Structure-Based Drug Discovery with Deep Learning.

Artificial intelligence (AI) in the form of deep learning has promise for drug discovery and chemical biology, for example, to predict protein structure and molecular bioactivity, plan organic synthesis, and design molecules de novo. While most of the deep learning efforts in drug discovery have focused on ligand-based approaches, structure-based drug discovery has the potential to tackle unsolved challenges, such as affinity prediction for unexplored protein targets, binding-mechanism elucidation, and the rationalization of related chemical kinetic properties. Advances in deep-learning methodologies and the availability of accurate predictions for protein tertiary structure advocate for a renaissance in structure-based approaches for drug discovery guided by AI. This review summarizes the most prominent algorithmic concepts in structure-based deep learning for drug discovery, and forecasts opportunities, applications, and challenges ahead.

Epidemiological time-trend of amyotrophic lateral sclerosis (ALS) over two decades: The French population-based register of ALS in Limousin (FRALim register).

INTRODUCTION: Population-based registers are key to understanding disease patterns. Taking advantage of the long-standing operation of the French register of amyotrophic lateral sclerosis (ALS) in Limousin (FRALim register), we sought to determine the time trends in incidence, clinical features and survival of ALS patients from 2000 to 2020. METHODS: FRALim register included incident cases through multiple sources of ascertainment. A capture-recapture method was used to assess the exhaustiveness of case ascertainment. Crude and standardized incidences were calculated per 100,000 person-years of follow-up (PYFU). Time-period was divided (period 2000 to 2010 and period 2011 to 2020) to compare incidence rates and clinical features. Survival was analyzed using Kaplan-Meier method. Cox proportional hazards model was performed to calculate hazards for the time periods. RESULTS: Overall, 501 incident cases were identified during 21 years. The overall crude incidence was 3.26 (95% CI 2.97 to 3.55) per 100 000 PYFU. The exhaustiveness of the register was estimated at 98.8% (95% CI 97.4-99.6%) by capture-recapture analysis. Several fluctuations were observed without a consistent trend over the last two decades. The crude and standardized incidences were higher in males than females. The peak of incidence was observed in the 75-79 years age band. Almost one-third of the cases exhibited a bulbar onset. There were significant differences in clinical features between time periods. Four hundred and ninety-one cases were included in the survival analysis. The median survival time from diagnosis was 16.0 months (95% CI 14.3 to 17.7 months). Patients in the last decade experienced a lower risk of dying but the difference did not reach statistical significance (adjusted HR: 0.89 (95% CI 0.73 to 1.08, P=0.229). CONCLUSION: We provided reliable epidemiological data over two decades. We showed that incidence has been relatively stable, while clinical variability was observed. A slight improvement in survival time was found in the last decade but it was not statistically significant. Further quality register data are needed to improve our understanding of ALS epidemiological trends.

Trace element adsorption from acid mine drainage and mine residues on nanometric hydroxyapatite.

Mining Ag, Cu, Pb, and Zn sulfides by flotation produces great volume of residues, which oxidized through time and release acid solutions. Leachates from tailing heaps are a concern due to the risk of surface water pollution. Hydroxyapatite nanoparticles may remove trace elements from acid leachate collected from an oxidized tailing heap (pH ranged 1.69 ± 0.3 to 2.23 ± 0.16; [SO42-] = 58 ± 0.67 to 60.69 ± 0.39 mmol). Based on the batch experiments under standard conditions, the average removal efficiency was 96%, 92%, 86%, and 67% for Cd, Pb, Zn, and Cu, respectively. The Zn adsorption was modeled by the Freundlich equation, but Cd, Cu, and Pb isotherms do not fit to Freundlich nor Lagmuir equations. Adsorption and other mechanisms occur during trace elements removal by hydroxyapatite. In the polymetallic system, trace elements saturate the specific surface of hydroxyapatite in the following order Zn, Cd, Cu, and Pb. The pH values must be higher than 7.5 to adsorb trace elements. The dose of 3.8% of hydroxyapatite to acid mine drainage removed efficiently > 80% of the soluble Fe, Cu, Mn, Zn, Cd, Ni, and Pb: 4020.0, 37.3, 34.8, 432.0, 4.4, 0.7, and 0.11 mg L-1 from leachate A and 3357.1, 46.6, 27.8, 569.0, 4.7, 0.6, and 1.7 from leachate B, respectively. The application of 0.7% of hydroxyapatite decreased the extractable Pb in unoxidized tailing heaps from 272 to 100 mg kg-1. It is likely to use hydroxyapatite to control trace element mobility from mine residues to surrounding soils and surface water.

