New frontiers in intraoperative neurophysiologic monitoring: a narrative review.

Background and Objective: Neurological insults during surgery arise from anatomic and/or physiologic perturbations. Intraoperative neurophysiologic monitoring (IONM) fills a critical role of ensuring that any neurological insults during certain surgical procedures are caught in real-time to prevent patient harm. IONM provides immediate feedback to the surgeon and anesthesiologist about the need for an intervention to prevent a neurologic deficit postoperatively. As important as it seems to have IONM available to any patient having surgery where a neurological injury is possible, the truth is that IONM is unavailable to large swaths of people around the world. This review is intended to bring attention to all of the ways IONM is critically important for a variety of surgeries and highlight the barriers preventing most patients around the world from benefiting from the technology. Expansion of IONM to benefit patients from all over the world is the new frontier. Methods: We searched all English language original papers and reviews using Embase and MEDLINE/PubMed databases published from 1995 to 2022. Different combinations of the following search terms were used: intraoperative neuromonitoring, neurosurgery, low-income countries, cost, safety, and efficacy. Key Content and Findings: We describe common IONM modalities used during surgery as well as explore barriers to implementation of IONM in resource-limited regions. Additionally, we describe ongoing efforts to establish IONM capabilities in new locations around the world. Conclusions: In this paper, we performed a review of the literature on IONM with an emphasis on the basic understanding of clinical applications and the barriers for expansion into resource-limited settings. Finally, we provide our interpretation of "new frontiers" in IONM quite literally facilitating access to the tools and education so a hospital in Sub-Saharan Africa can incorporate IONM for their high-risk surgeries.

Evaluating the Cooling Efficiency of Polymer Injection Molds by Computer Simulation Using Conformal Channels.

Injection molds are production tools that require detailed analysis based on the quality of the resulting part, the impact on cycle times, and the expected production volume. Cooling channels also play a critical role in mold performance and product quality as they largely determine cycle time. Designs that incorporate conformal cooling channel (CCC) geometries that conform to or align with the part contour are currently being explored as an alternative to conventional cooling channel designs in injection molds. In this study, a simulation of CCC geometries was performed and their effects on mold temperatures and warpage were investigated. Two cross-sectional geometries, circular and square, were selected for a three-factor level design of experiments (DOE) analysis. The response variables used were mold temperatures and part warpage. A cup-shaped part with upper and lower diameters of 54 and 48 mm, respectively, a height of 23 mm and a thickness of 3 mm was used for the injection molded part. A comparison was also made between two materials for the injection mold, steel and polycarbonate. The DOE results showed that the distance between the CCC and the injected part and the diameter or side of the square have significant effects on the response variables for both systems (steel and polycarbonate molds). In addition, a comparison between conventional and conformal cooling channels was analyzed using a cup-shaped part and a less rigid part geometry. The finite element simulation results show a 9.26% reduction in final warpage in the cup-shaped part using CCCs compared with the conventional cooling methods in steel. When using parts with lower geometry stiffness, the use of CCCs reduced final part warpage by 32.4% in metal molds and by 59.8% in polymer molds.

Analysis of the Stress Field in Photoelasticity Used to Evaluate the Residual Stresses of a Plastic Injection-Molded Part.

The degree of quality of thermoplastic injection-molded parts can be established based on their weight, appearance, and defects. However, the conditions of the injection process may induce effects on the mechanical performance of the injected parts, and the residual stresses can cause cracks or early failures when an external load or force is applied. To evaluate these mechanical behaviors, different experimental techniques have been reported in the literature, where digital photoelasticity has stood out both for being a non-contact technique and for achieving quantitative results through sophisticated computational algorithms. Against this background, our proposal consists of analyzing the overall residual stress distribution of parts injected under different molding conditions by using digital photoelasticity. In this case, the specimens are subjected to bending strength tests to identify possible effects of the injection process conditions. The findings show that, at mold temperatures of 80 °C, flow-induced residual stresses increase with packing pressure. However, these internal stress levels do not affect the external load applied by the mechanical bending test, while the mass injected at higher levels of packing pressure helps to increase the bending strength of the injected part. At lower mold temperatures (50 °C), the mechanical strength of the injected part is slightly reduced, possibly due to a lower effect of the packing pressure.

