Immunostimulating activity of Uncaria tomentosa in RAW 264.7 macrophages.

Uncaria tomentosa is a plant native to the Amazon that has immunomodulatory and antitumor properties due to the alkaloids found in the plant, being able to modify the immune response by potentiating or suspending the action of cytokines secreted by macrophages that induce the immune response, either by the classical route (M1) or through the alternative route (M2). Macrophages activated by M1 convert L-arginine into L-citrulline and nitric oxide (NO), whereas macrophages activated by the M2 pathway use the enzymatic activity of arginase to convert the same substrate into L-ornithine and urea. The aim of this work was to evaluate the immunostimulating activity of the crude hydroalcoholic extract from the bark of the U. tomentosa stem in RAW 264.7 macrophages. Concentrations of 0.2, 0.1 and 0.05 mg/mL of U. tomentosa extract associated with LPS, INF-γ and IL-4 inducers were tested by determining NO production and arginase enzyme activity. Nitric oxide production was enhanced by the extract when associated with LPS and LPS + INF-γ inducers. In the activity of the arginase enzyme, the extract decreased the stimulation of IL-4 on the enzyme, mainly at 0.2 mg/mL concentration. Therefore, it is concluded that the crude hydroalcoholic extract of the stem bark of U. tomentosa in RAW 264.7 cells, at a concentration of 0.2 mg/mL, showed considerable pro-inflammatory activity.

Nasal fractures: a dedicated clinic providing reduction under local anaesthesia improves time to manipulation.

INTRODUCTION: Guidelines for nasal injury state that assessment should be at 7-10 days post-injury and manipulation within 14 days. We performed a plan, do, study, act improvement cycle to assess whether a dedicated nasal fracture service led to better outcomes. MATERIALS AND METHODS: A retrospective study was carried out of all patients undergoing manipulation under anaesthesia for nasal trauma between February 2013 and December 2016 in a district general hospital. A dedicated nasal fracture clinic providing manipulation under local anaesthesia was implemented followed by a prospective study of all patients presenting to the clinic between February and November 2017. Main outcome measures included time from injury to otolaryngology assessment, time from injury to manipulation and incidence of secondary septorhinoplasty. RESULTS: The retrospective series involved 525 patients including 381 males (72.6%) and 144 females (27.4%). Mean time from injury to assessment was 10 days. Mean time from injury to surgery was 14.5 days. Mean time from assessment to surgery was five days. The incidence of septorhinoplasty was 2.3%. The prospective series involved 119 patients including 78 males (65.5%) and 41 females (34.5%). Following implementation of a nasal fracture clinic, mean time from injury to assessment and manipulation was 6.1 days and 5.4% of patients underwent septorhinoplasty for secondary deformity. DISCUSSION: Implementation of a nasal fracture clinic providing reduction under local anaesthesia reduced the time to assessment and manipulation. The incidence of septorhinoplasty is low following reduction under general or local anaesthesia. Assessment earlier than seven days is feasible and advice for referral can be changed accordingly.

Temperature dependence of thermal properties of ex vivo liver tissue up to ablative temperatures.

Thermal properties of ex vivo bovine liver were measured as a function of temperature, by heating tissue samples in a temperature-controlled oil bath over a temperature range from about 21 °C to about 113 °C. Results evidenced temperature-dependent non-linear changes of the thermal properties, with the temperature of 100 °C representing a break point: the thermal properties increased with temperature up to 99 °C and then decreased above 100 °C. The rate of increase appeared dramatic between 90 °C and 99 °C, owing to the onset of vaporisation of water contained in the tissue. In particular, at 99 °C, the thermal conductivity reported an increase of about four times with respect to the value measured at 90 °C, whilst about a two-fold increase was reported for both the volumetric heat capacity and the thermal diffusivity. Temperatures higher than 100 °C were reached only after complete vaporisation of water contained in the tissue, resulting in about 70% loss of weight from the tissue. An overall decrease of about 71% and 63% was reported for the thermal conductivity and volumetric heat capacity, respectively, in the temperature range 101 °C-113 °C. A decrease of about 25% was reported in the measured values of the thermal diffusivity in the temperature range 101 °C-108 °C, whilst a slight increase of measured values, not statistically significant, was observed in the temperature range 108 °C-113 °C. The temperature dependent changes of the thermal parameters were modelled with non-linear regression analysis to calculate the best-fit curves interpolating measured data. The proposed regression models could be used to numerically assess the changes in the thermal properties of biological tissues at supra-physiological temperatures relevant in thermal ablation procedures, as well as their effect on the prediction of the ablation zone dimensions in computational models for treatment planning.

