Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study.

BACKGROUND: Sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs). Fetal hemoglobin (HbF) interferes with this polymerization, but HbF is epigenetically silenced from infancy onward by DNA methyltransferase 1 (DNMT1). METHODS AND FINDINGS: To pharmacologically re-induce HbF by DNMT1 inhibition, this first-in-human clinical trial (NCT01685515) combined 2 small molecules-decitabine to deplete DNMT1 and tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that otherwise rapidly deaminates/inactivates decitabine, severely limiting its half-life, tissue distribution, and oral bioavailability. Oral decitabine doses, administered after oral THU 10 mg/kg, were escalated from a very low starting level (0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg) to identify minimal doses active in depleting DNMT1 without cytotoxicity. Patients were SCD adults at risk of early death despite standard-of-care, randomized 3:2 to THU-decitabine versus placebo in 5 cohorts of 5 patients treated 2X/week for 8 weeks, with 4 weeks of follow-up. The primary endpoint was ≥ grade 3 non-hematologic toxicity. This endpoint was not triggered, and adverse events (AEs) were not significantly different in THU-decitabine-versus placebo-treated patients. At the decitabine 0.16 mg/kg dose, plasma concentrations peaked at approximately 50 nM (Cmax) and remained elevated for several hours. This dose decreased DNMT1 protein in peripheral blood mononuclear cells by >75% and repetitive element CpG methylation by approximately 10%, and increased HbF by 4%-9% (P < 0.001), doubling fetal hemoglobin-enriched red blood cells (F-cells) up to approximately 80% of total RBCs. Total hemoglobin increased by 1.2-1.9 g/dL (P = 0.01) as reticulocytes simultaneously decreased; that is, better quality and efficiency of HbF-enriched erythropoiesis elevated hemoglobin using fewer reticulocytes. Also indicating better RBC quality, biomarkers of hemolysis, thrombophilia, and inflammation (LDH, bilirubin, D-dimer, C-reactive protein [CRP]) improved. As expected with non-cytotoxic DNMT1-depletion, platelets increased and neutrophils concurrently decreased, but not to an extent requiring treatment holds. As an early phase study, limitations include small patient numbers at each dose level and narrow capacity to evaluate clinical benefits. CONCLUSION: Administration of oral THU-decitabine to patients with SCD was safe in this study and, by targeting DNMT1, upregulated HbF in RBCs. Further studies should investigate clinical benefits and potential harms not identified to date. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01685515.

Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype.

BACKGROUND AND AIMS: Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. METHODS: We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH4 responsiveness and growth outcome. RESULTS: No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial= -0.57 ± 1.54; final=-0.52 ± 1.29; BMI Z-score: initial=0.17 ± 1.05; final=0.18 ± 1.00) or the diet-only group (height Z-score: initial=-0.92 ± 0.96; final= -0.78 ± 1.08; BMI Z-score: initial=0.17 ± 0.97; final=-0.07 ± 1.03) over the 1-year observation period. Furthermore, we found no significant differences (p>0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6-60.3] to 56.5 [39.8-68.3] mgkg(-1)day(-1)) and natural protein intake (from 1.0 [0.8-1.7] to 1.5 [1.0-1.8] g kg(-1)day(-1)), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p<0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration. CONCLUSIONS: Our study indicates that treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes.

Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine.

The deoxycytidine analog decitabine (DAC) can deplete DNA methyl-transferase 1 (DNMT1) and thereby modify cellular epigenetics, gene expression, and differentiation. However, a barrier to efficacious and accessible DNMT1-targeted therapy is cytidine deaminase, an enzyme highly expressed in the intestine and liver that rapidly metabolizes DAC into inactive uridine counterparts, severely limiting exposure time and oral bioavailability. In the present study, the effects of tetrahydrouridine (THU), a competitive inhibitor of cytidine deaminase, on the pharmacokinetics and pharmacodynamics of oral DAC were evaluated in mice and nonhuman primates. Oral administration of THU before oral DAC extended DAC absorption time and widened the concentration-time profile, increasing the exposure time for S-phase-specific depletion of DNMT1 without the high peak DAC levels that can cause DNA damage and cytotoxicity. THU also decreased interindividual variability in pharmacokinetics seen with DAC alone. One potential clinical application of DNMT1-targeted therapy is to increase fetal hemoglobin and treat hemoglobinopathy. Oral THU-DAC at a dose that would produce peak DAC concentrations of less than 0.2µM administered 2×/wk for 8 weeks to nonhuman primates was not myelotoxic, hypomethylated DNA in the γ-globin gene promoter, and produced large cumulative increases in fetal hemoglobin. Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy.

