Utility of the combination of hederagenin glucoside saponins and chromane hydrazone in the topical treatment of canine cutaneous leishmaniasis. An observational study.

Canine cutaneous leishmaniasis (CCL) is an emerging zoonotic infection endemic in several countries of the world. Due to variable response to therapy and frequency of relapses, a more effective, safer, and inexpensive treatment is needed. Recently, it was reported that the hederagenin glucoside saponins (SS) and chromane-derived hydrazone (TC2) combined in a 1:1 ratio has high potential in antileishmanial therapy since both compounds alter the survival of Leishmania and the ability to infect adjacent macrophage. Not only the skin permeation and the absorption of an ointment containing 2% TC2 and 2% SS (w/w) was determined in this work, but also the acute dermal toxicity in both in vitro and in vivo assays. Last, the effectiveness and safety of the topical therapy with 2% TC2-2% SS ointment was evaluated in an observational study in dogs with diagnosis of cutaneous leishmaniasis (CL). Both TC2 and SS diffused through pig ear skin and traces of TC2 (but not SS) were detected in the stratum corneum of mice at 6-24 h. Neither TC2 nor SS was detected in plasma. The acute dermal toxicity was negative. Treatment with 2% TC2-2% SS ointment produced a complete long-term clinical cure in 56 dogs (24 females and 32 males) from the Orinoco and Amazonas regions in southeastern Colombia without adverse effects. All dogs have remained disease-free for the last 24 months. In conclusion, these results support the use of this topical therapy as a safer and new first-line local treatment of CCL that could help limit the spread of CL from dogs to humans.

Inter-rater reliability of clinical mobility measures in ankylosing spondylitis.

BACKGROUND: Several measurements are often used in daily clinical practice in the assessment of Ankylosing Spondylitis (AS) patients. The Assessment in SpondyloArthiritis International Society (ASAS) recommend in its core set: chest expansion modified Schöber test, Occiput to wall distance, lateral lumbar flexion, cervical rotation and The Bath Ankylosing Spondylitis Metrology Index (BASMI). BASMI also includes five measurements, some of them recommended by ASAS. Three versions of BASMI have been published with different scales and intervals for each component of the index. Though studies about reliability of these measurements are needed. The aim of this study was to analyze inter-rater reliability of recommended spinal mobility measures in AS. METHODS: We examined reproducibility of spinal mobility measurements on 33 AS patients performed by two experienced rheumatologists in the same day. Descriptive statistics, Intraclass Correlation Coefficients (ICC), and Smallest Detectable Difference (SDD) using the Bland-Altman criteria were obtained for all the measurements. RESULTS: Chest expansion showed the lowest value of ICC (0.66) and occiput-wall the highest (0.97). SDD was 2.43 units for BASMI2 and 1.27 units for BASMI10. CONCLUSIONS: Reliability according to ICC was moderate to high in all measurements. BASMI10, instead BASMI2, must be used: measurements used to calculate are the same but there is better reliability. Inter-rater variation, expressed as SDD, must be taken in account: smaller improvements do not demonstrate the efficacy of treatment because they can be due to experimental error and not to the treatment itself.

The electronic structure of metal-molecule hybrids in charged interfaces: surface-enhanced Raman selection rules derived from plasmon-like resonances.

DFT calculations predict that plasmon-like excitations in small metal clusters are able to selectively modify the relative intensities of specific SERS bands of adsorbed molecules. These electronic resonances provide new kinds of SERS selection rules which can explain the huge enhancement of mode 9a of pyridine in the spectra recorded at negative electrode potentials.

Single-stage treatment with intraoperative ERCP: management of patients with possible choledocholithiasis and gallbladder in situ in a non-tertiary Spanish hospital.