Quantitative phase retrieval with low photon counts using an energy resolving quantum detector.

X-ray phase contrast imaging (PCI) combined with phase retrieval has the potential to improve soft-material visibility and discrimination. This work examined the accuracy, image quality gains, and robustness of a spectral phase retrieval method proposed by our group. Spectroscopic PCI measurements of a physical phantom were obtained using state-of-the-art photon-counting detectors in combination with a polychromatic x-ray source. The phantom consisted of four poorly attenuating materials. Excellent accuracy was demonstrated in simultaneously retrieving the complete refractive properties (photoelectric absorption, attenuation, and phase) of these materials. Approximately 10 times higher SNR was achieved in retrieved images compared to the original PCI intensity image. These gains are also shown to be robust against increasing quantum noise, even for acquisition times as low as 1 s with a low-flux microfocus x-ray tube (average counts of 250 photons/pixels). We expect that this spectral phase retrieval method, adaptable to several PCI geometries, will allow significant dose reduction and improved material discrimination in clinical and industrial x-ray imaging applications.

Phenotypic variability in amyotrophic lateral sclerosis.

Clinically, ALS phenotypes depend on the areas of the body that are affected, the different degrees of involvement of upper and lower motor neurons, the degrees of involvement of other systems, particularly cognition and behavior, and rates of progression. Phenotypic variability of ALS is characteristic and can be declined on the distribution of motor manifestations but also on the presence of extra-motor signs present in a variable manner in ALS patients. Neuropathologically, ALS is defined by the loss of UMN and LMN and the presence of two representative motor neuronal cytoplasmic inclusions, Bunina bodies and 43kDa Transactivation Response DNA Binding Protein (TDP-43) - positive cytoplasmic inclusions. The distribution of cytopathology and neuronal loss in patients is variable and this variability is directly related to phenotypic variability. Key regulators of phenotypic variability in ALS have not been determined. The functional decrement of TDP-43, and region-specific neuronal susceptibility to ALS, may be involved. Due to the selective vulnerability among different neuronal systems, lesions are multicentric, region-oriented, and progress at different rates. They may vary from patient to patient, which may be linked to the clinicopathological variability across patients.

Asymmetrical influence of a standard light/dark cycle and constant light conditions on the alanyl-aminopeptidase activity of the left and right retinas in adult male rats.

The retina acts as an independent clock informing the central pacemaker, the suprachiasmatic nucleus, under environmental light conditions, with consequences of such inputs for the central and peripheral nervous system. Differences in the behavior of the left and right retinas depending on environmental light conditions may influence the information projected to the brain hemispheres. The retina possesses neuropeptides that act as neurotransmitters or neuromodulators. Alanyl-aminopeptidase (AlaAP, EC 3.4.11.2) activity regulates some of these neuropeptides and therefore reflects their function. We analyzed AlaAP activity in the left and right retinas of adult male rats at successive time points under standard (12/12 h light/dark cycle) and nonstandard (constant light) conditions. AlaAP activity was measured fluorometrically using alanyl-beta-naphthylamide as the substrate. Under standard conditions, there were no differences in the left or right retina between time points, with the left retina predominating, particularly in the light period. In contrast, under constant light, no left versus right differences were observed, but significant differences between time points appeared. In comparison with standard conditions, constant conditions led to significantly higher AlaAP activity. Considering all the left retina data in comparison with all the right retina data, no correlation was found between the left and right retinas under standard conditions, but a significant positive correlation was observed under constant light. These results demonstrate an asymmetrical response of retinal AlaAP activity to changes in environmental light conditions, which may affect the functions in which the substrates of AlaAP are involved and the information projected to the brain hemispheres.