Influence of CYP2B6 Genotype on Methadone Dosage in Patients from the Methadone Maintenance Treatment (MMT) Program in Pereira, Colombia.

Methadone treatment reduces the use of heroin and withdrawal symptoms; however, methadone is an expensive medication with a narrow safety margin. We compared the retention rates, persistence of heroin use, and quality of life of a group of patients undergoing conventional Methadone Maintenance Treatment (MMT) with a group for whom the CYP2B6 516G>T polymorphism was used in addition to the MMT to calculate the required methadone dose. Over 12 weeks, the retention rate, heroin usage, and quality of life of patients under conventional treatment (n = 34) were compared with those of patients for whom we used genetic markers to calculate methadone dosage (n = 38). At the end of the study, 26.4% of patients abandoned the program, and neither demographic nor clinical variables were associated with treatment adherence. Of the remaining patients, 16% of the control group and 8% of patients in the pharmacogenetic group reported heroin use, while both groups showed a 64% reduction in the use of cocaine/crack (no significant differences between the groups were found). Starting in the second week, the methadone dosage was lower among the patients for whom methadone was prescribed based on genotype. Although there were six individuals in the control group and three in the pharmacogenetic group with QTc intervals > 450 ms (a threshold that is considered dangerous), we did not find a relationship between the QTc interval and methadone dosage. There were no differences in the perception of quality of life between the two groups. The results of this pilot study suggest that concerning methadone therapy, the CYP2B6 genotype contributes to reduced effective doses and treatment costs.

Development, Simulation of Temperatures, and Experimentation in Injection Molds Obtained through Additive Manufacturing with Photocurable Polymeric Resins.

Additive manufacturing (AM) is a relatively new option in mold manufacturing for rapid tooling (RT) in injection processes. This paper presents the results of experiments with mold inserts and specimens obtained by stereolithography (SLA), which is a kind of AM. A mold insert obtained by AM and a mold produced by traditional subtractive manufacturing were compared to evaluate the performance of the injected parts. In particular, mechanical tests (in accordance with ASTM D638) and temperature distribution performance tests were carried out. The tensile test results of specimens obtained in a 3D printed mold insert were better (almost 15%) than those produced in the duralumin mold. The simulated temperature distribution closely matched its experimental counterpart-the difference in average temperatures was merely 5.36 °C. These findings support the use of AM in injection molding and RT as an excellent alternative for small and medium-sized production runs in the global injection industry.

Desempeño Mecánico de Compuestos de Madera Plástica de Matriz Poliolefínica / Mechanical performance of polyolefinic wood plastic composites / Desempenho mecânicos de compostos de Madeira Plástica de Matriz Poliolefina

Resumen Los polímeros termoplásticos, pueden ser mezclados con diferentes tipos de cargas con el propósito de mejorar su rendimiento físico-mecánico, al mismo tiempo que permiten en muchos casos, generar soluciones a problemáticas ambientales como por ejemplo la disposición final de residuos de madera. Los compuestos de madera plástica son productos elaborados mediante la incorporación de fibras o partículas de madera en la matriz polimérica, donde la interacción entre los dos materiales (nula o con acople) es clave para lograr un adecuado desempeño del producto final. En esta revisión se establecen las matrices poliméricas y los tipos de maderas empleadas comúnmente en la elaboración de productos de madera plástica, al mismo tiempo que se definen los tratamientos previos que deben ser realizados tanto en la madera como en el polímero con el propósito de mejorar la compatibilidad de los dos materiales, y de esta manera mejorar propiedades como la absorción de agua, la resistencia a la descomposición, a la intemperie y el desempeño mecánico. En cuanto a las propiedades mecánicas, al adicionar un contenido de madera en el polímero se modifica la rigidez del material polimérico y la resistencia en tensión, flexión e impacto; sin embargo, se establece que es clave el uso de agentes funcionalizantes para que el efecto de la incorporación de la madera en polímero sea positivo. Finalmente se estudian las nuevas tendencias en el uso de diferentes tipos de residuos y matrices poliméricas para la elaboración de maderas plásticas.

