To describe the profile of the practice of physical activity in the daily life of Brazilian adults with arterial hypertension and to analyze whether the practice performed complies with the recommendations of the World Health Organization.  Cross-sectional data were obtained from the Surveillance System of Risk Factors and Protection for Chronic Noncommunicable Diseases of 2014, involving 40,853 adults aged 18 years and over in all Brazilian capitals, interviewed by telephone survey.  Walking, soccer and water aerobics were the main modalities of exercise and sport practiced. The weekly volume of effort led 35% of practitioners to reach the recommended goal of the World Health Organization. The low weekly frequency of activities stood out among hypertensives who did not reach the goal.  Health services should clarify the need for regularity of physical activity for hypertensive individuals to benefit substantially. Worldwide, it has been recorded that approximately one-third of hypertensive patients are unaware of their condition, consequently, there is a risk increase regarding myocardial infarction, stroke and kidney diseases. Hypertension also accounts for almost 9.4 million deaths and 10% cost in health. It is estimated that, in 2025, hypertension will affect nearly 1.6 billion people of both sexes According to a study that was carried out in 190 countries from 2001 to 2011, Brazil has the sixth largest rate of hypertensive people in the world  with a 13.2% increase in this disease during this trial p <0.001), caused by aerobic training performed 3 to 5 times a week for about 30 to 60 min. This result was later corroborated by other studies -Fagard In Brazil, a population study based on data from the National System for Monitoring Hypertension and its risk factors analyzed the PA level of 9,038 in self-reported hypertensive participants, 60 years old or more. The answers showed a high prevalence of insufficient AP during leisure time  p= 0.001) Another representative study concerning Brazilian population analyzed 11,453 hypertensive patients of 18 years old or more and showed 59.5% (95% CI: 57.8-61.0) of inactive/sedentary patients, 10.1% (95% CI: 8.8 - 12.2) of insufficient actives and 30.4% (95% CI: 26.8-32.8) of sufficient actives  accompanied by the United States Department of Health and supported by clear evidence that health benefits of hypertensive individuals occur despite which physical exercise someone works out and by different effort intensity. There is an aim of working out for 150 min a week on aerobic activities of moderate intensity or 75 min of vigorous intensity or an equivalent combination of both, preferably, but not necessarily distributed throughout the week. Although, it should be highlighted the exercise and frequency of activity based on each individual's ability and health limitations In this perspective, this study proposed to describe the participation profile of hypertensive Brazilian adults PA, who live in some Brazilian capitals and in the Federal District as well as analyze their workout intensity/ how intense were their physical exercises according to WHO recommendations.Cross-sectional data from the Surveillance of Risk Factors and Protection for Non-Communicable Chronic Diseases system were examined by telephone interview (Vigitel) in Brazil based on 2014 year, whose own methodology can be accessed in a previous publication Thus, in order to adjust the adult population of each city, a final weight was assigned to each individual interviewed by Vigitel, named as post-stratified weight. This aimed at correcting the representation of socio-demographic strata that could occur due to the non-universal coverage of the fixed-line network This study considered as hypertensive the participant who answered yes to this question: has any doctor ever told you that you have high blood pressure? For estimates of PA level, it was considered the sum of weekly frequency and the duration of activities practiced in free time or on his way to the work and/or school. So, the following questions were used: "have you practiced any kind of physical exercise or sport during the last three months? Yes/No/Which?" And the question: "do you do any walking or cycling when going to or coming from your work/ school? Yes/No". The effort intensity for each kind of physical exercise or sports followed the classification established by Vigitel in 2014 edition.Thus, walking, treadmill walk, water aerobics, general gymnastics, swimming, cycling and volleyball were classified as moderate PA practices. Running, treadmill running, bodybuilding, aerobic exercise, martial arts/fights, soccer, basketball and tennis were classified as vigorous PA practices. The daily effort duration was determined by asking: "on the day you exercise or practice a sport, how long does this activity last?" "How much time do you spend to go back and forth on this route (on foot or by bicycle)?" The analysis was categorized into six groups: less than 10 min; 10 to 19 min; 20 to 29 min; 30 to 39 min; 45 to 59 min; And equal to or greater than 60 min.Therefore, an activity that lasts less than 10 min was not considered for calculation purposes The analysis of PA participation considered only the last three months prior to the interview. Originally, the Vigitel survey assessed PA