The Veterinary Anti-Parasitic Selamectin Is a Novel Inhibitor of the Mycobacterium tuberculosis DprE1 Enzyme.

Avermectins are macrocyclic lactones with anthelmintic activity. Recently, they were found to be effective against Mycobacterium tuberculosis, which accounts for one third of the worldwide deaths from antimicrobial resistance. However, their anti-mycobacterial mode of action remains to be elucidated. The activity of selamectin was determined against a panel of M. tuberculosis mutants. Two strains carrying mutations in DprE1, the decaprenylphosphoryl-ß-D-ribose oxidase involved in the synthesis of mycobacterial arabinogalactan, were more susceptible to selamectin. Biochemical assays against the Mycobacterium smegmatis DprE1 protein confirmed this finding, and docking studies predicted a binding site in a loop that included Leu275. Sequence alignment revealed variants in this position among mycobacterial species, with the size and hydrophobicity of the residue correlating with their MIC values; M. smegmatis DprE1 variants carrying these point mutations validated the docking predictions. However, the correlation was not confirmed when M. smegmatis mutant strains were constructed and MIC phenotypic assays performed. Likewise, metabolic labeling of selamectin-treated M. smegmatis and M. tuberculosis cells with 14C-labeled acetate did not reveal the expected lipid profile associated with DprE1 inhibition. Together, our results confirm the in vitro interactions of selamectin and DprE1 but suggest that selamectin could be a multi-target anti-mycobacterial compound.

Overcoming the Prokaryote/Eukaryote Barrier in Tuberculosis Treatment: A Prospect for the Repurposing and Use of Antiparasitic Drugs.

Antimicrobial resistance, the so-called silent pandemic, is pushing industry and academia to find novel antimicrobial agents with new mechanisms of action in order to be active against susceptible and drug-resistant microorganisms. In the case of tuberculosis, the need of novel anti-tuberculosis drugs is specially challenging because of the intricate biology of its causative agent, Mycobacterium tuberculosis. The repurposing of medicines has arisen in recent years as a fast, low-cost, and efficient strategy to identify novel biomedical applications for already approved drugs. This review is focused on anti-parasitic drugs that have additionally demonstrated certain levels of anti-tuberculosis activity; along with this, natural products with a dual activity against parasites and against M. tuberculosis are discussed. A few clinical trials have tested antiparasitic drugs in tuberculosis patients, and have revealed effective dose and toxicity issues, which is consistent with the natural differences between tuberculosis and parasitic infections. However, through medicinal chemistry approaches, derivatives of drugs with anti-parasitic activity have become successful drugs for use in tuberculosis therapy. In summary, even when the repurposing of anti-parasitic drugs for tuberculosis treatment does not seem to be an easy job, it deserves attention as a potential contributor to fuel the anti-tuberculosis drug pipeline.

Trombectomía mecánica primaria como tratamiento de la oclusión aguda de arterias intracerebrales / Primary mechanical thrombectomy for acute occlusions of cerebral arteries

La isquemia cerebral por oclusión de las arterias principales intracraneales causa una importante morbimortalidad. Nuevos dispositivos para la trombectomía mecánica permiten la extracción del trombo en un tiempo reducido. Se muestran los resultados de la trombectomía mecánica primaria sin el uso de fibrinolisis intravenosa utilizando el dispositivo Solitaire. Desde enero de 2010 hasta abril de 2013, 24 pacientes presentaron una oclusión de vasos intracerebrales principales y fueron tratados mediante trombectomía primaria. El tiempo de inicio de síntomas hasta la recanalización fue de 268 (11,3) min (rango: 143-486 min). La recanalización se consiguió en 19 pacientes (79,2%), con un tiempo punción-revascularización de 63,9 (35,5) min. El NIHSS (National Institute of Health Stroke Scale) al ingreso fue de 21 (7,5) (7-38). Un mRS (modified Rankin scale) inferior o igual a 2 al alta se observó en 15 pacientes (62,5%) y en 13 a los 3 meses. Tres pacientes (12,5%) fallecieron por hemorragia cerebral o infarto. Se concluye que aproximadamente dos de cada tres pacientes se beneficiaron de la extracción mecánica primaria con ninguna o mínima discapacidad al alta, después de un ictus isquémico de vasos principales y sin utilizar la fibrinolisis intravenosa (AU)