Abstract Polymeric materials, especially thermoplastics, can be mixed with different types of fillers to improve their physical-mechanical performance, at the same time they allow, in many cases, to generate solutions to environmental problems such as the final disposal of wood waste. The plastic wood composites are products made by incorporating wood fibers in the polymer matrix, where the interaction between the two materials is key to achieve an adequate performance of the final product. This review establishes the polymer matrices and the types of wood commonly used in the production of plastic wood products, at the same time defining the previous treatments that must be carried out in the wood and in the polymer to improve the compatibility of the two materials, and in this way improve properties such as water absorption, resistance to decomposition, resistance to weathering and mechanical performance. Related to the mechanical properties, adding the wood fibers in the polymer modifies the rigidity of the polymeric material and the resistance in tension, bending and impact; however, it is established that the use of functionalizing agents is a fundamental key to improve the effect of wood incorporation into the polymer matrix. Finally, the new trends in the use of different types of waste and polymeric matrices to produce plastic wood are studied.

Resumo Os materiais poliméricos, principalmente os termoplásticos, podem ser misturados a diferentes tipos de cargas para melhorar seu desempenho físico-mecânico, ao mesmo tempo que, em muitos casos, permitem gerar soluções para problemas ambientais como a destinação final de resíduos. madeira. Os compósitos madeira-plástico são produtos obtidos pela incorporação de fibras de madeira à matriz polimérica, onde a interação entre os dois materiais é fundamental para um desempenho adequado do produto final. Nesta revisão, são estabelecidas as matrizes poliméricas e os tipos de madeira comumente utilizados na produção de produtos plásticos de madeira, ao mesmo tempo em que são definidos os tratamentos anteriores que devem ser realizados na madeira e no polímero para melhorar a compatibilidade dos dois materiais, e desta forma melhorar propriedades como absorção de água, resistência à decomposição, intempéries e desempenho mecânico. Em relação às propriedades mecânicas, ao adicionar as fibras de madeira ao polímero, a rigidez do material polimérico e a resistência à tração, flexão e impacto são modificadas; porém, está estabelecido que o uso de agentes funcionalizantes é fundamental para que o efeito da incorporação da madeira no polímero seja positivo. Por fim, são estudadas as novas tendências no uso de diferentes tipos de resíduos e matrizes poliméricas para a produção de madeira plástica.

Analysis and Advances in Additive Manufacturing as a New Technology to Make Polymer Injection Molds for World-Class Production Systems.

The currently growing demand for metallic and polymeric products has undoubtedly changed the rules of manufacturing, enabling customers to more functionally define their products based on their needs. Nowadays, a new technique for rapid tooling, Additive Manufacturing (AM), can create customized products with more complex geometries and short life cycles (flexibility) in order to keep up with the new variables imposed by the manufacturing environment. In the last two decades, the migration from subtractive manufacturing to AM has materialized such products with reduced costs and cycle times. AM has been recently promoted to develop polymer molds for product manufacturing. This paper reviews the main findings in the literature concerning polymer molds created by AM compared to conventional (metal) molds obtained by subtractive manufacturing. Information about specific topics is scarce or nonexistent, for example, about the characterization of the most commonly injected materials and molds used in this type of technology, their mechanical properties (part and mold), designs for all types of geometries, and costs. These aspects are addressed in this literature review, highlighting the advantages of this alternative manufacturing process, which is considered a desirable technology worldwide.

Segmental Cervical Aplasia in a Colombian Creole Mare with Mosaic X-Chromosome Aneuploidy.