[Neurological complications in critical patients with COVID-19]. / Complicaciones neurológicas en pacientes críticos por SARS-CoV-2.

Introduction: We analysed the neurological complications of patients with severe SARS-CoV-2 infection who required intensive care unit (ICU) admission. Patients and methods: We conducted a retrospective, observational, descriptive study of consecutive patients admitted to the ICU due to severe respiratory symptoms secondary to SARS-CoV-2 infection between 1 April and 1 June 2020. Results: We included 30 patients with neurological symptoms; 21 were men (72.40%), and mean age (standard deviation [SD]) was 57.41 years (11.61). The mean duration of ICU stay was 18.83 days (14.33). The neurological conditions recorded were acute confusional syndrome in 28 patients (93.33%), neuromuscular disease in 15 (50%), headache in 5 (16.66%), cerebrovascular disease in 4 (13.33%), and encephalopathies/encephalitis in 4 (13.33%). CSF analysis results were normal in 6 patients (20%). Brain MRI or head CT showed alterations in 20 patients (66.6%). EEG was performed in all patients (100%), with 8 (26.66%) showing abnormal findings. In 5 of the 15 patients with clinical myopathy, diagnosis was confirmed with electroneuromyography. We found a correlation between older age and duration of ICU stay (P = .002; 95% CI: 4.032-6.022; OR: 3,594). Conclusions: Severe COVID-19 mainly affects men, as observed in other series. Half of our patients presented acute myopathy, and almost all patients left the ICU with acute confusional syndrome, which fully resolved; no correlation was found with EEG or neuroimaging findings. Older age is associated with longer ICU stay.

Equine blastocyst production under different incubation temperatures and different CO2 concentrations during early cleavage.

Some basic parameters for equine invitro embryo production have not yet been established, including the optimum temperature for maturation and embryo culture, and the optimum CO2 concentration and pH during early embryo development. To explore this, we first performed cultures in incubators set at 37.2°C, 37.7°C or 38.2°C. At these temperatures, the corresponding maturation rates were 33%, 38% and 42%; cleavage rates were 84%, 86% and 88%; and blastocyst rates were 35%, 44% and 44% per injected oocyte. These rates did not differ significantly (P>0.2). We then evaluated three different CO2 concentrations (6%, 6.5% or 7% CO2) in 5% O2 for culture over Days 0-5 after intracytoplasmic sperm injection, using a commercial human embryo medium with added serum, at 38.2°C. The pH values of these media were 7.36, 7.33 and 7.29 respectively. In the presence of 6%, 6.5% or 7% CO2, cleavage rates were 68%, 80% and 70% respectively, and blastocyst rates per injected oocyte were 42%, 54% and 27% respectively. The blastocyst rate for the 7% CO2 treatment was significantly lower than that for the 6.5% CO2 treatment (P<0.05). We conclude that equine invitro embryo production is equally effective within the range of 37.2-38.2°C, but that equine early cleavage stage development is sensitive to small changes in CO2 atmosphere and/or medium pH.

Intrafollicular oocyte transfer in the horse: effect of autologous vs. allogeneic transfer and time of administration of ovulatory stimulus before transfer.