separately in four domains: PA during leisure time; Occupational PA (work); Residential PA (domestic cleaning); And PA on moving from home to work or school (on foot or by bicycle). In this study, only information concerning PA leisure and active displacement were used to define the participants' PA level. The activities that were done at home or work were not considered because the Vigitel questionnaire did not predict duration or weekly frequency in those activities.Brazilian regions separation attended the grouping of the Federation units. Currently, in Brazil, there are five official regions: Central-West Region with three states  and the Federal District; Northeastern Region with nine states ; Northern Region with seven states ; Southeastern Region with four States ; Southern Region with three states .The determination of PA level applied WHO global parameters of 2010, which considered adequate a moderate practice that lasts at least 150 minutes or as vigorous PA, the one that last 75 minutes a week, regardless of its weekly frequency 2) of Pearson test. The results with p lower than 0.05 were considered with statistically significant difference. And Stata ® 11.0 and Microsoft(r) Excel 10.0 programs were used to process statistical data and analyses.PA prevalence of hypertensive participants and their respective 95% confidence intervals were presented according to individual PA level, by region and by exercise and/or sport modality. PA characteristics in hypertensive population were described in order to try to compare them with characteristics of the population in general. The possible differences in PA prevalence according to the presence or absence of a disease were evaluated using the chi-square .Free and informed consent was obtained orally at the time of telephone contact with the interviewees and anonymity was guaranteed for participants. In the database, made publicly available by the Ministry of Health at: http://svs.aids.gov.br/bases_vigitel_viva/vigitel.php, the participants are numbered sequentially, without any possibility to be identified, according to resolution 466/2012 of the National Health Council Cross-sectional data from Vigitel of 2014 were analyzed, with 40,853 interviewees, whose mean age was 48.3 ± 17.6 years old, 15,521 men with mean age of 45.9 ± 17.5 years old and 25,332 women whose mean age was 49.7 ± 17.5 years old. The majority declared to be white (44.9%) or brunette (40.9%). Only 1.6% of them declared to be indigenous and 9.8% declared themselves as black. Brazilian regions with the highest number of states showed higher gross participation, although post-stratification weights were assigned to each individual to get closer to sociodemographic composition of the sample to that one observed in the Demographic Census in each city.p= 0.001). Palmas city had the lowest prevalence of hypertension (15.2%) and Porto Alegre, the highest one (29.2%). The distribution of hypertensive people was unequal according to schooling, with 38.1% (95% CI: 36.6-40.8) in people with up to 8 years of schooling; 19.3% (95% CI: 17.5-21.7) between 9 to 11 years and 14.6% (95% CI: 11.9-16.6) over 12 years of schooling (p= 0.001).A total of 1,405 participants (3.4%) were excluded, although they have reported to have some kind of PA practice, and they did not report their weekly frequency or duration of exercise. Thus, the calculation base considered 39,448 participants. Among 23.5% (95% CI: 21.6-25.4), who confirmed the diagnosis of hypertension, there were more women 25.8% (95% CI: 22.2-27.6) than men 20.3% (95% CI: 18.4-22.9) (p= 0.01). In both sexes, hypertension prevalence was higher with advancing age. It affected approximately 4.6% of 18-24 year-old people and 59.9% of 65 years of age or older.Brunet people had the lowest prevalence of hypertension (4.7%), while Asian descendants showed the highest answer (10.4%)  among men and 86.2% (95% CI: 80.0-92.3) among women.This cross-sectional study aimed at describing the daily PA profile of Brazilian adults with self-reported arterial hypertension in 2014 and at verifying if the weekly frequency of activities meets the WHO recommendations. Walking, soccer and water aerobics were the main modalities of exercise and sport practiced by hypertensive individuals. The weekly frequency of effort led 35% participants to achieve the recommended goal. The reduced weekly frequency of once to twice a week was highlighted as a barrier for hypertensive individuals and could not reach the recommended goal.The increase in cases resulting from hypertension complications has reflected on the management of health system and increased costs for its control and treatment The Ministry of Health, based on its guidelines, does not predict the anaerobic efforts duration and does not present the basis of studies that show the hypotensive effects of anaerobic exercise practice ,,In this study, effort duration was in agreement with most of international recommendations, which lasts 30 min or more. Investments should focus on encouraging increased regularity of activities. Many hypertensive patients, who did not reach the recommended goal, reported to take part of physical activities only once to twice a week. In general, PA level of hypertensive individuals was low and only 35% of them have reached this goal. However, the most