A 4-year-old Colombian Creole mare was presented for diagnosis because the external orifice of her cervix was not detectable when a uterine lavage as therapy for uterine fluid accumulation was attempted. Clinical and ultrasonographic evaluation of the genital tract revealed that ovaries were of normal size and showed structures suggestive of regular ovarian activity. However, granular free-floating fluid material distending the uterus was detected by ultrasound. Upon vaginal examination, the normal external cervical morphology was not evident. The vagina ended in a blind bag with a small papilla with no evident external cervical os. Cytology of uterine fluid obtained by transvaginal aspiration showed findings compatible with mucometra. Cytogenetic analysis revealed an abnormal karyotype (63,X and 64,XX both 45% and 65,XXX 10%). A diagnosis of congenital segmental cervical aplasia was proposed possibly related to the mosaicism detected. To our knowledge, this is the first case of this reproductive pathology in a mare with regular ovarian activity and confirmed aneuploidy in mosaic form of the X sex chromosome.

Transformation of coffee-growing landscapes across Latin America. A review.

In Latin America, the cultivation of Arabica coffee (Coffea arabica) plays a critical role in rural livelihoods, biodiversity conservation, and sustainable development. Over the last 20 years, coffee farms and landscapes across the region have undergone rapid and profound biophysical changes in response to low coffee prices, changing climatic conditions, severe plant pathogen outbreaks, and other drivers. Although these biophysical transformations are pervasive and affect millions of rural livelihoods, there is limited information on the types, location, and extent of landscape changes and their socioeconomic and ecological consequences. Here we review the state of knowledge on the ongoing biophysical changes in coffee-growing regions, explore the potential socioeconomic and ecological impacts of these changes, and highlight key research gaps. We identify seven major land-use trends which are affecting the sustainability of coffee-growing regions across Latin America in different ways. These trends include (1) the widespread shift to disease-resistant cultivars, (2) the conventional intensification of coffee management with greater planting densities, greater use of agrochemicals and less shade, (3) the conversion of coffee to other agricultural land uses, (4) the introduction of Robusta coffee (Coffea canephora) into areas not previously cultivated with coffee, (5) the expansion of coffee into forested areas, (6) the urbanization of coffee landscapes, and (7) the increase in the area of coffee produced under voluntary sustainability standards. Our review highlights the incomplete and scattered information on the drivers, patterns, and outcomes of biophysical changes in coffee landscapes, and lays out a detailed research agenda to address these research gaps and elucidate the effects of different landscape trajectories on rural livelihoods, biodiversity conservation, and other aspects of sustainable development. A better understanding of the drivers, patterns, and consequences of changes in coffee landscapes is vital for informing the design of policies, programs, and incentives for sustainable coffee production. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13593-021-00712-0.

Incorporating the recovered carbon black produced in an industrial-scale waste tire pyrolysis plant into a natural rubber formulation.

This paper presents the experimental results obtained after incorporating the recovered Carbon Black (rCB) produced in an industrial-scale waste tire pyrolysis plant into a Natural Rubber (NR) formulation. The purpose of this study is to increase the technical knowledge on the use of rCB as a sustainable raw material in the rubber industry. The rCB and virgin Carbon Black (vCB) (ref. N550) under study were characterized using elemental and proximate analyses, X-Ray Fluorescence (XRF), Fourier Transform Infrared (FTIR) spectroscopy, and Scanning Electron Microscopy (SEM) were used, and different measures, including the Brunauer-Emmett-Teller (BET) surface area (SBET), particle size distribution (PSD), specific gravity, and pH, were estimated. The effect of rCB incorporation on the rheological, thermal, structural, and mechanical properties of the NR composites was assessed and compared to those obtained with vCB alone. The NR composites were prepared using different loads of vCB (20, 30, 40, and 50 phr), which was also replaced with rCB at different proportions (0, 50, and 100%). According to the characterization results, rCB offers lower reinforcement properties than vCB, which is attributable to its higher volatile matter and ash contents, higher apparent PSD, lower presence of acidic functional groups, and lower SBET. Despite this, interesting performances can be achieved when rCB is partially incorporated into the formulations or by increasing its load in the composites. For instance, when 50% of vCB was replaced with rCB, the values of the aforementioned properties were found to be between those obtained with the NR composites prepared with vCB and rCB. In addition, when increasing the rCB loading, some properties matched the behavior exhibited by vCB alone, thus compensating for the low reinforcement properties of rCB. These results are expected to provide an important impetus to move towards circular economy strategies having very positive impacts from the sustainable perspective.

