315 research outputs found
Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers
RATIONALE: Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects. OBJECTIVES: To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler. METHODS: Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation. RESULTS AND DISCUSSION: Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 μg/L in all samples. CONCLUSION: Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted
Effective Interactions and Volume Energies in Charged Colloids: Linear Response Theory
Interparticle interactions in charge-stabilized colloidal suspensions, of
arbitrary salt concentration, are described at the level of effective
interactions in an equivalent one-component system. Integrating out from the
partition function the degrees of freedom of all microions, and assuming linear
response to the macroion charges, general expressions are obtained for both an
effective electrostatic pair interaction and an associated microion volume
energy. For macroions with hard-sphere cores, the effective interaction is of
the DLVO screened-Coulomb form, but with a modified screening constant that
incorporates excluded volume effects. The volume energy -- a natural
consequence of the one-component reduction -- contributes to the total free
energy and can significantly influence thermodynamic properties in the limit of
low-salt concentration. As illustrations, the osmotic pressure and bulk modulus
are computed and compared with recent experimental measurements for deionized
suspensions. For macroions of sufficient charge and concentration, it is shown
that the counterions can act to soften or destabilize colloidal crystals.Comment: 14 pages, including 3 figure
The osmotic pressure of charged colloidal suspensions: A unified approach to linearized Poisson-Boltzmann theory
We study theoretically the osmotic pressure of a suspension of charged
objects (e.g., colloids, polyelectrolytes, clay platelets, etc.) dialyzed
against an electrolyte solution using the cell model and linear
Poisson-Boltzmann (PB) theory. From the volume derivative of the grand
potential functional of linear theory we obtain two novel expressions for the
osmotic pressure in terms of the potential- or ion-profiles, neither of which
coincides with the expression known from nonlinear PB theory, namely, the
density of microions at the cell boundary. We show that the range of validity
of linearization depends strongly on the linearization point and proof that
expansion about the selfconsistently determined average potential is optimal in
several respects. For instance, screening inside the suspension is
automatically described by the actual ionic strength, resulting in the correct
asymptotics at high colloid concentration. Together with the analytical
solution of the linear PB equation for cell models of arbitrary dimension and
electrolyte composition explicit and very general formulas for the osmotic
pressure ensue. A comparison with nonlinear PB theory is provided. Our analysis
also shows that whether or not linear theory predicts a phase separation
depends crucially on the precise definition of the pressure, showing that an
improper choice could predict an artificial phase separation in systems as
important as DNA in physiological salt solution.Comment: 16 pages, 5 figures, REVTeX4 styl
Models of HoTT and the Constructive View of Theories
Homotopy Type theory and its Model theory provide a novel formal semantic framework for representing scientific theories. This framework supports a constructive view of theories according to which a theory is essentially characterised by its methods.
The constructive view of theories was earlier defended by Ernest Nagel and a number of other philosophers of the past but available logical means did not allow these people to build formal representational frameworks that implement this view
The Pharmacogenetics Research Network: From SNP Discovery to Clinical Drug Response
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109975/1/cpt6100087.pd
Multidrug resistance-associated protein-1 (MRP1) genetic variants, MRP1 protein levels and severity of COPD
<p>Abstract</p> <p>Background</p> <p>Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in <it>MRP1 </it>significantly associate with level of FEV<sub>1 </sub>in two independent population based cohorts. The aim of our study was to assess the associations of <it>MRP1 </it>SNPs with FEV<sub>1 </sub>level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients.</p> <p>Methods</p> <p>Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in <it>MRP1 </it>were genotyped in 110 COPD patients. The effects of <it>MRP1 </it>SNPs were analyzed using linear regression models.</p> <p>Results</p> <p>One SNP, rs212093 was significantly associated with a higher FEV<sub>1 </sub>level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV<sub>1 </sub>level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies.</p> <p>Conclusions</p> <p>This is the first study linking <it>MRP1 </it>SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of <it>MRP1 </it>SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies.</p
Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study
<p>Abstract</p> <p>Background</p> <p>Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation.</p> <p>Methods</p> <p>114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV<sub>1 </sub>63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue<sup>+</sup>) area (%), proliferating (Ki-67<sup>+</sup>) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies.</p> <p>Results</p> <p>Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters (<3.5 years) and current smokers. Long-term quitters (≥3.5 years) had less goblet cell area than both current smokers and short-term quitters (medians: 7.9% vs. 14.4%, p = 0.005; 7.9% vs. 13.5%, p = 0.008; respectively), and less proliferating cell numbers than current smokers (2.8% vs. 18.6%, p < 0.001).</p> <p>Conclusion</p> <p>Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years).</p> <p>Trial registration</p> <p>NCT00158847</p
Molecule-Electrode Interface Energetics in Molecular Junction: a Transition Voltage Spectroscopy Study
We assess the performances of the transition voltage spectroscopy (TVS)
method to determine the energies of the molecular orbitals involved in the
electronic transport though molecular junctions. A large number of various
molecular junctions made with alkyl chains but with different chemical
structure of the electrode-molecule interfaces are studied. In the case of
molecular junctions with clean, unoxidized electrode-molecule interfaces, i.e.
alkylthiols and alkenes directly grafted on Au and hydrogenated Si,
respectively, we measure transition voltages in the range 0.9 - 1.4 V. We
conclude that the TVS method allows estimating the onset of the tail of the
LUMO density of states, at energy located 1.0 - 1.2 eV above the electrode
Fermi energy. For oxidized interfaces (e.g. the same monolayer measured with Hg
or eGaIn drops, or monolayers formed on a slightly oxidized silicon substrate),
lower transition voltages (0.1 - 0.6 V) are systematically measured. These
values are explained by the presence of oxide-related density of states at
energies lower than the HOMO-LUMO of the molecules. As such, the TVS method is
a useful technique to assess the quality of the molecule-electrode interfaces
in molecular junctions.Comment: Accepted for publication in J. Phys. Chem C. One pdf file including
manuscript, figures and supporting informatio
The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions
UK Biobank is a population-based cohort of half a million participants aged 40–69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world’s largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future direction
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