Enhancing effect of glucose microspheres in the viability of human mesenchymal stem cell suspensions for clinical administration.

PURPOSE: A critical limiting factor of cell therapy is the short life of the stem cells. In this study, glucose containing alginate microspheres were developed and characterized to provide a sustained release system prolonging the viability of human mesenchymal stem cells (hMSCs) in a suspension for clinical application. METHODS: The glucose microspheres were satisfactorily elaborated with alginate by emulsification/internal gelation method. Particle size was evaluated by light diffraction and optical microscopy. Shape and surface texture by scanning electron microscopy (SEM). Zeta potential, infrared spectra and release studies were also conducted. Also, rheological properties and stability of hMSCs suspensions with microspheres were tested. The viability of hMSCs was determined by trypan blue dye exclusion staining. RESULTS: Microspheres of 86.62 µm, spherical shaped and -32.54 mV zeta potential with excellent stability, good encapsulation efficiency and providing an exponential release of glucose were obtained. hMSCs had better survival rate when they were packed with glucose microspheres. Microspheres maintained the aseptic conditions of the cell suspension without rheological, morphological or immunophenotypic disturbances on hMSCs. CONCLUSIONS: Developed microspheres were able to enhance the functionality of hMSC suspension. This strategy could be broadly applied to various therapeutic approaches in which prolonged viability of cells is necessary.

Inflammatory response in mixed viral-bacterial community-acquired pneumonia.

BACKGROUND: The role of mixed pneumonia (virus+bacteria) in community-acquired pneumonia (CAP) has been described in recent years. However, it is not known whether the systemic inflammatory profile is different compared to monomicrobial CAP. We wanted to investigate this profile of mixed viral-bacterial infection and to compare it to monomicrobial bacterial or viral CAP. METHODS: We measured baseline serum procalcitonin (PCT), C reactive protein (CRP), and white blood cell (WBC) count in 171 patients with CAP with definite etiology admitted to a tertiary hospital: 59 (34.5%) bacterial, 66 (39.%) viral and 46 (27%) mixed (viral-bacterial). RESULTS: Serum PCT levels were higher in mixed and bacterial CAP compared to viral CAP. CRP levels were higher in mixed CAP compared to the other groups. CRP was independently associated with mixed CAP. CRP levels below 26 mg/dL were indicative of an etiology other than mixed in 83% of cases, but the positive predictive value was 45%. PCT levels over 2.10 ng/mL had a positive predictive value for bacterial-involved CAP versus viral CAP of 78%, but the negative predictive value was 48%. CONCLUSIONS: Mixed CAP has a different inflammatory pattern compared to bacterial or viral CAP. High CRP levels may be useful for clinicians to suspect mixed CAP.

Tetrahydrobiopterin therapy vs phenylalanine-restricted diet: impact on growth in PKU.

BACKGROUND: Treatment of phenylketonuria based upon strict vegetarian diets, with very low phenylalanine intake and supplemented by phenylalanine-free formula, has proven to be effective in preventing the development of long-term neurological sequelae due to phenylalanine accumulation. On the other hand, such diets have occasionally been reported to hinder normal development, some individuals presenting with growth retardation. Tetrahydrobiopterin therapy has opened up new treatment options for a significant proportion of phenylketonuric patients, enabling them to eat normal diets and be freed from the need to take synthetic supplements. However, little is known about how this therapy affects their physical development. METHODS: We conducted a retrospective longitudinal study examining anthropometric characteristics (height, weight, body mass index and growth speed Z-scores) in a cohort of phenylketonuric patients on tetrahydrobiopterin therapy (38 subjects) comparing their characteristics with those of a group of phenylketonuric patients on phenylalanine-restricted diets (76 subjects). Nutritional issues were also considered, to further explore the possibility of higher natural protein intake being associated with better physical development. Data were collected every six months over two different periods of time (two or five years). RESULTS: No improvement was observed in the aforementioned anthropometric variables in the cohort on tetrahydrobiopterin therapy, from prior to starting treatment to when they had been taking the drug for two or five years. Rather, in almost all cases there was a fall in the mean Z-score for the variables during these periods, although the changes were not significant in any case. Further, we found no statistically differences between the two groups at any considered time point. Growth impairment was also noted in the phenylketonuric patients on low-phenylalanine diets. Individuals on tetrahydrobiopterin therapy increased their natural protein intake and, in some instances, this treatment enabled individuals to eat normal diets, with protein intake meeting RDAs. No association was found, however, between higher protein intake and growth. CONCLUSION: Our study identified growth impairment in patients with phenylketonuria on tetrahydrobiopterin, despite higher intakes of natural proteins. In fact, individuals undergoing long-term tetrahydrobiopterin treatment seemed to achieve similar developmental outcomes to those attained by individuals on more restricted diets.