BACKGROUND: The best way to reduce endoscopic retrograde cholangiopancreatography (ERCP) complications is not to perform it if it is unnecessary. Both intraoperative and postoperative ERCP rely on use of intraoperative cholangiography as a final diagnostic test for choledocholithiasis (CLD) whenever clinical data are unable to rule out CLD. Intraoperative ERCP could become a therapeutic option when a previous preoperative ERCP fails. We present our experience with intraoperative ERCP. PATIENTS AND METHODS: This is a descriptive and prospective study of a cohort of 82 patients with moderate risk of CLD. They were operated on by laparoscopic cholecystectomy with intraoperative cholangiography (IOC). We performed intraoperative ERCP using the rendezvous technique. RESULTS: Thirty-six out of 82 patients had an abnormal IOC study. Mean age was 58.7 years (standard deviation, SD 16.6, 25-83 years), and 60.6% were females. Ultrasound study showed that 51.4% of patients had a dilated bile duct. Magnetic resonance cholangiography (MRC) was performed on three patients (8.3%). The success rate of intraoperative ERCP was 88.2%. Three out of the 36 patients (8.8%) had ERCP complications [2 mild papillary bleeding (5.8%), 1 acute pancreatitis (2.9%)]. The rate of conversion to open surgery was 5% with a surgical complications rate of 4% [one injured duct and two surgical bleeding which required re-operation (2.5%)]. There were no mortalities. Four patients (11.1%) needed post-surgical ERCP, with a residual CLD rate of 5.6% (two patients) in the postoperative period. Mean surgical time was 181 min (SD 60, 75-345 min). Mean hospital stay was 6.2 days (SD 4.7, 2-24 days). CONCLUSIONS: Intraoperative ERCP is an option to prevent performing ERCP unnecessarily on patients with moderate risk of CLD not confirmed using appropriate radiological studies. It can resolve the biliary disease in a single step with a similar success rate to standard ERCP, but with low morbidity, especially of acute pancreatitis. The residual CLD rate is also very low.

Online Signature Verification Based on Generative Models.

The success of generative models for online signature verification has motivated many research works on this topic. These systems may use hidden Markov models (HMMs) in two different modes: user-specific HMM (US-HMM) and user-adapted universal background models (UBMs) (UA-UBMs). Verification scores can be obtained from likelihood ratios and a distance measure on the Viterbi decoded state sequences. This paper analyzes several factors that can modify the behavior of these systems and which have not been deeply studied yet. First, we study the influence of the feature set choice, paying special attention to the role of dynamic information order, suitability of feature sets on each kind of generative model-based system, and the importance of inclination angles and pressure. Moreover, this analysis is also extended to the influence of the HMM complexity in the performance of the different approaches. For this study, a set of experiments is performed on the publicly available MCYT-100 database using only skilled forgeries. These experiments provide interesting outcomes. First, the Viterbi path evidences a notable stability for most of the feature sets and systems. Second, in the case of US-HMM systems, likelihood evidence obtains better results when lowest order dynamics are included in the feature set, while likelihood ratio obtains better results in UA-UBM systems when lowest dynamics are not included in the feature set. Finally, US-HMM and UA-UBM systems can be used together for improved verification performance by fusing at the score level the Viterbi path information from the US-HMM system and the likelihood ratio evidence from the UA-UBM system. Additional comparisons to other state-of-the-art systems, from the ESRA 2011 signature evaluation contest, are also reported, reinforcing the high performance of the systems and the generality of the experimental results described in this paper.

Chromone-3-carboxylic acid as a potential electron scavenger: a surface-enhanced Raman scattering study.

A SERS study of chromone 3-carboxylic acid adsorbed on silver colloids was undertaken, in order to assess the ability of this compound to accept electrons in charge transfer (CT) processes. Theoretical SERS intensities under photoinduced CT resonant conditions have been carried out for both the neutral and the deprotonated species allowing to conclude, by comparison with the experimental data, that the recorded SER corresponds to the anionic form of the acid linked to the metal. It was shown that the SERS-CT mechanism predominates for this particular compound, thus explaining the strong enhancement of the band at ca. 1600 cm(-1) assigned to the 8a ring stretching mode. The identification of CT processes is of the utmost importance for understanding the mechanism through which these benzopyranes may act as antioxidants.

Stratum corneum is an effective barrier to TiO2 and ZnO nanoparticle percutaneous absorption.