worrying situation for hypertensive health was the complete absence of PA for 60% of them. Although there are some divergences concerning different PA recommendations, especially with regard to the ideal way of obtaining the minimum frequency, it is a consensus among the guidelines that the dose-response ratio is greater when inactive individuals incorporate some PA level than by increasing activity among the moderated active ones The obstacles to take part of PA may differ according to sex, city size, physical environment, mood, and health condition of an individual. According to the data found out by Andrade et al.,Thus, aesthetic and functional adaptations of a physical environment around residential areas, creation of safe environments on sidewalks and crossings, reduction of traffic speed, preventive policing, extending of opening hours on physical facilities and dissemination of correct places for PA may be appropriate as a facilitating strategy for hypertensive individuals to remain and become active The walking practice was preferred by almost 67% of hypertensive adults that were studied in this trial as the main modality of exercise or sport. This adherence by hypertensive patients was higher than the one observed for public in general (43%) Knowing the previous diagnosis of hypertension and obtaining information about PA benefits on this health disorder may reinforce the idea for hypertensive patients to be or remain physically active. Consequently, these actions may contribute indirectly to prevent disease complications or the emergence of comorbidities related to sedentary habits. Thus, it seems opportune to add intersectional public health efforts in order to encourage and adapt the participation of hypertensive patients on physical activities (PA).This study has some restrictions that must be addressed. Vigitel data only included the main modality practiced during the last three months and does not allow capturing information from other complementary practices. The measurement of self-referenced survey effort does not provide the real level of an effort for each individual. Direct and more accurate decision-makings are expensive and logistically difficult in a large sample as in this study. Since PA is conceived by the population as a desirable practice, it should be considered the possibility of reluctance to be declared as inactive.et al.in loco. Another limitation refers to the use interviews by landlines (telephones), since it does not consider people who do not have landlines. The use of post-stratified weights minimizes possible differences between the total population and the studied one.However, Monteiro The strengths of this study include information on a large sample of Brazilian adults with hypertension and their participation in PA, detailing what kind of PA they practice, their weekly frequency and effort duration. This study provides relevant evidences, especially for health professionals and stakeholders interested in planning and promoting PA for hypertensive patients, in order to reinforce actions to encourage people to be more active, to reduce inequalities of access between sexes and age groups as well as to ensure suitable and safe public spaces in order to put in practice PA.Primary Care services in a public and universal health system are also important to be highlighted as a feasible place that focuses on PA benefits, due to they are close and can easily get in touch with population, especially among the hypertensive ones.It is concluded that, in Brazil, the number of inactive hypertensive people (60%) is significant, mainly among women. It was also recorded that hypertensive people seldom practice exercise in a week, thus, they did not reach the goal recommended by the WHO. Consequently, it is essential to understand how PA participation is inserted in different areas. There is also a requirement of health professionals and public policy managers to encourage inactive hypertensive patients to adopt active living habits as a priority due to their frequency in physical activities. Se estima que en escala mundial hay un tercio de hipertensos no conscientes de su condición, aumentando el riesgo de infarto de miocardio, accidente cerebrovascular y enfermedad renal. En el mundo la hipertensión es responsable de alrededor 9.4 millones de muertes y 10% del costo de la salud. Según las estimaciones en el año 2025, la hipertensión alcanzará cerca de 1.6 millones de personas de ambos sexos p <0,001) causada por el entrenamiento aerobio realizado de 3 a 5 veces a la semana y 30 a 60 min de duración. Este resultado fue confirmado por otros estudios -En este escenario, un aspecto positivo es la posibilidad de que la hipertensión arterial se puede controlar con el uso de medicamentos antihipertensivos y con la adopción de hábitos de vida saludables. El efecto antihipertensivo causado por la actividad física regular (AF) ha apoyado su práctica terapéutica como una medida complementaria. Un metaanálisis realizado por Fagard p = <0.001) En Brasil, uu estudio basado en la monitorización de la hipertensión analizó el nivel de AF de 9,038 sujetos con hipertensión (60 años o más de edad), resultando en una alta prevalencia de AF insuficiente  ,Actualmente, varias organizaciones recomiendan AF para promover la salud de los hipertensos. A