Low temperature highlights the functional role of the cell wall integrity pathway in the regulation of growth in Saccharomyces cerevisiae.

Unlike other stresses, the physiological significance and molecular mechanisms involved in the yeast cold response are largely unknown. In the present study, we show that the CWI (cell wall integrity) pathway plays an important role in the growth of Saccharomyces cerevisiae at low temperatures. Cells lacking the Wsc1p (wall integrity and stress response component 1) membrane sensor or the MAPKs (mitogen-activated protein kinases) Bck1p (bypass of C kinase 1), Mkk (Mapk kinase) 1p/Mkk2p or Slt2p (suppressor of lyt2) exhibited cold sensitivity. However, there was no evidence of either a cold-provoked perturbation of the cell wall or a differential cold expression program mediated by Slt2p. The results of the present study suggest that Slt2p is activated by different inputs in response to nutrient signals and mediates growth control through TORC1 (target of rapamycin 1 complex)-Sch9p (suppressor of cdc25) and PKA (protein kinase A) at low temperatures. We found that absence of TOR1 (target of rapamycin 1) causes cold sensitivity, whereas a ras2Δ mutant shows increased cold growth. Lack of Sch9p alleviates the phenotype of slt2Δ and bck1Δ mutant cells, as well as attenuation of PKA activity by overexpression of BCY1 (bypass of cyclase mutations 1). Interestingly, swi4Δ mutant cells display cold sensitivity, but the phenotype is neither mediated by the Slt2p-regulated induction of Swi4p (switching deficient 4)-responsive promoters nor influenced by osmotic stabilization. Hence, cold signalling through the CWI pathway has distinct features and might mediate still unknown effectors and targets.

Haptoglobin 1 allele predicts higher serum haptoglobin concentration and lower multiorgan failure risk in sickle cell disease.

Haptoglobin (HP) is an acute-phase protein and the main scavenger of cell-free hemoglobin. When HP is depleted, as observed in hemolytic conditions such as sickle cell disease (SCD), cell-free hemoglobin can lead to acute organ damage. The impact of the HP 1-1, 2-1, and 2-2 isoforms on HP and cell-free hemoglobin concentrations and SCD-related complications is unclear. In a longitudinal cohort of patients with SCD, the HP 1 allele was associated with higher HP and lower cell-free hemoglobin concentrations at a routine clinic visit as well as during hospitalization for a vaso-occlusive episode or acute chest syndrome. With a median follow-up of 6.8 years, acute chest syndrome occurred in 42% (n = 163) and multiorgan failure in 14% (n = 53) of 391 patients with SCD with a minimum follow-up of 6 months. The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model hazard ratio, 0.5; P < .001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to the HP genotype may help to identify patients with SCD at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy.

Asociación del signo de Moore con la presencia de absceso profundo de cuello de espacio retrofaríngeo.

BACKGROUND: Deep neck abscesses can cause life-threatening complications. They are diagnosed by physical examination, and contrasted tomography as the gold standard. There are no studies about the association of Moore's sign with infections of the retropharyngeal space. OBJECTIVE: To determine the usefulness of Moore's sign in the diagnosis of deep retropharyngeal abscess. METHOD: Observational, analytical, cross-sectional, study of patients with deep neck abscess, from May 1, 2019, to August 30, 2021, with report of Moore's sign. RESULTS: 87 patients were included, 49 (56.3%) males (p = 0.45). Of those who developed complications, 77.8% had a negative Moore's sign (p = 0.001). Of those admitted to the ICU, 72% had a negative Moore's sign (p = 0.001). The sensitivity of the absence of the sign with retropharyngeal involvement was 95.4%, and the specificity was 86.3%. By logistic regression, it was found that those with retropharyngeal involvement are 467 times more likely to present a negative sign (p < 0.05). CONCLUSIONS: The presence of abscess in the retropharynx is associated with complications and a worse prognosis. The evaluation of Moore's sign can be a useful tool to suspect compromise of this space.

