237 research outputs found
Pharmacokinetics, Safety, and Antiviral Effects of Multiple Doses of the Respiratory Syncytial Virus (RSV) Fusion Protein Inhibitor, JNJ-53718678, in Infants Hospitalized With RSV Infection: A Randomized Phase 1b Study
BACKGROUND: This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to /=6 to /=3 to 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction. RESULTS: Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng x hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL. CONCLUSIONS: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed. CLINICAL TRIALS REGISTRATION: NCT02593851
The nutrigenetic influence of the interaction between dietary vitamin E and TXN and COMT gene polymorphisms on waist circumference: a case control study
Journal Article; Research Support, Non-U.S. Gov't;BACKGROUND
Abdominal obesity (AO) is a common modifiable risk factor for certain non-communicable diseases associated with enhanced oxidative stress (OS). The objective of this work was to investigate whether the interaction between antioxidant vitamin intake and OS-related polymorphisms modulates gene-associated anthropometry in a Spanish population.
METHODS
A total of 246 subjects with AO, and 492 age and gender matched non-AO subjects were included in the study. Anthropometric, biochemical, and OS parameters, and antioxidant dietary intake data were assessed using validated procedures. DNA from white blood cells was isolated and the genotype of seven polymorphisms from genes involved in OS (pro-oxidant and antioxidant) were analyzed using the SNPlex system. The effects of the c.-793T > C polymorphism on promoter activity and thus thioredoxin (TXN) activity were examined using reporter assays.
RESULTS
The AO group had higher 8-Oxo-2'-deoxyguanosine levels and took in less vitamin A and vitamin E compared to the non-AO group. Logistic regression analysis revealed that the rs2301241 polymorphism in TXN and rs740603 in catechol-O-methyltransferase (COMT) were associated with waist circumference (WC) and AO. Moreover, these polymorphisms were more strongly associated with variations in WC in subjects with low vitamin E intakes. A promoter assay revealed that the T to C conversion at c.-793 (rs2301241) induced a more than two fold increase in reporter gene expression.
CONCLUSIONS
WC is associated both with dietary vitamin E intake and genetic variants of TXN and COMT suggesting that existence of a complex nutrigenetic pathway that involves regulation of AO.This work was co-funded with European Funds for Regional Development (FEDER), the Spanish Science and Technology Ministry [SAF2005-02883]; the health research fund from the Carlos III Health Institute [PI070497], CIBER
Fisiopatología Obesidad y Nutrición (CIBERobn) [CB06/03], and CIBER de Diabetes y Enfermedades Metabólicas Relacionadas (CIBERDEM). CIBEROB and CIBERDEM are initiatives by the Carlos III Health Institute in Madrid and the Spanish Health Ministry. Funding also came from GRUPOS 03/101, PROMETEO/2009/029 and 2005/027, AMP07/075, and ACOMP/2009/201 from the Valencian Government and European Network of Excellence InGenious HyperCare (EPSS-037093) from the European Commission.Ye
GEICAM Guidelines for the Management of Patients with Breast Cancer During the COVID-19 Pandemic in Spain
Breast cancer (BC) is the most common cancer in women in
Spain. During the COVID-19 pandemic caused by the SARSCoV-2 virus, patients with BC still require timely treatment
and follow-up; however, hospitals are overwhelmed with
infected patients and, if exposed, patients with BC are at
higher risk for infection and serious complications if infected.
Thus, health care providers need to evaluate each BC treatment and in-hospital visit to minimize pandemic-associated
risks while maintaining adequate treatment efficacy. Here we
present a set of guidelines regarding available options for BC
patient management and treatment by BC subtype in the
context of the COVID-19 pandemic. Owing to the lack of evidence about COVID-19 infection, these recommendations
are mainly based on expert opinion, medical organizations’
and societies’ recommendations, and some published evidence. We consider this a useful tool to facilitate medical
decision making in this health crisis situation we are facing
ELOVL6 Genetic Variation Is Related to Insulin Sensitivity: A New Candidate Gene in Energy Metabolism
BACKGROUND: The elongase of long chain fatty acids family 6 (ELOVL6) is an enzyme that specifically catalyzes the elongation of saturated and monounsaturated fatty acids with 12, 14 and 16 carbons. ELOVL6 is expressed in lipogenic tissues and it is regulated by sterol regulatory element binding protein 1 (SREBP-1). OBJECTIVE: We investigated whether ELOVL6 genetic variation is associated with insulin sensitivity in a population from southern Spain. DESIGN: We undertook a prospective, population-based study collecting phenotypic, metabolic, nutritional and genetic information. Measurements were made of weight and height and the body mass index (BMI) was calculated. Insulin resistance was measured by homeostasis model assessment. The type of dietary fat was assessed from samples of cooking oil taken from the participants' kitchens and analyzed by gas chromatography. Five SNPs of the ELOVL6 gene were analyzed by SNPlex. RESULTS: Carriers of the minor alleles of the SNPs rs9997926 and rs6824447 had a lower risk of having high HOMA_IR, whereas carriers of the minor allele rs17041272 had a higher risk of being insulin resistant. An interaction was detected between the rs6824447 polymorphism and the intake of oil in relation with insulin resistance, such that carriers of this minor allele who consumed sunflower oil had lower HOMA_IR than those who did not have this allele (P = 0.001). CONCLUSIONS: Genetic variations in the ELOVL6 gene were associated with insulin sensitivity in this population-based study
Association between long term exposure to particulate matter and incident hypertension in Spain