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

La medicina regenerativa: fundamentos y aplicaciones / Regenerative medicine: fundamentals and applications

Resumen Introducción. Se revisaron los fundamentos biológicos de la medicina regenerativa, en particular de las células madre y de los factores de crecimiento plaquetarios. Se presentan la clasificación, fuentes de obtención y mecanismos de acción propuestos para las células madre, así como los grandes desafíos biotecnológicos para el desarrollo de la medicina regenerativa y la evidencia clínica de su relación seguridad/efectividad en la práctica médica. Objetivo. Revisar y sistematizar la información actualizada acerca de los fundamentos y potenciales usos de la medicina regenerativa. Metodología. Se realizó una búsqueda sistemática de la literatura en las bases de datos Pubmed, Medline, Science y Cochrane, entre los años 2010 y el 2016, mediante las siguientes palabras clave: stem cells, mesenchymal stem cells, medicine regenerative, homing, platelet-rich plasma, platelet growth factors.

Abstract Introduction. We reviewed the biological fundaments of regenerative medicine, in particular of stem cells and the platelet growth factors. We presented the classification, sources of supply and proposed mechanisms of action for stem cells, as well as the great challenges of biotechnology for the development of regenerative medicine and the clinical evidence of its safety/efficacy relationship in medical practice. Objective. Review and systematize the updated information about the fundaments and potential uses of the regenerative medicine. Methodology. A systematic literature search was conducted in the Pubmed, Medline, Science and Cochrane databases, between 2010 and 2016, using the following key words: stem cells, mesenchymal stem cells, medicine regenerative, homing, platelet-rich plasma, platelet growth factors.

Evaluación del programa de mantenimiento con metadona del Hospital Mental de Risaralda / Evaluation of the Methadone Maintenance Program of the Risaralda Mental Hospital

Introducción: La atención psicosocial y el tratamiento de mantenimiento con metadona (TMM) son las estrategias preferidas para el manejo de adictos a heroína, pero los resultados siguen siendo insatisfactorios, lo que justifica la búsqueda e intervención sobre los factores que influyen en la respuesta al tratamiento. Métodos: Con el propósito de determinar la contribución de una serie de variables demográficas, clínicas y genéticas en las concentraciones séricas y la respuesta a la metadona, estudiamos a pacientes del TMM que estuvieran recibiendo metadona con supervisión y sin cambios en las dosis por lo menos durante las últimas 2 semanas. Se les registró edad, sexo, índice de masa corporal (IMC), tiempo de abuso de heroína, adicción a otras drogas, antecedentes delictivos, dosis diaria actual de metadona, tiempo de permanencia en el TMM, comorbilidad y comedicación. Se les tomaron muestras de sangre para determinar concentraciones séricas de metadona racémica y sus enantiómeros R-y S-, y para la tipificación de alelos candidatos de los genes POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH y ARRB2, todos ellos asociados con el metabolismo, la distribución tisular y el mecanismo de acción de la metadona. La cuantificación de metadona se hizo mediante HPLC-DAD y la detección de los marcadores genéticos por los métodos de PCR en tiempo real y VNTR. Resultados: Se incluyó a 80 personas de 23,5 ± 5a ˜nos (el 86% varones), todos policonsumidores de sustancias adictivas, el 60% con antecedentes delictivos, con 5,1 ± 2,9 años de consumo de heroína y 5,3 ± 4 meses de ingreso al TMM, con 41 ± 12 mg/día de meta-dona tomada con supervisión. Las concentraciones valle de RS-, R-y S-metadona fueron, respectivamente, 168 ± 77, 84 ± 40 y 84 ± 42 ng/ml. Todos los genotipos estuvieron en equilibrio de Hardy-Weinberg. Las dos pruebas de orina fueron negativas para heroína en el 61,3% (49/80) de los voluntarios; el descenso en el consumo de cocaína/basuco fue del 83%; el de marihuana, del 30% y el de otros psicoactivos (inhalantes, benzodiacepinas, anfetaminas) bajó a cero, mientras el consumo de tabaco permaneció en el 93,5% (75/80). Las concentraciones de metadona racémica y sus enantiómeros se correlacionaron significativamente con las dosis diaria del fármaco, pero ninguna de las demás variables demográficas, clínicas o genéticas incidió en la concentración sérica de metadona. En cuanto a los resultados del TMM, los no consumidores y los consumidores ocasionales de heroína, así como los que abandonaron el consumo de otros psicoactivos y los que no, tuvieron características similares con respecto a las variables demográficas, genéticas y clínicas, incluidas las concentraciones sanguíneas de metadona, con excepción de los individuos que no disminuyeron el consumo de otros psicoactivos distintos de heroína, quienes tuvieron significativamente (p = 0,03) mayores concentraciones sanguíneas de S-metadona que quienes sí abandonaron el consumo. Conclusiones: Hubo importante reducción en los consumos de heroína y otros psicoactivos y reinserción social de los pacientes; sin embargo, la amplia superposición entre las dosis efectivas e inefectivas de metadona apunta a la presencia de variables personales y sociales que trascienden el simple manejo farmacológico y probablemente deban ser abordadas con más éxito desde lo psicosocial, particularmente en lo que tiene que ver con la identificación y superación de las experiencias detonantes de recaídas y con ciertos rasgos del paciente, tales como su nivel de estrés psicológico o sus trastornos psiquiátricos.