BACKGROUND: There is increasing concern over the local and systemic side effects of TiO(2) and ZnO coated nanoparticles widely used in sun blockers. OBJECTIVE: To determine the localization and possible skin penetration of TiO(2) and ZnO nanoparticles, dispersed in 3 sunscreen formulations, under realistic in vivo conditions in normal and altered skin. METHODS: Nuclear microscopy techniques provided spatially resolved quantitative analysis of Ti and Zn nanoparticle distributions in transversal cryosections of skin obtained by biopsy with no further treatment. A test hydrophobic formulation containing coated 20-nm TiO(2) nanoparticles and 2 commercial sunscreen formulations containing TiO(2) alone or in combination with ZnO were tried, taking into account realistic use conditions by consumers and compared with the recommended standard condition for the sun protection factor test. The protocols consisted of an open test. RESULTS: Following a 2-hour exposure period of normal human skin to TiO(2)- and ZnO-containing sunscreens, detectable amounts of these physical blockers were only present at the skin surface and in the uppermost stratum corneum regions. Layers deeper than the stratum corneum were devoid of TiO(2) or exogenous ZnO, even after 48 h of exposure to the sunscreen, under occlusion. Deposition of TiO(2) and ZnO nanoparticles in the openings of the pilosebaceous follicles was also observed, suggesting a preferential fixation area. Penetration of nanoparticles into viable skin tissue could not be detected. CONCLUSIONS: TiO(2) or ZnO nanoparticles are absent or their levels are too low to be tested under the stratum corneum in human viable epidermal layers. Therefore, significant penetration towards the underlying keratinocytes is unlikely.

Should we consider a 'fourth 90' for tuberculosis?

The international community has committed to end the tuberculosis (TB) epidemic by 2030. To facilitate the meeting of the global incidence and mortality indicators set by the World Health Organization's End TB Strategy, the Stop TB Partnership launched the three 90-(90)-90 diagnostic and treatment targets in 2014. In this paper, we argue that a 'fourth 90'-Ensuring that 90% of all people successfully completing treatment for TB can have a good health-related quality of life'-should be considered. Many individuals who successfully complete anti-TB treatment are burdened with lifelong comorbidities-human immunodeficiency virus (HIV) and diabetes mellitus, obstructive and restrictive lung disease, involving lung destruction, cavitation, fibrosis and bronchiectasis, that either pre-existed or developed as a result of TB (e.g., chronic pulmonary aspergillosis), permanent disabilities such as hearing loss resulting from second-line anti-TB drugs, and mental health disorders. These need to be identified during TB treatment and appropriate care and support provided after anti-TB treatment is successfully completed. A 'fourth 90' has also been proposed for the UNAIDS 90-90-90 targets similar in scope to what is being suggested here for TB. Adoption by both HIV and TB control programmes would highlight the current focus on integrated person- and family-centred services.

Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

Design and evaluation of a new three-dimensional motion capture system based on video.

This technical note describes the development and evaluation of a low-cost motion capture and analysis system (SOMCAM3D). From diverse video sequences obtained by commercial cameras, synchronized by a certain event, and calibrated from a calibration process, the system is able to reconstruct three-dimensional positions in a reference system defined by the calibration process. From these positions, a wide variety of kinematic variables could be calculated. This system aims to analyze movement in applications of gait analysis, sports, animals, ergonomics, robotics, etc. It is designed to work with low-cost equipment (commercial cameras, computers, etc.). Also it allows us to work in 2D, outdoors, and without marks. Finally, this technical note includes a study of how precise and accurate this system is.

Successfully treated but not fit for purpose: paying attention to chronic lung impairment after TB treatment.

In 2013, 86% of patients with newly diagnosed tuberculosis (TB) successfully completed treatment and were discharged from care. However, long-term studies in industrialised and resource-poor countries all point to a higher risk of death in TB survivors than in the general population. The likely explanation is chronic restrictive and obstructive lung disease consequent to TB. We call for better linkages between TB control programmes and respiratory medicine services, a better understanding of the burden of respiratory disability at the end of anti-tuberculosis treatment, and political, programmatic, clinical and research action to improve the quality of life of affected patients.