Cerebral ischemia due to occlusion of the principal intracranial arteries is a significant cause of morbidity and mortality. New devices for mechanical thrombectomy can facilitate rapid extraction of the thrombus. This paper describes the results of primary mechanical thrombectomy with the Solitaire revascularization device without intravenous fibrinolysis. From January 2010 to April 2013, 24 patients with occlusions of the main intracerebral arteries were treated by primary thrombectomy. The mean (SD) time elapsed from onset of symptoms until revascularization was 268 (11.3) minutes (range, 143-486 minutes). Revascularization was achieved in 19 patients (79.2%) within a punctureto-revascularization time of 63.9 (35.5) minutes. The mean score on the National Institute of Health Stroke Scale on admission was 21 (7.5) (range, 7-38). A score on the modified Rankin scale of 2 or lower was recorded for 15 patients (62.5%) on discharge and for 13 patients at 3 months. Three patients (12.5%) died from cerebral hemorrhage or infarct. It can be concluded that after ischemic stroke from occlusions of the main cerebral arteries, about 2 out of 3 of our patients benefited from primary mechanical extraction without intravenous fibrinolysis and had no or minimal disability on discharge (AU)

[Primary mechanical thrombectomy for acute occlusions of cerebral arteries]. / Trombectomía mecánica primaria como tratamiento de la oclusión aguda de arterias intracerebrales.

EN: Cerebral ischemia due to occlusion of the principal intracranial arteries is a significant cause of morbidity and mortality. New devices for mechanical thrombectomy can facilitate rapid extraction of the thrombus. This paper describes the results of primary mechanical thrombectomy with the Solitaire revascularization device without intravenous fibrinolysis. From January 2010 to April 2013, 24 patients with occlusions of the main intracerebral arteries were treated by primary thrombectomy. The mean (SD) time elapsed from onset of symptoms until revascularization was 268 (11.3) minutes (range, 143-486 minutes). Revascularization was achieved in 19 patients (79.2%) within a punctureto- revascularization time of 63.9 (35.5) minutes. The mean score on the National Institute of Health Stroke Scale on admission was 21 (7.5) (range, 7-38). A score on the modified Rankin scale of 2 or lower was recorded for 15 patients (62.5%) on discharge and for 13 patients at 3 months. Three patients (12.5%) died from cerebral hemorrhage or infarct. It can be concluded that after ischemic stroke from occlusions of the main cerebral arteries, about 2 out of 3 of our patients benefited from primary mechanical extraction without intravenous fibrinolysis and had no or minimal disability on discharge.

ES: La isquemia cerebral por oclusión de las arterias principales intracraneales causa una importante morbimortalidad. Nuevos dispositivos para la trombectomía mecánica permiten la extracción del trombo en un tiempo reducido. Se muestran los resultados de la trombectomía mecánica primaria sin el uso de fibrinolisis intravenosa utilizando el dispositivo Solitaire. Desde enero de 2010 hasta abril de 2013, 24 pacientes presentaron una oclusión de vasos intracerebrales principales y fueron tratados mediante trombectomía primaria. El tiempo de inicio de síntomas hasta la recanalización fue de 268 (11,3) min (rango: 143-486 min). La recanalización se consiguió en 19 pacientes (79,2%), con un tiempo punción-revascularización de 63,9 (35,5) min. El NIHSS (National Institute of Health Stroke Scale) al ingreso fue de 21 (7,5) (7-38). Un mRS (modified Rankin scale) inferior o igual a 2 al alta se observó en 15 pacientes (62,5%) y en 13 a los 3 meses. Tres pacientes (12,5%) fallecieron por hemorragia cerebral o infarto. Se concluye que aproximadamente dos de cada tres pacientes se beneficiaron de la extracción mecánica primaria con ninguna o mínima discapacidad al alta, después de un ictus isquémico de vasos principales y sin utilizar la fibrinolisis intravenosa.