Background: Psychosocial care and methadone maintenance treatment (MMT) are the preferred strategies for the management of heroin addicts, but the results are still unsa-tisfactory, justifying the search and intervention of the factors influencing the response to treatment. Methodology: In order to determine the contribution of demographic, clinical and genetic variables on serum concentrations and response to methadone, we investigated patients on MMT, who were receiving methadone in supervised and unchanged doses at least during the previous two weeks. The age, gender, body mass index (BMI), duration of heroin abuse, addiction to other drugs, criminal background, current daily methadone doses, time spent in the TMM, comorbidity and concomitant medication were recorded. Blood samples were taken for the determination of serum levels of racemic methadone and its R and S-enantiomers, and for typing of candidate alleles of POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH and ARRB2 genes, all associated with the metabolism, tissue distribution and mechanism of action of methadone. Methadone quantification was by HPLC-DAD, and the detection of genetic markers by Real Time PCR and VNTR methods. Results: A total of 80 subject volunteers were enrolled, with a mean age of 23.5 (5) years (86% male), all of them were addicts of multiple drugs, 60% with a criminal background, 5.1 (2.9) years taking heroin, and 5.3 (4) months on MMT, and taking a supervised dose of 41 (12) mg/day methadone. The (R), (S) and (R, S) methadone enantiomer trough plasma levels were, 84 (40), 84 (42), and 168 (77) ng/mL, respectively. All genotypes were in Hardy-Weinberg equilibrium. The two urine tests were negative for heroin in 61.3% (49/80) of the volunteers, the decline in cocaine/crack use was 83%, 30% of marijuana, and other psychoactives (inhalants, benzodiazepines, amphetamines) decreased to zero, while the consumption of snuff remained at 93.5% (75/80). Blood concentrations of racemic methadone and its enantiomers were significantly associated with the dose/day of the medication, but none of the other demographic, clinical or genetic variables impacted on serum levels of methadone. As for the results of the MMT, non-users and occasional users of heroin, as well as those who stopped taking other psychoactive drugs, and the ones who did not, were similar as regards the demographic, genetic and clinical variables. This included the blood metahdone concentrations, except for individuals who did not reduce their consumption of other psychoactives other than heroin, who had significantly (P = .03) higher blood levels of S-methadone, compared with those who did stop taking them. Conclusions: There was a significant reduction in the consumption of heroin and other psychoactives, and social rehabilitation of patients. However, the extensive overlap between effective and ineffective doses of methadone suggests the presence of personal and social variables that transcend the simple pharmacological management. These probably need to be addressed more successfully from the psychosocial features, particularly as regards to identifying and overcoming relapse-trigger experiences, as well as certain features of the patient, such as their psychological distress level or their psychiatric disorders.

