clusters not dominated by a single species but containing multiple (facultative) anaerobes (KRST-III/IV/V). Women in clusters KRST-I and II had lower mean concentrations of interleukin (IL)-1α (p < 0.001) and Granulocyte Colony Stimulating Factor (G-CSF) (p = 0.01), but higher concentrations of interferon-γ-induced protein (IP-10) (p < 0.01) than women in clusters KRST-III/IV/V. A lower proportion of women in cluster KRST-I tested positive for bacterial sexually transmitted infections (STIs; ptrend = 0.07) and urinary tract infection (UTI; p = 0.06), and a higher proportion of women in clusters KRST-I and II had vaginal candidiasis (ptrend = 0.09), but these associations did not reach statistical significance. Women who reported unusual vaginal discharge were more likely to belong to clusters KRST-III/IV/V (p = 0.05).
Vaginal dysbiosis in African women was significantly associated with vaginal inflammation; the associations with increased prevalence of STIs and UTI, and decreased prevalence of vaginal candidiasis, should be confirmed in larger studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0831-1) contains supplementary material, which is available to authorized users.
Bacterial vaginosis; Vaginal microbiome; Vaginal microbiota; Lactobacillus; Candidiasis; Sexually transmitted infections; Urinary tract infections; Women; HIV; Africa
The major cycling “Grand Tours” have shown an attenuation of performance over the last decade. This has been interpreted as circumstantial evidence that newer anti-doping strategies have reduced the use of performance-enhancing drugs. To examine this idea under more controlled conditions, speed trends for world class 5000 m, 10000 m, and marathon performances by men from 1980 to 2013 were analyzed. We obtained comprehensive records from the International Association of Athletics Federations, Association of Road Racing Statisticians, and the Track and Field All-time Performances database webpages. The top 40 performances for each event and year were selected for regression analysis. For the three distances, we noted cumulative performance improvements in the 1990s thru the mid-2000s. After the peak speed years of the mid 2000 s, there has been limited improvement in the 5000 m and 10,000 m and world records set during that time remain in place today, marking the longest period of time between new records since the early 1940s. By contrast marathon speed continues to increase and the world record has been lowered four times since 2007, including in 2013. While the speed trends for 5000 m and 10000 m track results parallel those seen in elite cycling, the marathon trends do not. We discuss a number of explanations other than improved anti-doping strategies that might account for these divergent findings.
Three known (leoleorins A-C) and eight new (leoleorins D-J and 16-epi-leoleorin F) labdane diterpenoids, were isolated from leaves of Leonotis leonurus. The absolute configurations of leoleorins A and D were established by X-ray crystallographic analyses. In competitive binding assay all isolated compounds showed inhibition in excess of 50% at various CNS receptors. Leoleorin C showed moderate binding affinity (Ki = 2.9 μM) for the Sigma 1 receptor.
Leonotis leonurus; Lamiaceae; Psychoactive plant; Labdane diterpenoids; Leoleorins A-J; X-ray diffraction; G-protein-coupled receptors
Phytochemical investigation of the leaves of Cecropia schreberiana Miq. (Urticaceae) led to the isolation of four triterpenoids (1–4), three flavone C-glycosides (5–7), two flavan-3-ols (8, 9), two flavanolignans (10, 11), and two proanthocyanidins (12, 13). All compounds were isolated from C. schreberiana for the first time. This is the first report demonstrating the presence of arjunolic acid (4), cinchonain Ia (10), and cinchonain Ib (11) in the Urticaceae family. The occurrence of flavanolignans within the family Urticaceae supports the likelihood that such compounds are more common within the class Magnoliopsida than previously thought.
Urticaceae; Cecropia schreberiana; Triterpenoid; Flavonoid; Proanthocyanidin; Flavanolignan
Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective κ-opioid receptor agonist. To better understand the ligand-receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ, δ, and μ-opioid receptors. Most of the analogues show high affinity to the κ-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki = 2 nM), analogues 5, 7, and 14 exhibit significant affinity for the κ-receptor (Ki = 21, 36 and 39 nM).
Salvia divinorum; Salvinorin A and B; Dicarboxylic ester-type ligands; Kappa opioid receptor agonists
In this multinational, phase III study, the safety and efficacy of NEPA, a convenient, fixed-dose antiemetic combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a distinct 5-HT3 RA, were evaluated over multiple cycles of highly and moderately emetogenic chemotherapy. NEPA was shown to be safe, well tolerated and highly effective over 1961 chemotherapy cycles.
Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC.
Patients and methods
This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1–4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue).
Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0–120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles.
NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.
neurokinin-1 receptor antagonist; NEPA; netupitant; palonosetron; CINV; multiple chemotherapy cycles
Chemical examination of the methanolic extract of the leaflets of Cycas circinalis L. led to the isolation of one new biflavonoid, (2S, 2″S)-2,3,2″,3″-tetrahydro-4′,4‴-di-O-methylamentoflavone (tetrahydroisoginkgetin; 2), and 15 known compounds, 11 of which are reported for the first time from C. circinalis. Chromatographic separation of the chloroform extract of C. revoluta Thunb. leaflets afforded 12 compounds, seven of which are reported for the first time from this species. The isolated compounds from both species include 14 biflavonoids, three lignans, three flavan-3-ols, two flavone-C-glucosides, two nor-isoprenoids, and one flavanone. This is the first report of NMR and CD data of 2,3,2″,3″-tetrahydro-4′-O-methyl- and 2,3-dihydro-4′-O-methyl-amentoflavone (6) and (7). The effect of O-methylation on the chemical shifts of the neighboring carbons in the 13C NMR spectra of the dihydro- and tetrahydro-amentoflavone skeletons provides a tool to identify the location of the methoxy groups. Compounds 2, 6, and 18 displayed moderate antibacterial activity against Staphylococcus aureus (IC50 values of 3.8, 9.6, and 8.2 μM, respectively) and methicillin-resistant S. aureus (MRSA; IC50 values of 5.9, 12.5, and 11.5 μM, respectively).
Cycadaceae; Cycas circinalis; Cycas revolute; biflavonoid; lignin; flavan-3-ol; nor-isoprenoid; flavone-C-glucoside; antibacterial activity
Ten new bis-spirolabdane diterpenoids, leonepetaefolins A–E (1, 3, 5, 7, 9) and 15-epi-leonepetaefolins A-E (2, 4, 6, 8, 10), together with eight known labdane diterpenoids (11–18) as well as two known flavonoids apigenin and cirsiliol, were isolated from the leaves of Leonotis nepetaefolia. The structures of the new compounds were determined on the basis of 1D-and 2D-NMR experiments including 1H, 13C, DEPT, 1H-1H COSY, HSQC, HMBC, and NOESY. The absolute configuration of an epimeric mixture of 1 and 2 was determined by X-ray crystallographic analysis. The compounds isolated were evaluated for their binding propensity in several CNS G protein-coupled receptor assays in vitro.
Novel metabolic pathways initiated by the enzymatic action of CYP11A1 on 7DHC (7-dehydrocholesterol), ergosterol, vitamins D3 and D2 were characterized with help of chemical synthesis, UV and mass spectrometry and NMR analyses. The first pathway follows the sequence 7DHC→22(OH)7DHC → 20,22(OH)27DHC → 7DHP (7-dehydropregnenolone), which can further be metabolized by steroidogenic enzymes. The resulting 5,7-dienes can be transformed by UVB to corresponding, biologically active, secosteroids. Action of CYP11A1 on vitamin D3 and D2 produces novel hydroxyderivatives with OH added at positions C17, C20, C22, C23 and C24, some of which can be hydroxylated by CYP27B1 and/or by CYP27A1 and/ or by CYP24A1.The main products of these pathways are biologically active with a potency related to their chemical structure and the target cell type. Main products of CYP11A1-mediated metabolism on vitamin D are non-calcemic and non-toxic at relatively high doses and serve as partial agonists on the vitamin D receptor. New secosteroids are excellent candidates for therapy of fibrosing, inflammatory or hyperproliferative disorders including cancers and psoriasis.
skin; keratinocytes; melanocytes; melanoma cells; dermal fibroblasts; vitamin D; 5,7-dienes
High concentrations of pro-inflammatory cytokines have been previously observed in the genital fluids of women enrolled in microbicide trials and may explain observed increased HIV transmission in some of these trials. Although the longitudinal nature of these studies allows within-subject comparisons of post-product levels to baseline levels, the fact that the physiologic variations of these cytokines and other markers of immune activation are not fully defined in different populations, makes it difficult to assess changes that can be directly attributed to microbicide use as opposed to other biological and behavioural factors.
Cervicovaginal lavage samples were collected from 30 healthy Caucasian and assayed for concentrations of ten cytokines/chemokines, total protein content and two antimicrobial proteins using a multiplex immunoassay and ELISA. Cellular markers were characterized by flow cytometry on mononuclear cells collected from the endocervix using flocked swabs. Bacterial quantification was performed using quantitative PCR.
Ectopy, menstrual cycle phase, prostate-specific antigen and presence of leucocytes in endocervical cells' supernatant were associated with the concentrations of cyto-/chemokines in cervicovaginal secretions. Approximately 3% of endocervical cells collected were monocytes of which a median of 52% (SD = 17) expressed both CD4 and CCR5 markers. Approximately 1% of the total cells were T-cells with a median of 61% (SD = 10) CD4 and CCR5 expression. Around 5% of the monocytes and 16% of the T-cells expressed the immune activation marker HLA-DR. Higher percentages of T-cells were associated with greater quantities of IL-1RA, GM-CSF and elafin.
We demonstrate the presence of selected soluble and cellular immune activation markers and identify their predictors in the female genital tract of healthy women. Future clinical trials should consider ectopy, sexual activity, menstrual cycle phase and presence of bacterial species as possible confounders when evaluating the possible inflammatory effects of microbicide compounds.