PURPOSE: To assess meiotic and developmental competence after transfer of immature cumulus-oocyte complexes (COCs) to the preovulatory follicles of mares (intrafollicular oocyte transfer (IFOT)). METHODS: In Experiment 1, mares received an ovulatory stimulus at IFOT. Thirty hours later, COCs were recovered from the follicle, and mature oocytes underwent ICSI and embryo culture. In Experiments 2 and 3, autologous vs. allogeneic COCs were used. The mares were inseminated and embryos were recovered. In Experiment 3, the ovulatory stimulus was administered 9 h (autologous) and 15 h (allogeneic) before IFOT. In Experiment 4, only allogeneic COCs were used; the ovulatory stimulus was administered 9 or 15 h before IFOT. Excess embryos (autologous) and parentage-verified embryos (allogeneic) were considered IFOT-derived. RESULTS: In Experiment 1, 36/54 IFOT oocytes (67%) were recovered, of which 56% were mature, vs. 49% of in vitro matured oocytes (P > 0.1). After ICSI, blastocyst rates were 25% and 18%, respectively (P > 0.1). In Experiment 2, 0/6 autologous and 2/6 allogeneic IFOT yielded IFOT-derived embryos. In Experiment 3, 0/7 autologous and 2/5 allogeneic IFOT yielded IFOT-derived embryos. The proportion of mares yielding IFOT-derived embryos was lower after autologous vs. allogeneic IFOT (0/13 vs. 4/11; P < 0.05). In Experiment 4, 1/8 9-h and 1/7 15-h IFOT yielded IFOT-derived embryos. CONCLUSIONS: Transferred oocytes mature within the follicle and can maintain developmental competence. Allogeneic IFOT was more efficient than was autologous IFOT. The time of ovulatory stimulation did not affect embryo yield. The IFOT procedure is still not repeatable enough to be recommended for clinical use.

Electromagnetic behavior of dielectric objects on metallic periodically nanostructured substrates.

In this research, we investigate the electromagnetic behavior of a metallic thin-film with a periodic array of subwavelength apertures when dielectric objects are located on it. The influence of size, geometry and optical properties of the objects on the transmission spectra is numerically analyzed. We study the sensitivity of this system to changes in the refractive index of the illuminated volume induced by the presence of objects with sizes from hundreds of nanometers (submicron-sized objects) to a few microns (micron-sized objects). Parameters such as the object volume within the penetration depth of the surface plasmon in the buffer medium or the contact surface between the object and the nanostructured substrate strongly affect the sensitivity. The proposed system models the presence of objects and their detection through the spectral shifts undergone by the transmission spectra. Also, we demonstrate that these can be used for obtaining information about the refractive index of a micron-sized object immersed in a buffer and located on the nanostructured sensitive surface. We believe that results found in this study can help biomedical researchers and experimentalists in the process of detecting and monitoring biological organisms of large sizes (notably, cells).

The reactivation time in the treatment of AMD: a forgotten key parameter?

OBJECTIVE: Summarize and compare the available evidence on the reactivation times in patients with age-related macular degeneration treated with Ranibizumab (RNB). METHOD: Systematic review of studies that reported the reactivation time of patients (direct method) or the number of injections received in a certain period of follow-up (indirect method). RESULTS: Only 18 of 89 selected studies reported the average reactivation time of patients in a manifest form, without the need of any calculation. The average calculated, weighted reactivation time was 101.8 days with the direct method and 99.8 days in the indirect method (84 studies included). With both methods, it was found that the average reactivation time of the RCTs was between 2 and 3 weeks less than the average time identified in the observational studies. These differences are also reflected in the clinical results, there being a correlation between the number of doses received and the change in BCVA. The analysis of 11 comparative studies showed a difference in reactivation times between patients treated with RNB or Bevacizumab (BVZ). CONCLUSION: There are few direct studies of reactivation time, but calculation from the PRN dose number turns out to be a good approximation for retrospective study of the variable. The use of the PRN, with criteria not based on optical coherence tomography scans, delays the application of doses between 2 or 3 weeks, and patients suffer loss of clinical benefits. RNB enables patients to receive less injections than BVZ throughout treatment.

Toxicity assessment of cobalt ferrite nanoparticles on wheat plants.