Transmittance and optical constants of Ca films in the 4-1000 eV spectral range.

The low expected absorption of Ca in the extreme ultraviolet (EUV) makes it an attractive material for multilayers and filters because most materials in nature strongly absorb the EUV. Few optical constant data had been reported for Ca. In this research, Ca films of various thicknesses were deposited on grid-supported C films and their transmittance measured in situ from the visible to the soft x-rays. The measurement range contains M2,3 and L2,3 absorption edges. Transmittance measurements were used to obtain the Ca extinction coefficient k. A minimum k of 0.017 was obtained at ∼23 eV, which makes Ca a promising low-absorption material for EUV coatings. A second spectral range of interest for its low absorption is below the Ca L3 edge at ∼343 eV. Measured k data and extrapolations were used to calculate the refractive index n using Kramers-Krönig relations. This is the first self-consistent data set on Ca covering a wide spectral range including the EUV.

Self-consistent optical constants of sputter-deposited B4C thin films.

The optical constants of ion-beam-sputtered B4C films have been measured by ellipsometry in the 190-950 nm range. The set of data has been extended toward both shorter and longer wavelengths with data in the literature, along with interpolations and extrapolations, in order to obtain a self-consistent set of data by means of Kramers-Krönig analysis. All data correspond to films that were deposited by sputtering on nonheated substrates, and hence they are expected to be amorphous. The B4C bandgap was calculated as a fitting parameter of Tauc equations for indirect transitions using the present optical constants. Good global accuracy of the data was estimated through the use of various sum rules. The consistent data set includes the visible to the extreme UV (EUV); this large spectrum of characterization will enable the design of multilayer coatings that combine a relatively high reflectance in parts of the EUV with a desired performance at a secondary range, such as the visible.

Self-consistent optical constants of SiC thin films.

The optical constants of ion-beam-sputtered SiC films have been measured by ellipsometry in the 190 to 950 nm range. The set of data has been extended both toward shorter and longer wavelengths with data in the literature, along with inter- and extrapolations, in order to obtain a self-consistent set of data by means of Kramers-Krönig analysis. All data correspond to films that were deposited by sputtering on nonheated substrates, and hence they are expected to be amorphous. A bandgap of 1.9 eV for the films was fitted from the obtained optical constants. A good global accuracy of the data was estimated through the use of various sum rules. The consistent dataset includes the visible to the extreme ultraviolet (EUV); this large spectrum of characterization will enable the design of multilayer coatings that combine a high reflectance in parts of the EUV with desired performance at a secondary range, such as the visible. To our knowledge, this paper provides the first compilation of the optical constants of amorphous SiC films.

Transmittance and optical constants of erbium films in the 3.25-1580 eV spectral range.

The optical constants of erbium (Er) films were obtained in the 3.25-1580 eV range from transmittance measurements performed at room temperature. Thin films of Er were deposited by evaporation in ultra high vacuum conditions and their transmittance was measured in situ. Substrates consisted of a thin C film supported on a grid. Transmittance measurements were used to obtain the extinction coefficient k of the Er films. The refractive index n of Er was calculated using the Kramers-Krönig analysis. k data were extrapolated both on the high- and low-energy parts of the spectrum by using experimental data and calculated k values available in the literature. Er, similar to other lanthanides, has a low-absorption band below the O(2,3) edge onset; the smallest absorption was measured at ~22.5 eV. Therefore, Er is a promising material for filters and multilayer coatings in the energy range below the O(2,3) edge, in which materials typically have an absorption stronger than at other energies. Good consistency of the data resulted from the application of f and inertial sum rules.