Treatment planning in microwave thermal ablation: clinical gaps and recent research advances.

Microwave thermal ablation (MTA) is a minimally invasive therapeutic technique aimed at destroying pathologic tissues through a very high temperature increase induced by the absorption of an electromagnetic field at microwave (MW) frequencies. Open problems, which are delaying MTA applications in clinical practice, are mainly linked to the extremely high temperatures, up to 120 °C, reached by the tissue close to the antenna applicator, as well as to the ability of foreseeing and controlling the shape and dimension of the thermally ablated area. Recent research was devoted to the characterisation of dielectric, thermal and physical properties of tissue looking at their changes with the increasing temperature, looking for possible developments of reliable, automatic and personalised treatment planning. In this paper, a review of the recently obtained results as well as new unpublished data will be presented and discussed.

Numerical models to evaluate the temperature increase induced by ex vivo microwave thermal ablation.

Microwave thermal ablation (MTA) therapies exploit the local absorption of an electromagnetic field at microwave (MW) frequencies to destroy unhealthy tissue, by way of a very high temperature increase (about 60 °C or higher). To develop reliable interventional protocols, numerical tools able to correctly foresee the temperature increase obtained in the tissue would be very useful. In this work, different numerical models of the dielectric and thermal property changes with temperature were investigated, looking at the simulated temperature increments and at the size of the achievable zone of ablation. To assess the numerical data, measurement of the temperature increases close to a MTA antenna were performed in correspondence with the antenna feed-point and the antenna cooling system, for increasing values of the radiated power. Results show that models not including the changes of the dielectric and thermal properties can be used only for very low values of the power radiated by the antenna, whereas a good agreement with the experimental values can be obtained up to 20 W if water vaporization is included in the numerical model. Finally, for higher power values, a simulation that dynamically includes the tissue's dielectric and thermal property changes with the temperature should be performed.

Effects of FGF10 on bovine oocyte meiosis progression, apoptosis, embryo development and relative abundance of developmentally important genes in vitro.

Fibroblast growth factor (FGF10) acts at the cumulus oocyte complex, increasing the expression of cumulus cell expansion-related genes and oocyte competency genes. We tested the hypothesis that addition of FGF10 to the maturation medium improves oocyte maturation, decreases the percentage of apoptotic oocytes and increases development to the blastocyst stage while increasing the relative abundance of developmentally important genes (COX2, CDX2 and PLAC8). In all experiments, oocytes were matured for 22 h in TCM-199 supplemented with 0, 2.5, 10 or 50 ng/ml FGF10. In Experiment 1, after maturation, oocytes were stained with Hoechst to evaluate meiosis progression (metaphase I, intermediary phases and extrusion of the first polar body) and submitted to the TUNEL assay to evaluate apoptosis. In Experiment 2, oocytes were fertilized and cultured to the blastocyst stage. Blastocysts were frozen for analysis of COX2, CDX2 and PLAC8 relative abundance. In Experiment 1, 2.5 ng/ml FGF10 increased (p < 0.05) the percentage of oocytes with extrusion of the first polar body (35%) compared to 0, 10 and 50 ng/ml FGF10 (21, 14 and 12%, respectively) and FGF10 decreased the percentage of oocytes that were TUNEL positive in all doses studied. In Experiment 2, there was no difference in the percentage of oocytes becoming blastocysts between treatments and control. Real-time RT-PCR showed a tendency of 50 ng/ml FGF10 to increase the relative abundance of COX2 and PLAC8 and of 10 ng/ml FGF10 to increase CDX2. In conclusion, the addition of FGF10 to the oocyte maturation medium improves oocyte maturation in vitro, decreases the percentage of apoptotic oocytes and tends to increase the relative abundance of developmentally important genes.

Effect of reduced dietary protein and supplementation with a docosahexaenoic acid product on broiler performance and meat quality.