Statistical and prognostic analysis of dynamic changes of platelet count in ICU patients.

Laboratory tests are a primary resource to diagnose patient's diseases. However, physicians often make decisions based on the available information, which commonly includes the last test results as a static picture and have limited perspective of the role of trends in commonly measured parameters in enhancing the diagnostic process. By providing a dynamic patient profile the diagnosis could be more accurate and, as a consequence, physicians could anticipate changes in recovery trajectory and prescribe interventions more effectively. Intensive care unit (ICU) patients need continuous monitoring, which commonly includes the assessment of several blood components. One of these components is the platelet count which is used in assessing blood clotting. However, platelet counts represent a dynamic equilibrium of many simultaneous processes including altered capillary permeability, inflammatory cascades, as well as the coagulation process. To characterize the value of dynamic changes in platelet counts we applied analytic methods to datasets of critically ill patients in (i) a homogeneous population of ICU cardiac surgery patients, where an observation appears to be predictive of patient's complications and mortality and (ii) a heterogeneous group of ICU patients to confirm the previous observation.

N-Arylsulfonylindole derivatives as serotonin 5-HT(6) receptor ligands.

A series of N(1)-arylsulfonyltryptamines were found to be potent ligands of the human serotonin 5-HT(6) receptor with the 5-methoxy-1-benzenesulfonyl analogue (19) having the highest affinity. Additionally, it was discovered that a group such as 3-(3-methoxybenzyl)-1,2,4-oxadiazol-5-yl in the 2-position of the indole ring (43) can replace the arylsulfonyl substituent in the 1-position with no loss of affinity. This suggested that the binding conformation of the aminoethyl side chain at this receptor was toward the 4-position of the indole ring and was supported by the fact that the 4-(aminoethyl)indoles (45) also displayed high affinity, as did the conformationally rigid 1,3,4,5-tetrahydrobenz[c,d]indole (49). Molecular modeling showed that 19, 43, and 45 all had low-energy conformers that overlaid well onto 49. Both 19 and 49 had good selectivity over other serotonin receptors tested, with 49 also showing excellent selectivity over all dopamine receptors. In a functional adenylate cyclase stimulation assay, 19 and 49 had no agonist activity, whereas 45 behaved as a partial agonist. Finally, it was shown that 19 had good activity in the 5-HT(2A) centrally mediated mescaline-induced head twitch assay, which implies that it is brain-penetrant.

Synthesis and serotonergic activity of 5-(oxadiazolyl)tryptamines: potent agonists for 5-HT1D receptors.

The synthesis and 5-HT1D receptor activity of a novel series of 5-(oxadiazolyl)tryptamines is described. Modifications of the oxadiazole 3-substituent, length of the linking chain (n), and the amine substituents are explored and reveal a large binding pocket in the 5-HT1D receptor domain. Oxadiazole substituents such as benzyl are accommodated without loss of agonist potency or efficacy. The incorporation of polar functionality on a phenyl or benzyl spacer group results in a 10-fold increase in affinity and functional potency. Optimal 5-HT1D activity is observed when the heterocycle is conjugated with the indole and the benzyl sulfonamides 20t and 20u represent some of the most potent 5-HT1D agonists known. Replacement of O for S in the heterocycle leads to a further increase in potency. Deletion of oxadiazole N-2 does not reduce activity, suggesting the requirement for only one H-bond acceptor in this location. The selectivity of these compounds for 5-HT1D receptors over other serotonergic receptors is discussed. Sulfonamide 20t shows > or = 1000-fold selectivity for 5-HT1D over 5-HT2, 5-HT1C, and 5-HT3 receptors and 10-fold selectivity with respect to 5-HT1A receptors. The functional activity of this series of compounds is studied and demonstrates high 5-HT1D receptor potency and efficacy comparable to that of 5-HT.