ANTECEDENTES: Los abscesos profundos de cuello pueden ocasionar complicaciones letales. Se diagnostican por exploración física, y la tomografía contrastada es el método de referencia. No existen estudios de asociación del signo de Moore con infecciones del espacio retrofaríngeo. OBJETIVO: Determinar la utilidad del signo de Moore en el diagnóstico de absceso profundo en el espacio retrofaríngeo. MÉTODO: Estudio observacional, transversal y analítico, de pacientes con absceso profundo de cuello, del 1 de mayo de 2019 al 30 de agosto de 2021, con reporte de signo de Moore. RESULTADOS: Se incluyeron 87 pacientes, de los cuales 49 (56.3%) eran de sexo masculino (p = 0.45). De los que desarrollaron complicaciones, el 77.8%, tenían el signo de Moore negativo (p = 0.001). De los que ingresaron a la unidad de cuidados intensivos, el 72% tenían negativo el signo de Moore (p = 0.001). La sensibilidad de la ausencia del signo con afección del espacio retrofaríngeo fue del 95.4%, y la especificidad del 86.3%. Por regresión logística se encontró que aquellos con afección del espacio retrofaríngeo tienen 467 veces más posibilidades de presentar signo negativo (p < 0.05). CONCLUSIONES: La presencia de un absceso en el espacio retrofaríngeo se asocia a complicaciones y peor pronóstico. La evaluación del signo de Moore puede ser una herramienta útil para sospechar compromiso de ese espacio.

Anthropometric characteristics and nutrition in a cohort of PAH-deficient patients.

BACKGROUND & AIMS: Treating phenylketonuria based upon strict vegetarian diets has occasionally been found to hamper physical development, some patients presenting with growth retardation and malnutrition. In addition, some researchers have reported an association between higher protein intakes and attaining better developmental outcomes, although it remains unclear which protein fraction (natural or synthetic) has the greatest influence on growth. The present study aimed to evaluate anthropometric characteristics and nutrition in a cohort of patients with phenylketonuria and mild-hyperphenylalaninaemia from birth to adulthood. METHODS: We conducted a retrospective longitudinal study comparing anthropometric characteristics (weight, height, body mass index, and growth rate) in our patients and healthy subjects, with the measurements expressed as z-scores. Nutritional issues were also considered. Data were collected every 6 months from birth to 18 years of age. RESULTS: Growth impairment was observed in phenylketonuric patients. Specifically, there were two well-differentiated periods throughout which height fell well below z-score = 0: from birth to two years of age, and on reaching adulthood. We also found height and weight to be positively correlated with phenylalanine intake. No growth retardation was seen in the patients with mild-hyperphenylalaninaemia. CONCLUSIONS: Phenylketonuric patients showed growth impairment in the early stages, with higher phenylalanine intakes being associated with attaining better developmental outcomes in this period. Therefore, prescribing very stringent diets in the early years might predispose phenylketonuric patients to retarded growth later in life, with growth outcomes in adulthood being well below the 50th percentile for healthy subjects.

Doxorubicin-loaded nanoparticles: new advances in breast cancer therapy.

Doxorubicin, one of the most effective anticancer drugs currently known, is commonly used against breast cancer. However, its clinical use is restricted by dose-dependent toxicity (myelosuppression and cardiotoxicity), the emergence of multidrug resistance and its low specificity against cancer cells. Nanotechnology is a promising alternative to overcome these limitations in cancer therapy as it has been shown to reduce the systemic side-effects and increase the therapeutic effectiveness of drugs. Indeed, the numerous nanoparticle-based therapeutic systems developed in recent years have shown low toxicity, sustained drug release, molecular targeting, and additional therapeutic and imaging functions. Furthermore, the wide range of nanoparticle systems available may provide a solution to the different problems encountered during doxorubicin-based breast cancer treatment. Thus, a suitable nanoparticle system may transport active drugs to cancer cells using the pathophysiology of tumours, especially their enhanced permeability and retention effects, and the tumour microenvironment. In addition, active targeting strategies may allow doxorubicin to reach cancer cells using ligands or antibodies against selected tumour targets. Similarly, doxorubicin resistance may be overcome, or at least reduced, using nanoparticles that are not recognized by P-glycoprotein, one of the main mediators of multidrug resistance, thereby resulting in an increased intracellular concentration of drugs. This paper provides an overview of doxorubicin nanoplatform-based delivery systems and the principal advances obtained in breast cancer chemotherapy.