1. Chicken breast meat is a lean meat due to its low content of intramuscular fat (IMF) resulting in an overall lower acceptability by consumers due to a decrease in juiciness, flavour and increased chewiness. Recently, studies performed in pigs suggested the possibility of increasing IMF by decreasing dietary crude protein (CP) content, an effect possibly mediated through an increased lipogenesis. 2. Dietary supplementation with lipids rich in omega 3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) may modulate an increase in the content of these fatty acids in meat from monogastric animals and, thus, promote the daily intake of n-3 LC-PUFA by humans. 3. LC-PUFA are very susceptible to oxidation, resulting in off-flavours that affect meat quality and consumers' acceptability. 4. This trial was conducted to assess the effect of reducing dietary CP, from 21% to 17%, on chicken's meat IMF content and, simultaneously, to evaluate if a complementary supplementation with a proprietary n-3 LC-PUFA source (DHA Gold™) could improve meat quality. These effects were assessed by measuring productive performance and meat quality, oxidative stability, sensory traits and fatty acid profile. 5. A reduction in CP content of broiler diets, from 21% to 17%, balanced for lysine, improved performance while it was not sufficient to increase IMF content in chicken meat. In contrast, DHA Gold™ supplementation had a positive impact both in broiler productive parameters and in meat fatty acid profile. 6. In addition, incorporation of 7.4% of DHA Gold™ in the diet promoted carcass yield but negatively affected chicken meat acceptability by consumers, due to a decrease of meat oxidative stability. 7. Overall the data suggest that neither a dietary supplementation with DHA Gold™ nor a reduction in CP have a direct positive effect in the levels of IMF present in broiler meat.

Food and nutritional safety of hospitalized patients under treatment with enteral nutrition therapy in the Jequitinhonha Valley, Brazil / Seguridad alimentaria y nutricional de los pacientes hospitalizados de un tratamiento con nutrición enteral en el Valle del Jequitinhonha, Brasil

The Enteral Nutrition Therapy (ENT) has been widely used in hospital and home care assistance. However, research works are needed to make this technique more efficient and cheaper. Objective: Evaluate the nutritional quality of handmade enteral diets used in a charity hospital in the Jequitinhonha Valley, Brazil, and propose qualitative and quantitative adjustments, when necessary, and compare the data available in tables of chemical composition of foods with the data achieved by laboratory analyses. Materials and methods: The study was carried out in partnership with a charity organization of the region and the Universidade Federal dos Vales do Jequitinhonha e Mucuri, where the collection of the handmade enteral diets was performed. The analyses of the physical-chemical and centesimal composition of 36 samples of diets were carried out in the laboratories of the university. Results: It was observed that the daily energy offer of the diets was below the recommended standards and presented a percentage distribution different from that estimated for patients receiving ENT. Besides, it can be seen that the nutrient values of the data achieved in laboratory do not agree with those available in tables of food chemical composition. Conclusions: Significant losses of nutrients were verified during the processing and preparation of handmade enteral diets. It challenges nutritionists to standardize these diets and corroborates the relevance of new studies to determine the nutritional content of handmade enteral diets, since these diets have been widely used in poor regions of Brazil and in other countries (AU)

La terapia de nutrición enteral (TNE) se ha utilizado ampliamente en la asistencia hospitalaria y domiciliaria. Sin embargo, se necesitan trabajos de investigación para hacer que esta técnica sea más eficiente y barata. Objetivo: Evaluar la calidad nutricional de dietas enterales elaboradas de forma casera en un hospital de caridad del valle de Jequitinhonha, Brasil, y proponer ajustes cualitativos y cuantitativos, cuando sean necesarios, y comparar los datos disponibles en las tablas de la composición química de los alimentos con los datos obtenidos en los análisis de laboratorio. Materiales y métodos: El estudio se realizó en colaboración con la organización de caridad de la región y la Universidad Federal dos Vales do Jequitinhonha e Mucuri, donde se realizó la recogida de las ditas enterales caseras. Los análisis de la composición fisicoquímica y centesimal de las 36 muestras de las dietas se realizaron en los laboratorios de la universidad. Resultados: Se observó que la oferta energética diaria de las dietas estaba por debajo de las recomendaciones estándar y presentaba un porcentaje de distribución diferente de la estimada para pacientes que reciben TNE. Además, se pudo ver que los valores nutricionales de los datos obtenidos en el laboratorio no concordaban con los disponibles en las tablas de composición química de los alimentos. Conclusiones: Se comprobó una pérdida significativa de nutrientes durante el procesamiento y preparación de las dietas enterales realizadas caseramente. Supone un reto para los nutricionistas para estandarizar estas dietas y corroborar la relevancia de nuevos estudios para determinar el contenido nutricional de las dietas enterales de realización casera, puesto que estas dietas se han empleado ampliamente en regiones pobres de Brasil y otros países (AU)

Food and nutritional safety of hospitalized patients under treatment with enteral nutrition therapy in the Jequitinhonha Valley, Brazil.