Synthesis and biological activity of 3-[2-(dimethylamino)ethyl]-5-[(1,1-dioxo-5-methyl-1,2,5-thiadiazolidin- 2-yl)-methyl]-1H-indole and analogues: agonists for the 5-HT1D receptor.

A novel series of 5-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)tryptamines was designed, synthesized, and evaluated as 5-HT1D receptor agonists. Compounds such as 8d,f,k were identified which had comparable affinity, potency, and receptor selectivity to that of the antimigraine drug sumatriptan. Both 8d,k were found to be well absorbed in the rat with oral bioavailabilities of 66% and 62%, respectively. Additionally, 8d was found to be selective over other non-serotonergic receptors and exhibited relatively low central nervous system penetration.

5-(Piperidin-2-yl)- and 5-(homopiperidin-2-yl)-1,4-benzodiazepines: high-affinity, basic ligands for the cholecystokinin-B receptor.

The design, synthesis, and biological activity of a series of high-affinity, basic ligands for the cholecystokinin-B receptor are described. The compounds, which incorporate a piperidin-2-yl or a homopiperidin-2-yl group attached to C5 of a benzodiazepine core structure, are substantially more basic (e.g., 9d, pKa = 9.48) than previously reported antagonists based on 5-amino-1,4-benzodiazepines (e.g., 5, pKa = 7.1) and have improved aqueous solubility. In view of their basicity, it would be tempting to speculate that the present series of compounds might be binding to the CCK-B receptor in their protonated form. Compounds such as 9d, e and 10d showed high affinity for this receptor (IC50 < 2.5 nM) and very good selectivity over CCK-A (CCK-A/CCK-B > 2000), even as the racemates. Additionally, a significantly improved in vivo half-life was observed for a selection of compounds compared to the clinical candidate L-365, -260 (1).

3-[3-(Piperidin-1-yl)propyl]indoles as highly selective h5-HT(1D) receptor agonists.

Several 5-HT(1D/1B) receptor agonists are now entering the marketplace as treatments for migraine. This paper describes the development of selective h5-HT(1D) receptor agonists as potential antimigraine agents which may produce fewer side effects. A series of 3-[3-(piperidin-1-yl)propyl]indoles has been synthesized which has led to the identification of 80 (L-772,405), a high-affinity h5-HT(1D) receptor full agonist having 170-fold selectivity for h5-HT(1D) receptors over h5-HT(1B) receptors. L-772,405 also shows very good selectivity over a range of other serotonin and nonserotonin receptors and has excellent bioavailability following subcutaneous administration in rats. It therefore constitutes a valuable tool to delineate the role of h5-HT(1D) receptors in migraine. Molecular modeling and physical properties have been utilized to postulate the binding conformation of these compounds in the receptor cavity.

Controlled modification of acidity in cholecystokinin B receptor antagonists: N-(1,4-benzodiazepin-3-yl)-N'-[3-(tetrazol-5-ylamino) phenyl]ureas.

The design, synthesis, and biological activity of a novel series of CCK-B receptor antagonists (1) which incorporate a tetrazol-5-ylamino functionality attached to the phenyl ring of the arylurea moiety of L-365,260 are described. In these compounds, the acidity of the tetrazole was gradually modified by utilization of simple conformational constraints, and X-ray crystallographic data were obtained to support the conformational depenence of the pK(a) of the aminotetrazoles. Compounds to emerge from the present work such as 1f and 2c,d are among the highest affinity and, in the case of 1f, most selective (CCK-A/CCK-B, 37 000) antagonists so far reported for this receptor. The C(5)-cyclohexyl compound 2c (L-736,380) dose-dependently inhibited gastric acid secretion in anesthetized rats (ID(50), 0.064 mg/kg) and ex vivo binding of [(125)I]CCK-8S in BKTO mice brain membranes (ED(50), 1.7 mg/kg) and is one of the most potent acidic CCK-B receptor antagonists yet described.

3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT(2A) receptor antagonists.

The development of very high affinity, selective, and bioavailable h5-HT(2A) receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT(2A) receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pK(a) of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT(2A) receptors, with bioavailability of 80% and half-life of 12 h in rats.