[Tobacco control initiatives in Colombia's Congress, 1992-2007]. / Las iniciativas para el control del tabaco en el Congreso de Colombia: 1992-2007.

OBJECTIVES: To review tobacco bills introduced in Colombia's Congress and to compare these proposed measures to those of the World Health Organization Framework Convention on Tobacco Control (FCTC). METHODS: Bills on tobacco-related products in the Congress of the Republic of Colombia in July 1992-July 2007 were identified from the records of the Senate and the House of Representatives' Legal Office. Eighteen semistructured interviews of key players were conducted and the debate proceedings of three bills were observed. RESULTS: Eighteen bills were evaluated; none was comprehensive-even when FCTC measures were included, these were partial or went in a different direction, indicating little awareness of the most effective tobacco control measures. Little compromise was observed on the part of the Congress, the Executive Branch, or the authors who were themselves seeking approval of the proposal. None of these bills became law. CONCLUSIONS: The tobacco bills in the Colombian Congress during the study period could not ensure the development of legislation that is sufficiently effective in controlling tobacco in the country and could not provide a successful journey through a rigorous legislative process. Bills must be comprehensive, even when measures evolve gradually, and more attention must be given to the legislative process that must be completed for approval.

Las iniciativas para el control del tabaco en el Congreso de Colombia: 1992-2007 / Tobacco control initiatives in Colombia's Congress, 1992-2007

OBJETIVOS: Analizar los proyectos de ley presentados en el Congreso colombiano relacionados con el control del tabaco y contrastar las medidas propuestas con las contenidas en el Convenio Marco para el Control del Tabaco (CMCT). MÉTODOS: Se identificaron los proyectos de ley relacionados con el control de los productos derivados del tabaco radicados en el Congreso de la República de Colombia entre julio de 1992 y julio de 2007, a partir de los libros de las oficinas de leyes del Senado y de la Cámara de Representantes. Se realizaron 18 entrevistas semiestructuradas a actores clave y se asistió a los debates de tres proyectos de ley. RESULTADOS: Se analizaron 18 proyectos; ninguno de ellos era integral, pues si bien incluían medidas contempladas en el CMCT, estas eran parciales y no siempre iban en su misma dirección, lo que reflejó un escaso conocimiento de las medidas más eficaces para el control del tabaco. Se observó poco compromiso por parte del Congreso, el Ejecutivo y los propios autores para la aprobación de los proyectos. Ninguno de estos proyectos se convirtió en ley. CONCLUSIONES: Los proyectos de ley para el control del tabaco radicados en el Congreso colombiano en el período estudiado no garantizaban el desarrollo de una legislación suficientemente eficaz para controlar el tabaquismo en el país y no se garantizó su tránsito exitoso a través de los trámites legislativos de rigor. Los proyectos de ley deben ser integrales, aún cuando las medidas se desarrollen gradualmente, y se debe prestar mayor atención a los trámites legislativos que deben cumplir para su aprobación.

OBJECTIVES: To review tobacco bills introduced in Colombia's Congress and to compare these proposed measures to those of the World Health Organization Framework Convention on Tobacco Control (FCTC). METHODS: Bills on tobacco-related products in the Congress of the Republic of Colombia in July 1992-July 2007 were identified from the records of the Senate and the House of Representatives' Legal Office. Eighteen semistructured interviews of key players were conducted and the debate proceedings of three bills were observed. RESULTS: Eighteen bills were evaluated; none was comprehensive-even when FCTC measures were included, these were partial or went in a different direction, indicating little awareness of the most effective tobacco control measures. Little compromise was observed on the part of the Congress, the Executive Branch, or the authors who were themselves seeking approval of the proposal. None of these bills became law. CONCLUSIONS: The tobacco bills in the Colombian Congress during the study period could not ensure the development of legislation that is sufficiently effective in controlling tobacco in the country and could not provide a successful journey through a rigorous legislative process. Bills must be comprehensive, even when measures evolve gradually, and more attention must be given to the legislative process that must be completed for approval.