Cobalt ferrite nanoparticles (NPs) have received increasing attention due to their widespread therapeutic and agricultural applicability. In the environmental field, dry powder- and ferrofluid-suspended cobalt ferrite NPs were found to be useful for removing heavy metals and metalloids from water, while diluted suspensions of cobalt ferrite NP have been promisingly applied in medicine. However, the potential toxicological implications of widespread exposure are still unknown. Since cobalt ferrite NPs are considered residual wastes of environmental or medical applications, plants may serve as a point-of-entry for engineered nanomaterials as a result of consumption of these plants. Thus, the aim of this study was to assess the effects of dry powder and fresh cobalt ferrite NP on wheat plants. Seven-day assays were conducted, using quartz sand as the plant growth substrate. The toxicity end points measured were seed germination, root and shoot lengths, total cobalt (Co) and iron (Fe) accumulation, photosynthetic pigment production, protein (PRT) production, and activities of catalase (CAT), ascorbate peroxidase (APX), and guaiacol peroxidase (GPX). Increasing total Co and Fe in plant tissues indicated that wheat plants were exposed to cobalt ferrite NP. Seed germination and shoot length were not sufficiently sensitive toxicity end points. The effective concentration (EC50) that diminished root length of plants by 50% was 1963 mg/kg for fresh ferrite NPs and 5023 mg/kg for powder ferrite NP. Hence, fresh ferrite NPs were more toxic than powder NP. Plant stress was indicated by a significant decrease in photosynthetic pigments. CAT, APX, and GPX antioxidant enzymatic activity suggested the generation of reactive oxygen species and oxidative damage induced by cobalt ferrite NP. More studies are thus necessary to determine whether the benefits of using these NPs outweigh the risks.

Lower blastocyst quality after conventional vs. Piezo ICSI in the horse reflects delayed sperm component remodeling and oocyte activation.

PURPOSE: The aim of this study was to evaluate the differential effects of conventional and Piezo-driven ICSI on blastocyst development, and on sperm component remodeling and oocyte activation, in an equine model. METHODS: In vitro-matured equine oocytes underwent conventional (Conv) or Piezo ICSI, the latter utilizing fluorocarbon ballast. Blastocyst development was compared between treatments to validate the model. Then, oocytes were fixed at 0, 6, or 18 h after injection, and stained for the sperm tail, acrosome, oocyte cortical granules, and chromatin. These parameters were compared between injection techniques and between sham-injected and sperm-injected oocytes among time periods. RESULTS: Blastocyst rates were 39 and 40%. The nucleus number was lower, and the nuclear fragmentation rate was higher, in blastocysts produced by Conv. Cortical granule loss started at 0H after both sperm and sham injection. The acrosome was present at 0H in both ICSI treatments, and persisted to 18H in significantly more Conv than Piezo oocytes (72 vs. 21%). Sperm head area was unchanged at 6H in Conv but significantly increased at this time in Piezo; correspondingly, at 6H significantly more Conv than Piezo oocytes remained at MII (80 vs. 9.5%). Sham injection did not induce significant meiotic resumption. CONCLUSIONS: These data show that Piezo ICSI is associated with more rapid sperm component remodeling and oocyte meiotic resumption after sperm injection than is conventional ICSI, and with higher embryo quality at the blastocyst stage. This suggests that there is value in exploring the Piezo technique, utilized with a non-toxic fluorocarbon ballast, for use in clinical human ICSI.

Evaluation of teratogenicity and genotoxicity induced by kramecyne (KACY).

Kramecyne (KACY), a polymer isolated from Krameria cytisoides Cav, has anti-inflammatory, anti-nociceptive, anti-arthritic and anti-ulcerogenic properties. As a part of standard preclinical safety tests, the present study sought to determine potential developmental toxicity (in female rats) and genotoxicity (in male mice) of KACY. Pregnant female rats were divided into six groups: the negative control (vehicle), the positive control (250 mg/kg of acetylsalicylic acid (ASA)), and four experimental groups (50, 250, 500 and 1000 mg/kg of KACY). To evaluate genotoxicity by in vivo micronuclei (MN) and sister chromatid exchange (SCE) tests, male mice were divided into five groups: the negative control (vehicle), the positive control (1.5 and 2.5 mg/kg of doxorubicin for MN and SCE, respectively), and three experimental groups (50, 500 and 1000 mg/kg of KACY). All treatments were administered by oral gavage. A slight maternal toxicity was evidenced by lower weight gain for rats receiving 500 and 1000 mg/kg of KACY, but no fetal malformations were found. However, there were less live fetuses/litter and greater post-implantation loss/litter at these two doses. Manifestations of developmental toxicity were limited to a higher rate of skeletal alterations. The MN tests did not evidence genotoxicity or cytotoxicity. KACY caused a slightly but significantly increased frequency of SCE. Although KACY-treated rats had skeletal alterations, these apparently were not caused by a mechanism of genotoxicity. Furthermore, the same administration in adult male mice did not produce genotoxicity. Hence, KACY herein proved to be safe for rats during the period of organogenesis.