UNLABELLED: The Enteral Nutrition Therapy (ENT) has been widely used in hospital and home care assistance. However, research works are needed to make this technique more efficient and cheaper. OBJECTIVE: Evaluate the nutritional quality of handmade enteral diets used in a charity hospital in the Jequitinhonha Valley, Brazil, and propose qualitative and quantitative adjustments, when necessary, and compare the data available in tables of chemical composition of foods with the data achieved by laboratory analyses. MATERIALS AND METHODS: The study was carried out in partnership with a charity organization of the region and the Universidade Federal dos Vales do Jequitinhonha e Mucuri, where the collection of the handmade enteral diets was performed. The analyses of the physical-chemical and centesimal composition of 36 samples of diets were carried out in the laboratories of the university. RESULTS: It was observed that the daily energy offer of the diets was below the recommended standards and presented a percentage distribution different from that estimated for patients receiving ENT. Besides, it can be seen that the nutrient values of the data achieved in laboratory do not agree with those available in tables of food chemical composition. CONCLUSIONS: Significant losses of nutrients were verified during the processing and preparation of handmade enteral diets. It challenges nutritionists to standardize these diets and corroborates the relevance of new studies to determine the nutritional content of handmade enteral diets, since these diets have been widely used in poor regions of Brazil and in other countries.

The effectiveness of endoscopic epidurolysis in treatment of degenerative chronic low back pain: a prospective analysis and follow-up at 48 months.

The aim of this prospective study was to evaluate the efficacy of endoscopic epidurolysis in the treatment of degenerative chronic low back pain.Two hundred and thirty four patients affected by chronic low back pain, with VAS ≥ 5 and Oswestry Low Back Pain Disability Index (ODI) from 0 to 60% (0-20%, group A; 20-40%, group B; 40-60%, group C) were enrolled and treated prospectively with endoscopic epidurolysis by means of a flexible fiberoptic endoscope introduced into the caudal epidural space and by the intermittent instillation of saline solution added with 150 UI hyaluronidase. Targeted application of ozone (8 ml; 38 γ/ml) and 50 mg ciprofloxacin close to the abnormal areas was also performed. Short and long term efficacy (1 week, 3 months, 6, 12, 24, 36 and 48 months) was prospectively evaluated. VAS score <5 and ODI <40% were considered as a positive outcome.The treatment significantly reduced VAS score in all three groups of patients starting from the first week and throughout the entire follow-up period (P < 0.001). Disability Index (ODI) too showed encouraging results (P < 0.001) that was particularly evident at 3 months and maintained up to long-term follow-up intervals.Epiduroscopy by mechanical adhesiolysis and administration on targeted areas of ciprofloxacin and ozone seems to be, in this prospective study, an effective technique to provide a sensible and persisting pain relief and act of improving ODI in chronic low back pain.

Long-term follow up of abdominal rectosigmoidectomy with posterior end-to-side stapled anastomosis for Chagas megacolon.

AIM: Chagas' disease is an endemic parasitosis found in Latin America. The disease affects different organs, such as heart, oesophagus, colon and rectum. Megacolon is the most frequent long-term complication, caused by damage to the myoenteric and submucous plexus, ultimately leading to a functional barrier to the faeces. Patients with severe constipation are managed surgically. The study aimed to analyse the 10-year minimum functional outcome after rectosigmoidectomy with posterior end-to-side anastomosis (RPESA). METHOD: A total of 21 of 46 patients were available for follow up. Patients underwent clinical, radiological and manometric evaluation, and the results were compared with preoperative parameters. RESULTS: Of the 21 patients evaluated, 81% (17) were female, with a mean age of 60.6 years. Good function was achieved in all patients, with significant improvement in defaecatory frequency (P < 0.0001), usage of enemas (P < 0.0001) and patient satisfaction. Barium enema also showed resolution of the colonic and rectal dilatation in 19 cases evaluated postoperatively. CONCLUSION: Minimal 10-year follow up of RPESA showed excellent functional results, with no recurrence of constipation.