Exposure to air particulate matter has been linked with hypertension and blood pressure levels. The metabolic risks of air pollution could vary according to the specific characteristics of each area, and has not been sufficiently evaluated in Spain. We analyzed 1103 individuals, participants in a Spanish nationwide population based cohort study ([email protected]), who were free of hypertension at baseline (2008-2010) and completed a follow-up exam of the cohort (2016-2017). Cohort participants were assigned air pollution concentrations for particulate matter < 10 mu m (PM10) and < 2.5 mu m (PM2.5) during follow-up (2008-2016) obtained through modeling combined with measurements taken at air quality stations (CHIMERE chemistry-transport model). Mean and SD concentrations of PM10 and PM2.5 were 20.17 +/- 3.91 mu g/m(3) and 10.83 +/- 2.08 mu g/m(3) respectively. During follow-up 282 cases of incident hypertension were recorded. In the fully adjusted model, compared with the lowest quartile of PM10, the multivariate weighted ORs (95% CIs) for developing hypertension with increasing PM10 exposures were 0.82 (0.59-1.14), 1.28 (0.93-1.78) and 1.45 (1.05-2.01) in quartile 2, 3 and 4 respectively (p for a trend of 0.003). The corresponding weighted ORs according to PM2.5 exposures were 0.80 (0.57-1.13), 1.11 (0.80-1.53) and 1.48 (1.09-2.00) (p for trend 0.004). For each 5-mu g/m(3) increment in PM10 and PM2.5 concentrations, the odds for incident hypertension increased 1.22 (1.06-1.41) p = 0.007 and 1.39 (1.07-1.81) p = 0.02 respectively. In conclusion, our study contributes to assessing the impact of particulate pollution on the incidence of hypertension in Spain, reinforcing the need for improving air quality as much as possible in order to decrease the risk of cardiometabolic disease in the population
Common variants of the liver fatty acid binding protein gene influence the risk of type 2 diabetes and insulin resistance in Spanish population
Summary: The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated.
Methods: 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1-
4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model.
Results:One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2
in the original population. This association was further confirmed in the second population as well as in the pooled sample.
None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction
between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and
HOMA-IR was also present in the replication population.
Conclusions: The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians
The nutrigenetic influence of the interaction between dietary vitamin E and TXN and COMT gene polymorphisms on waist circumference: a case control study
Background: Abdominal obesity (AO) is a common modifiable risk factor for certain non-communicable diseases
associated with enhanced oxidative stress (OS). The objective of this work was to investigate whether the interaction
between antioxidant vitamin intake and OS-related polymorphisms modulates gene-associated anthropometry in a
Spanish population.
Methods: A total of 246 subjects with AO, and 492 age and gender matched non-AO subjects were included in the
study. Anthropometric, biochemical, and OS parameters, and antioxidant dietary intake data were assessed using validated
procedures. DNA from white blood cells was isolated and the genotype of seven polymorphisms from genes
involved in OS (pro-oxidant and antioxidant) were analyzed using the SNPlex system. The effects of the c.-793T > C
polymorphism on promoter activity and thus thioredoxin (TXN) activity were examined using reporter assays.
Results: The AO group had higher 8-Oxo-2′-deoxyguanosine levels and took in less vitamin A and vitamin E compared
to the non-AO group. Logistic regression analysis revealed that the rs2301241 polymorphism in TXN and
rs740603 in catechol-O-methyltransferase (COMT) were associated with waist circumference (WC) and AO. Moreover,
these polymorphisms were more strongly associated with variations in WC in subjects with low vitamin E intakes. A
promoter assay revealed that the T to C conversion at c.-793 (rs2301241) induced a more than two fold increase in
reporter gene expression.
Conclusions: WC is associated both with dietary vitamin E intake and genetic variants of TXN and COMT suggesting
that existence of a complex nutrigenetic pathway that involves regulation of AO
Measurement of the cosmic ray spectrum above eV using inclined events detected with the Pierre Auger Observatory
A measurement of the cosmic-ray spectrum for energies exceeding
eV is presented, which is based on the analysis of showers
with zenith angles greater than detected with the Pierre Auger
Observatory between 1 January 2004 and 31 December 2013. The measured spectrum
confirms a flux suppression at the highest energies. Above
eV, the "ankle", the flux can be described by a power law with
index followed by
a smooth suppression region. For the energy () at which the
spectral flux has fallen to one-half of its extrapolated value in the absence
of suppression, we find
eV.Comment: Replaced with published version. Added journal reference and DO
Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory
The Auger Engineering Radio Array (AERA) is part of the Pierre Auger
Observatory and is used to detect the radio emission of cosmic-ray air showers.
These observations are compared to the data of the surface detector stations of
the Observatory, which provide well-calibrated information on the cosmic-ray
energies and arrival directions. The response of the radio stations in the 30
to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of
the incoming electric field. For the latter, the energy deposit per area is
determined from the radio pulses at each observer position and is interpolated
using a two-dimensional function that takes into account signal asymmetries due
to interference between the geomagnetic and charge-excess emission components.
The spatial integral over the signal distribution gives a direct measurement of
the energy transferred from the primary cosmic ray into radio emission in the
AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air
shower arriving perpendicularly to the geomagnetic field. This radiation energy
-- corrected for geometrical effects -- is used as a cosmic-ray energy
estimator. Performing an absolute energy calibration against the
surface-detector information, we observe that this radio-energy estimator
scales quadratically with the cosmic-ray energy as expected for coherent
emission. We find an energy resolution of the radio reconstruction of 22% for
the data set and 17% for a high-quality subset containing only events with at
least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO
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