Tumor sólido pseudopilar del páncreas: un cáncer curable / Pseudopillar solid tumor of pancreas: a curable cancer

El tumor pseudopapilar sólido del páncreas (TPS) o también llamado tumor de Frantz es una rara afección neoplásica del páncreas con distintas características clínicas-patológicas. El diagnóstico puede ser difícil, pero debe ser sospechado como una posibilidad en mujeres jovenes quienes presentan una masa abdominal que envuelve el páncreas. En este reporte se describe la clínica, estudios imageneológicos y las características patológicas de dos pacientes jóvenes a quienes se les diagnósticaron un TPS del páncreas en forma incidental. La mayoría de los TPS tienen un comportamiento "benigno", solamente un pequeño número recurre o desarrollan metástasis después de la resección, pero aun en casos que metastizan tienen un crecimiento lento y son clasificados como de bajo grado de malignidad.

Tumor estromal gastrointestinal (GIST) en una adolescente y embarazo: caso clínico / Pregnant adolescent with gastrointestinal stromal tumor

Los Tumores Estromales Gastrointestinales (GIST) son tumores raros de células mesenquimáticas. Representan el 0,1-3 por ciento de todos los sarcomas digestivos. La incidencia mundial actual es de 10-20 casos/millón. Frecuentes en adultos masculinos entre la 5a-7a década, el 70 por ciento en estómago, el 20 por ciento intestino y el 10 por ciento en el resto del tracto digestivo. Son raros en niños-adolescentes, pero cuando se presentan, lo hacen con mayor frecuencia en niñas, de histología variable y negativos a C-KIT y PDGFRA. Paciente de 19 años, natural-procedente de Estado Miranda; primigesta, ingresa con embarazo de 18,3 semanas, pérdida de peso de 13 kilos, dispepsia, cambios en hábito intestinal, masa en hipocondrio izquierdo de 12 x 8 cm. Laparotomía exploradora halla tumor de raíz de mesenterio adherido a intestino, biopsia preoperatoria revela tumor fusocelular; se realiza anastomosis términolateral de duodeno-íleon. Egresa con 24,5 semanas y tocólisis oral. Biopsia definitiva e inmunohistoquímica diagnostican GIST de bajo índice mitótico, sin necrosis, negativo para C-KIT. Reingresa a las 30 semanas, se atiende parto pretérmino y se obtiene recién nacido masculino vivo. Seguimiento actual por Cirugía y Oncología

Efecto de dos plaguicidas intramuros en la función respiratoria de una población mexicana / Effecto to respiratory function for insecticides in household in mexican population

Antecedentes: en las grandes ciudades la utilización de pesticidas ha ido en aumento. Existen pocos estudios que demuestren la existencia de repercusiones en el aparato respiratorio. Objetivo: determinar el tipo de las alteraciones respiratorias que se producen en una población sana de la Ciudad de México ante la exposición a dos productos comerciales para el control de plagas intramuros y conocer las manifestaciones clínicas y funcionales que su uso conlleva. Material y método: se incluyeron 70 individuos voluntarios sanos de la Ciudad de México que habitaban en un departamento de 100 metros cuadrados de construcción, sin antecedentes de tabaquismo y sin proceso infeccioso al momento del estudio. El total de individuos seleccionados se dividió en dos grupos, ambos expuestos a los insecticidas. El grupo A correspondió a los insecticidas por combustión y el grupo B al de combustión eléctrica. A todos los participantes se les efectuó un estudio espirométrico al inicio y cada hora durante el tiempo de exposición. El análisis se hizo mediante t de Student. Resultados: el grupo A tuvo disminución del VEF1 durante el tiempo de estudio, con una p < 0.01 en la primera hora y < 0.028 en las siguientes, con fenómenos colaterales como: irritación ocular (74 por ciento), tos (43 por ciento), disnea (57 por ciento) y cefalea (28 por ciento). El grupo B tuvo una pequeña diferencia (p< 0.03) durante la primera hora y ninguna en las dos siguientes; no se observaron fenómenos colaterales. El análisis intergrupal demostró una diferencia significativa de p < 0.004 en la primera hora. Conclusión: el uso de insecticidas puede ser dañino para la salud y su exposición puede producir obstrucción de la vía aérea y síntomas clínicos de tipo irritativo, en especial con los derivados químicos inorganicos.