Niveles de citoquinas en suero de adictosa heroína bajo consumo activo o en terapia de mantenimiento con metadona y controles sanos en Pereira (Colombia) / Cytokine levels in serum of heroin addicts under active consumption or methadone maintenance therapy and healthy control in Pereira (Colombia)

Introducción: el tratamiento con metadona constituye el estándar de manejo de adictos a heroína. Durante la rehabilitación los pacientes mejoran su estado de salud y parecen volverse inmunocompetentes; hecho atribuido al abandono de prácticas de riesgo, mejor nutrición y suspensión de la heroína, cuyo efecto inmunodepresor es conocido. Pero como la metadona es también antagonista del glutamato, podría teneractividad inmunoestimulante adicional.Objetivo: comparar niveles séricos de las citoquinas FNT-α, IFN-γ e IL-10, entre adictos a heroína en consumo activo (CA=32), adictos tratados con metadona (Met=20) y controles sanos sin historia de adicción (Cont=20).Materiales y métodos: participaron 72 individuos de ambos sexos, mayores de edad, con pruebas serológicas para VIH/SIDA, hepatitis B y C negativas, que no utilizaran fármacos con efectos sobre el sistema inmune. Resultados: no hubo diferencias entre los grupos respecto a género (91,7% hombres), edad (25,2 ± 8 años) y tiempo de abuso de heroína (5,3 ± 2,9 años). Todos los adictosreportaron consumo de otras drogas ilícitas: 96% marihuana, 79 por ciento cocaína/basuco y 52 por ciento otros psicoactivos. Ningún individuo del grupo Met seguía consumiendo cocaína/basuco, pero la mayoría continuaba el consumo de marihuana. Se encontrarondiferencias significativas en los niveles de FNT-α (p=0,0004), IFN-γ (p=0,014) e IL- 10 (p=0,0001) entre los tres grupos estudiados; esta diferencia se conserva para las tres citoquinas cuando se comparan adictos con no adictos.Conclusión: se encontró un patrón de producción de citoquinas séricas diferencial entre adictos y no adictos, pero no fue posible determinar un patrón de respuesta inmune inducido por metadona.

Perception of the usefulness of drug/gene pairs and barriers for pharmacogenomics in Latin America.

Pharmacogenetics and Pharmacogenomics areas are currently emerging fields focused to manage pharmacotherapy that may prevent undertreatment while avoiding associated drug toxicity in patients. Large international differences in the awareness and in the use of pharmacogenomic testing are presumed, but not well assessed to date. In the present study we review the awareness of Latin American scientific community about pharmacogenomic testing and the perceived barriers for their clinical application. In order to that, we have compiled information from 9 countries of the region using a structured survey which is compared with surveys previously performed in USA and Spain. The most relevant group of barriers was related to the need for clear guidelines for the use of pharmacogenomics in clinical practice, followed by insufficient awareness about pharmacogenomics among clinicians and the absence of regulatory institutions that facilitate the use of pharmacogenetic tests. The higher ranked pairs were TPMT/thioguanine, TPMT/azathioprine, CYP2C9/warfarin, UGT1A1/irinotecan, CYP2D6/amitriptiline, CYP2C19/citalopram and CYP2D6/clozapine. The lower ranked pairs were SLCO1B1/simvastatin, CYP2D6/metoprolol and GP6D/chloroquine. Compared with USA and Spanish surveys, 25 pairs were of lower importance for Latin American respondents. Only CYP2C19/esomeprazole, CYP2C19/omeprazole, CYP2C19/celecoxib and G6PD/dapsone were ranked higher or similarly to the USA and Spanish surveys. Integration of pharmacogenomics in clinical practice needs training of healthcare professionals and citizens, but in addition legal and regulatory guidelines and safeguards will be needed. We propose that the approach offered by pharmacogenomics should be incorporated into the decision-making plans in Latin America.

[Evaluation of the Methadone Maintenance Program of the Risaralda Mental Hospital]. / Evaluación del programa de mantenimiento con metadona del Hospital Mental de Risaralda.