Synchronous behavior of two coupled electronic neurons.

We report on experimental studies of synchronization phenomena in a pair of analog electronic neurons (ENs). The ENs were designed to reproduce the observed membrane voltage oscillations of isolated biological neurons from the stomatogastric ganglion of the California spiny lobster Panulirus interruptus. The ENs are simple analog circuits which integrate four-dimensional differential equations representing fast and slow subcellular mechanisms that produce the characteristic regular/chaotic spiking-bursting behavior of these cells. In this paper we study their dynamical behavior as we couple them in the same configurations as we have done for their counterpart biological neurons. The interconnections we use for these neural oscillators are both direct electrical connections and excitatory and inhibitory chemical connections: each realized by analog circuitry and suggested by biological examples. We provide here quantitative evidence that the ENs and the biological neurons behave similarly when coupled in the same manner. They each display well defined bifurcations in their mutual synchronization and regularization. We report briefly on an experiment on coupled biological neurons and four-dimensional ENs, which provides further ground for testing the validity of our numerical and electronic models of individual neural behavior. Our experiments as a whole present interesting new examples of regularization and synchronization in coupled nonlinear oscillators.

Radiologic features of pediatric thalamic and hypothalamic tumors.

A variety of histologic subtypes of tumor may affect the thalamus and the hypothalamus in the pediatric population. These tumors have radiologic features that are useful in predicting pathology. We discuss the radiologic findings of childhood thalamic and hypothalamic tumors and provide imaging examples.

Reliable circuits from irregular neurons: a dynamical approach to understanding central pattern generators.

Central pattern generating neurons from the lobster stomatogastric ganglion were analyzed using new nonlinear methods. The LP neuron was found to have only four or five degrees of freedom in the isolated condition and displayed chaotic behavior. We show that this chaotic behavior could be regularized by periodic pulses of negative current injected into the neuron or by coupling it to another neuron via inhibitory connections. We used both a modified Hindmarsh-Rose model to simulate the neurons behavior phenomenologically and a more realistic conductance-based model so that the modeling could be linked to the experimental observations. Both models were able to capture the dynamics of the neuron behavior better than previous models. We used the Hindmarsh-Rose model as the basis for building electronic neurons which could then be integrated into the biological circuitry. Such neurons were able to rescue patterns which had been disabled by removing key biological neurons from the circuit.

Anti-hepatitis A virus antibody response elicited in mice by different forms of a synthetic VP1 peptide.

Peptide VP1 (11-25) of the capsid of hepatitis A virus was synthesized by the Fmoc-polyamide solid phase method, and administered to mice in different forms: (1) free, (2) encapsulated in multilamellar liposomes, (3) coupled to keyhole limpet hemocyanin (KHL), and (4) incorporated into a tetrameric branched lysine core. The highest anti-VP1 peptide responses were generated by synthetic peptides entrapped into liposomes and coupled to KLH. No anti-HAV response was generated with the free peptide, while all the other forms induced both anti-HAV and HAV-neutralizing antibodies. Maximum neutralization indices were observed in ascites from mice treated with liposome-entrapped and KLH peptides.

Disinfection of human enteric viruses in water by copper and silver in combination with low levels of chlorine.

The efficacy of copper and silver ions, in combination with low levels of free chlorine (FC), was evaluated for the disinfection of hepatitis A virus (HAV), human rotavirus (HRV), human adenovirus, and poliovirus (PV) in water. HAV and HRV showed little inactivation in all conditions. PV showed more than a 4 log10 titer reduction in the presence of copper and silver combined with 0.5 mg of FC per liter or in the presence of 1 mg of FC per liter alone. Human adenovirus persisted longer than PV with the same treatments, although it persisted significantly less than HRV or HAV. The addition of 700 micrograms of copper and 70 micrograms of silver per liter did not enhance the inactivation rates after the exposure to 0.5 or 0.2 mg of FC per liter, although on some occasions it produced a level of inactivation similar to that induced by a higher dose of FC alone. Virus aggregates were observed in the presence of copper and silver ions, although not in the presence of FC alone. Our data indicate that the use of copper and silver ions in water systems may not provide a reliable alternative to high levels of FC for the disinfection of viral pathogens. Gene probe-based procedures were not adequate to monitor the presence of infectious HAV after disinfection. PV does not appear to be an adequate model viral strain to be used in disinfection studies. Bacteroides fragilis bacteriophages were consistently more resistant to disinfection than PV, suggesting that they would be more suitable indicators, although they survived significantly less than HAV or HRV.