In situ reflectance and optical constants of ion-beam-sputtered SiC films in the 58.4 to 149.2 nm region.

The reflectance of freshly deposited SiC thin films is measured in situ for what we believe is the first time. SiC was deposited by means of ion-beam sputtering. Reflectance was measured as a function of the incidence angle in the far and extreme ultraviolet wavelengths from 58.4 to 149.2 nm. In situ measurements allowed obtaining the intrinsic reflectance of SiC films, which is somewhat larger than what had been measured for samples exposed to the atmosphere. Reflectance measurements were used to determine the optical constants of the material in the same spectral range. We compare our data to those of the literature corresponding to SiC films deposited by different techniques and exposed to the atmosphere. In situ determined optical constants will allow a more accurate design of multilayers containing ion-beam-sputtered SiC layers.

Narrowband multilayer coatings for the extreme ultraviolet range of 50-92 nm.

A new type of multilayer coatings with narrowband reflection properties and peaked in the approximately 50- 92 nm spectral range has been developed. Multilayers are based on Yb, Al, and SiO films and they have been prepared by thermal evaporation. Efficient multilayers based on Yb and Al, with an SiO protective layer were prepared, but they developed a dendrite structure, which was attributed to the reactivity between Al and Yb. Multilayers based on Yb and Al, with both SiO protective and barrier layers, resulted in efficient reflective filters, with no observable dendrite growth. The peak reflectance of aged multilayers was of the order of approximately 0.20, with bandwidths in the range of 12 to 22 nm FWHM.

Electron-beam deposited boron coatings for the extreme ultraviolet.

Boron films deposited by evaporation with an electron-beam were found to have a relatively high reflectance in the extreme ultraviolet with values similar to those of ion-beam-sputtered (IBS) SiC and IBS B(4)C. The largest reflectance was measured for an 11 nm thick boron film. Some reflectance degradation was observed for boron films stored in a desiccator. Reflectance degradation varied from sample to sample and was found to be either similar to that of IBS SiC and IBS B(4)C or larger.

Optical constants of Yb films in the 23-1700 eV range.

The optical constants of Yb films have been determined in the 23-1700 eV spectral range from transmittance measurements performed in situ on Yb films deposited by evaporation in ultrahigh vacuum conditions. Yb films were deposited over grids coated with a thin carbon film. Transmittance measurements were used to obtain the extinction coefficient of Yb films at each individual photon energy investigated. The energy range investigated encompasses Yb edges from M(4,5) to O(2,3). The current results, along with data in the literature, show that Yb has an interesting low-absorption band in the approximately 12-24 eV range, which may be useful for the development of transmittance filters and multilayer coatings. The current data along with literature data and extrapolations were used to obtain n, the real part of the complex refractive index, using a Kramers-Krönig analysis. The application of the sum rules showed a good consistency of the results.

Optical constants of electron-beam evaporated boron films in the 6.8-900 eV photon energy range.

The optical constants of electron-beam evaporated boron from 6.8 to 900 eV were calculated through transmittance measurements of boron thin films deposited onto carbon-coated microgrids or LiF substrates in ultrahigh-vacuum conditions. In the low-energy part of the spectrum the measurements were performed in situ on freshly deposited samples, whereas in the high-energy range the samples were exposed to the atmosphere before the measurements. The extinction coefficient was calculated directly from the transmittance data, and a Kramers-Kronig analysis that combined the current data with data from the literature was performed to determine the dispersive part of the index of refraction. Finally, two different sum-rule tests were performed that indicated the good consistency of the data.

Vacuum ultraviolet coatings of Al protected with MgF(2) prepared both by ion-beam sputtering and by evaporation.