BACKGROUND: Psychosocial care and methadone maintenance treatment (MMT) are the preferred strategies for the management of heroin addicts, but the results are still unsatisfactory, justifying the search and intervention of the factors influencing the response to treatment. METHODOLOGY: In order to determine the contribution of demographic, clinical and genetic variables on serum concentrations and response to methadone, we investigated patients on MMT, who were receiving methadone in supervised and unchanged doses at least during the previous two weeks. The age, gender, body mass index (BMI), duration of heroin abuse, addiction to other drugs, criminal background, current daily methadone doses, time spent in the TMM, comorbidity and concomitant medication were recorded. Blood samples were taken for the determination of serum levels of racemic methadone and its R and S-enantiomers, and for typing of candidate alleles of POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH and ARRB2 genes, all associated with the metabolism, tissue distribution and mechanism of action of methadone. Methadone quantification was by HPLC-DAD, and the detection of genetic markers by Real Time PCR and VNTR methods. RESULTS: A total of 80 subject volunteers were enrolled, with a mean age of 23.5 (5) years (86% male), all of them were addicts of multiple drugs, 60% with a criminal background, 5.1 (2.9) years taking heroin, and 5.3 (4) months on MMT, and taking a supervised dose of 41 (12) mg/day methadone. The (R), (S) and (R, S) methadone enantiomer trough plasma levels were, 84 (40), 84 (42), and 168 (77) ng/mL, respectively. All genotypes were in Hardy-Weinberg equilibrium. The two urine tests were negative for heroin in 61.3% (49/80) of the volunteers, the decline in cocaine/crack use was 83%, 30% of marijuana, and other psychoactives (inhalants, benzodiazepines, amphetamines) decreased to zero, while the consumption of snuff remained at 93.5% (75/80). Blood concentrations of racemic methadone and its enantiomers were significantly associated with the dose/day of the medication, but none of the other demographic, clinical or genetic variables impacted on serum levels of methadone. As for the results of the MMT, non-users and occasional users of heroin, as well as those who stopped taking other psychoactive drugs, and the ones who did not, were similar as regards the demographic, genetic and clinical variables. This included the blood metahdone concentrations, except for individuals who did not reduce their consumption of other psychoactives other than heroin, who had significantly (P=.03) higher blood levels of S-methadone, compared with those who did stop taking them. CONCLUSIONS: There was a significant reduction in the consumption of heroin and other psychoactives, and social rehabilitation of patients. However, the extensive overlap between effective and ineffective doses of methadone suggests the presence of personal and social variables that transcend the simple pharmacological management. These probably need to be addressed more successfully from the psychosocial features, particularly as regards to identifying and overcoming relapse-trigger experiences, as well as certain features of the patient, such as their psychological distress level or their psychiatric disorders.

Genetic variants associated with addictive behavior in Colombianaddicted and non-addicted to heroin or cocaine / Variantes genéticas asociadas con conducta adictiva en colombianos adictos y no adictos a heroína o cocaína

Objective:Determine the prevalence and compare somegenetic markers involved in addictive behavior in a groupof addicts to derivative of coca (cocaine/crack) or heroinand a control group of non-addicted people matched forgender, age and ethnicity.Methods:A 120 addicts and 120 non-addicts Colombianmale were surveyed and genotyped for 18 polymorphismof the OPRM1, DRD2, DRD4, SLC6A3, SLC6A4, ABCB1,DβH and CYP2B6 genes. For the identification of allelesmarkers were used mini-sequencing and fragment multi-plex PCR techniques; ethnicity of cases and controls wasanalyzed with 61 AIMs.Results:The age of onset use of heroin or coca derivati-ves (cocaine/crack) was 16,5±6 years and 99,2 percent of themconsume several illicit drugs. It showed that controlsand addicts belong to the same ethnic group. Significantdifferences between addicts and controls in relation toschooling, marital status, social security family historyof substance abuse (p<0,001), Int8-VNTR SLC6A3 gene(p=0,015) and SNP 3435C>T ABCB1 gene (p=0,001) werefound.Conclusion:The present results indicate that the VNTR-6R polymorphism of the gene SLC6A3 and the genoty-pe 3435CC in the ABCB1 gene, are both associated withaddictive behavior to heroin or cocaine.