Current issues in ALS epidemiology: Variation of ALS occurrence between populations and physical activity as a risk factor.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a fatal outcome. This review aims to report key epidemiological features of ALS in relation to the hypothesis of variation between populations, to summarize environmental hypothesis and to highlight current issues that deserve much considerations. Epidemiological ALS studies have shown a variation of incidence, mortality and prevalence between geographical areas and different populations. These data could support the notion that genetic factors, especially populations' ancestries, along with environmental and lifestyle factors, play a significant role in the occurrence of the disease. To date, there is no strong evidence to confirm an association between a particular environmental factor and ALS. Physical activity (PA) has been extensively evaluated. Recent studies support with the best evidence level that PA in general population is not a risk factor for ALS. However, further research is needed to clarify the association of PA in some occupations and some athletic activities. Epidemiological research based on multicenter international collaboration is essential to provide new data on ALS especially in some regions of the world that are to date poorly represented in the ALS literature.

Retrospective multicentre observational study on clinical management and treatment of different types of status epilepticus in clinical practice. / Estudio observacional multicéntrico retrospectivo sobre el manejo clínico y terapéutico de los diferentes tipos de estatus epiléptico en la práctica clínica.

INTRODUCTION: Status epilepticus (SE) is a neurological emergency associated with significant mortality and morbidity. We analyse characteristics of this entity in our population. METHODS: Data from electronic medical records of adults diagnosed with SE were collected retrospectively from 5 hospitals over 4 years. RESULTS: Data reflected 84 episodes of SE in 77 patients with a mean age of 60.3 years. Of this sample, 52.4% had a previous history of epilepsy. Status classification: 47.6% tonic-clonic, 21.4% complex partial, 17.9% partial motor, 6% partial simple, 3.6% myoclonic, and 3.6% subtle SE. Based on the duration of the episode, SE was defined in this study as early stage (up to 30min) in 13.1%, established (30-120min) in 20.2%, refractory (more than 120min) in 41.7%, and super-refractory (episodes continuing or recurring after more than 24h of anaesthesia) in 13.1%. Ten patients (11.9%) died when treatment failed to control SE. The cumulative percentage of success achieved was 8.3% with the first treatment, 27.3% for the second, 48.7% for the third, 58.2% for the fourth, 70.1% for the fifth, 80.8% for the sixth, 83.2% for the seventh, and 84.4% for the eighth. CONCLUSIONS: In our study, we found that SE did not respond to treatment within 2h in approximately half the cases and 11.9% of the patients died without achieving seizure control, regardless of the type of status. Half the patients responded by the third treatment but some patients needed as many as 8 treatments to resolve seizures. Using large registers permitting analysis of the different types and stages of SE is warranted.

Liquid self-diffusion of H2O and DMF molecules in Co-MOF-74: molecular dynamics simulations and dielectric spectroscopy studies.

In this work we use molecular dynamics simulations to study the diffusion of N,N-dimethylformamide (DMF) and H2O as a function of temperature within the well-known metal-organic framework Co2(dobdc)·[G] (G = 2DMF·1H2O), also known as Co-MOF-74. The molecular dynamics simulations show that the diffusivity of guest molecules, which is almost negligible at low temperatures (T < 200 K), increases in the range of 200 < T (K) < 400 up to 3 and 4 orders of magnitude for DMF and H2O, respectively. This molecular diffusion can be easily detected by dielectric spectroscopy as it gives rise to extrinsic interfacial polarization effects that result in an apparent "colossal" dielectric constant at room temperature, εr' ∼ 42 000 (T = 300 K, ν = 10 Hz). Furthermore, the measured dielectric constant exhibits a thermal dependence similar to that of the diffusion coefficient, revealing the parallelism of the dielectric response and the molecular diffusion as a function of temperature. These results highlight: (a) the great utility of the fast and non-destructive dielectric and impedance spectroscopy techniques for the study and detection of the molecular transport of small polar molecules within porous metal-organic frameworks and related materials; (b) the peculiarity and uniqueness of MOF materials with "medium" size nanopores containing guest molecules as they are solid materials in which the guest molecules display a liquid state-like behaviour close to room temperature; and

Left ventricular diastolic function and cardiometabolic factors in obese normotensive children.