Ion-beam sputtering (IBS) and evaporation are the two deposition techniques that have been used to deposit coatings of Al protected with MgF(2) with high reflectance in the vacuum ultraviolet down to 115 nm. Evaporation deposited (ED) Al protected with IBS MgF(2) resulted in a larger (smaller) reflectance below (above) 125 nm than the well-known all-evaporated coatings. A similar comparison is obtained when the Al film is deposited by IBS instead of evaporation. The lower reflectance of the coatings protected with IBS versus ED MgF(2) above 125 nm is because of larger absorption of the former. Both nonprotected IBS Al, as well as IBS Al protected with ED MgF(2), resulted in a band of reflectance loss that was peaked at 127 and 157 nm, respectively. This result was attributed to the excitation of surface plasmons due to the enhancement of surface roughness with large spatial wave vectors in the sputter deposition. This reflectance loss for IBS Al protected with MgF(2) is small at the short (lambda~120 nm) and long (lambda<350 nm) wavelengths investigated. IBS Al protected with ED MgF(2) is thus a promising coating for these two spectral regions. Coatings protected with IBS MgF(2) resulted in a reflectance as high as coatings protected with ED MgF(2) at wavelengths longer than 550 nm, whereas the former had a lower reflectance below this wavelength.

Determination of optical constants of scandium films in the 20-1000 eV range.

The transmittance of thin films of Sc deposited by evaporation in ultrahigh vacuum conditions has been investigated in the 20-1000 eV spectral range. Transmittance measurements were performed in situ on Sc layers that were deposited over grids coated with a C support film. Transmittance measurements were used to obtain the extinction coefficient of Sc films at each individual photon energy investigated. These data, along with the data available in the literature for the rest of the spectrum, were used to obtain the refractive index of Sc by means of the Kramers-Krönig analysis. Sum-rule tests indicated an acceptable consistency of the data.

Optical properties of scandium films in the far and the extreme ultraviolet.

The optical properties of thin Sc films deposited in ultrahigh-vacuum conditions have been investigated in the 6.7-174.4-nm spectral range. We measured transmittance and multiangle reflectance in situ in the 53.6-174.4 nm spectral range and used these measurements to obtain the complex refractive index of a Sc film at every individual wavelength investigated. Transmittance measurements were made of Sc samples that were deposited over grids coated with a support C film. The transmittance and the extinction coefficient of Sc films at wavelengths shorter than 30 nm were measured ex situ. The ex situ samples were protected with an additional top C film before their removal from vacuum. To our knowledge, these are the first optical measurements of Sc films reported in the spectral ranges cited.

Optical properties of ytterbium films in the far and the extreme ultraviolet.

The optical properties of thin film of ytterbium in the 53.6-183.6-nm spectral range are described. Yb film were deposited in ultrahigh-vacuum conditians, and their transmittance and reflectance were measured in situ. Transmittance measurements showed that Yb has a certain window of lower absorption at approximately 54-100 nm, which makes Yb an interesting material for filters in this difficult spectral range. The optical constants were obtained from transmittance measurements and from multiangle reflectance measurements. These are what we believe are the first reported optical measurements of fresh Yb films at wavelengths shorter than 107.8 nm. Aging studies were performed both under vacuum and in a desiccator and showed that the optical properties of Yb are strongly modified on aging.

Optical properties and quantum efficiency of thin-film alkali halides in the far ultraviolet.

The optical constants of thin films of CsI, KI, and KBr and the quantum efficiency (QE) of planar photocathodes made with these alkali halides in the 53.6-174.4-nm spectral range are presented. The optical constants were obtained from measurements of the reflectance as a function of incidence angle. The effect of film heating and exposure to UV irradiation on the optical properties and on the QE of the three alkali halides was investigated. KBr was found to be the most stable material for both heating and UV irradiation. KI appeared to be close to temperature stable, whereas UV exposure affected its optical constants. CsI optical constants changed after 420 K heating and after UV exposure. The changes in the optical constants were related to the QE changes, and a certain correlation between both variations was determined. However, it was also demonstrated that the QE changes cannot be explained solely by the changes in optical constants.