Plasma and liver selenium levels in the rat during supplementation with 0.5, 2, 6, and 15 ppm selenium in drinking water.

Plasma and liver selenium of Wistar rats were determined after 1, 3, and 6 mo supplementation with 0.5, 2, 6, or 15 ppm selenium as sodium selenite in drinking water. Plasma selenium was not different from control values at additional intake of 0.5 ppm but increased above usual levels at higher intakes. A highly significant correlation was observed between the total quantity of selenium ingested and plasma selenium after 1 mo treatment (r = 0.99, p < 0.01), but was less pronounced after 3 and 6 mo (0.94, p < 0.05, and 0.78, p < 0.05, respectively). The decrease in plasma selenium with time of treatment was more pronounced at higher intakes. There was also a highly significant correlation between total selenium intake and liver selenium concentration (r = 0.99, p < 0.01) after 1 mo of treatment, but this time liver selenium did not change with time, and the correlation remained highly significant throughout the investigation. Liver selenium therefore appears as a more sensitive and more representative measure of selenium intake than plasma selenium. Most supplements did not affect body weight and survival of animals, except when the diet was supplemented with 15 ppm for 6 mo; however, alterations in biochemical parameters concerning lipid status and hepatic function were observed at levels above 2.0 ppm.

Management of chronic myeloid leukemia in chronic phase with autologous stem cell transplantation and alpha-2 interferon: cytogenetic and clinical results.

Forty-eight patients with chronic myeloid leukemia (CML) in chronic phase (CP) were treated by autologous stem cells transplantation (ASCT) and alpha Interferon (IFN) with three approaches: 1) ASCT at diagnosis followed by IFN, 2) ASCT post IFN with cells collected after an interval from IFN discontinuance, followed by IFN, 3) ASCT in patients selected by cytoconversion obtained with IFN, performed soon after IFN discontinuance. Following ASCT, a major karyotype response (more than 65% Ph1 negative cells, MKR) was observed at least once in 40%, 53% and 83% of patients from the three groups, respectively. At last follow-ups (median 39, 40 and 21 months, respectively) 19%, 13% and 67% of patients still present a MKR with 2 patients from group 1 and 4 patients from group 3 being 100% Ph' negative. Projected survival from diagnosis is 77% at 52 months for patients from group 1 and 47% at 75 months for patients from group 2. Present data indicate that 1) IFN can stabilize results obtained with ASCT, 2) ASCT can potentiate responses to IFN, 3) combined ASCT and IFN can improve survival. Longer follow-up of patients and randomized studies are required to define the real impact on disease outcome by these treatment approaches.

Pneumoconiose em trabalhadores de industria de abrasivos / Pneumoconiosis in workers of abrasive industry

O desenvolvimento de pneumopatia profissional em operarios de industrias de material abrasivo e incomun, sendo ate recentemente considerada a silica como causadora da pneumoconiose. Analisamos 22 operarios destas industrias em que se detectaram alteracoes radiograficas de torax. Todos eram do sexo masculino, com idades variando de 29 a 59 anos. Dezenove trabalhavam na producao de carbeto de silicio, tres na producao de oxido de aluminio e um em ambos, tendo ficado expostos por um periodo de 8 a 27 anos. As alteracoes radiologicas (ILO-80) predominantes foram pequenas opacidades em 20 pacientes. Associacao de grandes e pequenas opacidades foram observadas em um caso e grandes opacidades isoladamente em um. As pequenas opacidades foram predominantemente difusas e arredondadas. Nos dois doentes com grandes opacidades, estas se enquadravam como categoria B. Conclui-se que operarios em industrias de abrasivos encontram-se sob risco de desenvolvimento de pneumopatia profissional mais provavelmente desencadeada pela inalacao de carbeto de silicio.