BACKGROUND AND AIM: Left ventricular (LV) hypertrophy and diastolic function have been found to be associated with obesity and hypertension in adults. However, there are scarce data about the association of obesity itself to cardiac alteration in children. The aim of this study was to detect early changes in LV structure and function in obese children and whether they are associated with the biomarkers of metabolic risk and endothelial activation. METHODS AND RESULTS: A total of 130 children aged 7-16 years (88 obese and 42 normal-weight children) were studied. All children had normal resting blood pressure. Two-dimensional ultrasound with M-mode imaging was performed to assess the LV mass index (LVMi), calculated as LV mass/height(2.7), and the peak diastolic of pulmonary venous flow velocity (PVFD). Tissue Doppler imaging was used to analyze ventricular performance through the ratio of the transmitral peak early filling velocity to the early average diastolic peak myocardial velocity (E/E'). The indicators of metabolic control, inflammation, and endothelial cell activation were evaluated. Compared to the controls, the obese subjects had significantly higher LVMi and E/E' and lower PVFD values, the two latest being found especially in severely obese subjects. In the multivariate analysis, the parameters of diastolic function (E/E' and PVFD) were independently associated with obesity, apolipoprotein A1, soluble vascular cell endothelial molecule-1 (sVCAM-1), and retinol-binding protein 4 (RBP4). CONCLUSION: An echocardiographic evaluation of diastolic function is a useful tool to detect early cardiac changes in obese children. Emergent cardiovascular risk markers such as apolipoprotein A1, RBP4, and sVCAM-1 are associated with the parameters of diastolic function.

First approach to characterize tilts through multiple pistons in the classical Ronchi test.

In this work, it is shown how a tilt can be introduced into a segmented surface through several piston terms, by using the classical Ronchi test. We have developed tilt error simulations by adding multiple constant terms to each point on the sagitta surface of a segment using ray tracing. Thereby a comparison between simulated Ronchigrams for piston and tilt has been performed for two adjacent segments, so that it is possible to appreciate the tilt and piston effects on the shape of the patterns. As a result, we show the behavior of the central maximum of the fringes in the presence of tilt and/or piston. Additionally we present evidence of introducing tilting without changing the surface shape by adding multiple pistons, and a description of how to characterize both piston and tilt using the Ronchi test.

Trends in the dispensation of antidepressant drugs over the past decade (2000-2010) in Andalusia, Spain.

PURPOSE: To study antidepressant drug dispensation in the Spanish region of Andalusia and in the Almeria Health Area (AHA) over the past decade, analyzing the variability, trends, and influential factors. METHODS: We conducted an observational ecological study of antidepressant drug dispensation between 2000 and 2010 in Andalusia. Dispensation was measured as Defined Daily Dose (DDD) per 1,000 inhabitants per day. A multilevel analysis (STATA 11.1) was performed to determine the variability among the basic health zones (BHZs) (2004-2010) and influential factors. RESULTS: Between 2000 and 2010, the total dispensation of antidepressant drugs increased by more than 100 % in Andalusia and in the AHA. This increase was primarily caused by the greater dispensation of selective serotonin reuptake inhibitors (ATC-N06AB) and other antidepressants (ATC-N06AX). Multilevel analysis revealed a wide variability in the levels and trends of antidepressant dispensation among BHZs. Urbanicity and the percentage of immigrants in the BHZ were negatively associated with their dispensation, which was positively influenced by a higher proportion of women and over 65-year-olds in the population. CONCLUSIONS: The elevated dispensation of several groups of antidepressant drugs in this study population indicates the need for health policies to rationalize their use. Further research is required into the differences in antidepressant dispensations between immigrant and native populations and the implications for public health policies.