primera vista, parece que hay ambigüedad en la distribución del volumen de AF en la semana. Sin embargo, están de acuerdo con la necesidad de alcanzar una dosis mínima para dar efectos significativos la salud. Por ejemplo, el Colegio Americano de Medicina Deportiva recomienda ejercicio moderado de una duración de 20 a 40 min por día, de forma continua o fraccionada en tres días en la semana no consecutivos En esta perspectiva, este trabajo tuvo como propósito describir el perfil de la AF de adultos brasileños portadores de hipertensión arterial que viven en las capitales de los estados de la Federación de Brasil y Distrito Federal y analizar si el volumen de AF esta de acuerdo con las recomendaciones de la OMS.Este es un estudio de tipo descriptivo y corte transversal con uso de datos secundarios del Sistema de Vigilancia de las Enfermedades Crónicas no Transmisibles y mediante Entrevistas Telefónicas (Vigitel), en Brasil, para el año 2014, cuya metodología se puede acceder a la publicación previa Este estudio consideró hipertenso todos los participantes que respondieron afirmativamente a la pregunta: ¿Alguna vez un médico le ha dicho que tiene la presión arterial alta? Para las estimaciones de nivel de AF considera la suma de la frecuencia semanal y duración de las actividades ejecutada durante el tiempo libre o ir al trabajo o estudio mediante a la preguntas: ¿En los últimos tres meses, se practica algún tipo de ejercicio o deportes físicos? ¿ Para ir a trabajo o estudio, hace algún camino a pie o en bicicleta?La intensidad del esfuerzo para cada tipo de ejercicio o deporte siguió a la clasificación establecida por lo Vigitel - 2014. Así, caminata, caminata en la cinta, aeróbico acuático, gimnasia general, natación, ciclismo y voleibol fueron clasificados como prácticas de AF de intensidad moderada. Carrera, carrera en la cinta, fisicoculturismo, gimnasia aeróbica, artes marciales, fútbol, básquetbol y tenis fueron clasificados como prácticas intensidad de AF vigorosas.La exposición diaria al ejercicio se determinó con las preguntas, "¿Cuál es la duración de su actividad?". La duración fue clasificada en seis grupos: menos de 10 min; 10 a 19 min; 20 a 29 min; 30 a 39 min; 45 a 59 min; igual o mayor que 60 min. Actividad que dura menos de 10 min no se consideró para fines del cálculo La frecuencia semanal de la AF se determinó por el número de días activos en la semana, mediante la pregunta: "¿cuántos días a la semana usted practica ejercicio físico o deporte?". Para el análisis, la frecuencia semanal se clasificó en cuatro grupos: a diario, de 5 a 6 días, 3 a 4 días y de 1 a 2 días a la semana.El análisis de la participación en la AF consideró sólo los últimos tres meses anteriores a la entrevista. Originalmente, la encuesta del Vigitel separada AF en cuatro áreas: AF de recreo (tiempo libre); AF ocupacional (de trabajo); AF en la casa (limpieza doméstica); y AF en los desplazamientos de casa al trabajo o estudio (a pie o en bicicleta). En este estudio, sólo las información de recreo y el transporte activo se utilizaron para establecer el nivel de AF de los participantes. Las actividades en el ámbito doméstico y ocupacional, no se consideraron debido este tipo de interrogatorio no permitir cuantificar su duración y frecuencia semanal.La división de las regiones del país atendió a la agrupación de unidades de la federación de Brasil. Actualmente, hay cinco regiones oficiales: la región Centro-Oeste con tres estados  y el Distrito Federal; región Nordeste con nueve estados ; región Norte con siete estados ; región Sudeste con cuatro estados ; región Sur con tres estados .El nivel de la AF se determinó mediante los parámetros de la OMS, que considera suficiente la práctica de 150 min de AF moderada y 75 min de AF vigorosa por semana Inicialmente, los participantes fueron agrupados en cuatro categorías: 1) Inactivo: negó la práctica de AF de recreo y el transporte activo; 2) insuficiente activo: mantiene AF por debajo de la recomendación; 3) Activo: alcanza a la meta recomendada; 4) muy activo: superó la meta recomendada. Posteriormente, se realizo un segundo agrupación con dos categorías: Grupo A: se compone de la suma de los participantes activos y muy activos. Grupo B: se compone de la suma de participantes inactivos y activos suficientes.p inferior a 0.05 se consideraron significativos a nivel estadístico. Para el procesamiento de los datos y el análisis estadístico se utilizó el Stata® 11.0 y 10.0 programas de Microsoft® Excel.La prevalencia de la AF de los hipertensos y sus respectivos intervalos de confianza de 95% se presentan según el nivel individual de la AF, por región y por tipo de ejercicio y/o deporte. Fueron descritas características de la AF de la población hipertensa comparándola con la población en general. Posibles diferencias estadisticas en la prevalencia de la AF de acuerdo con la presencia o no de la enfermedad se obtuvieron con la puebla de Chi cuadrado de Pearson (χ2). Los resultados con Este estudio se realizó con datos secundarios colectados por el sistema Vigitel. El proyecto Vigitel fue aprobado por la Comisión Nacional de Ética en Investigación en Seres Humanos del Ministerio de Salud (Conep - Parecer 26/06/2013 355.590 - CAAE: 16202813.2.0000.0008). Se obtuvo el consentimiento informado por vía oral en el momento del contacto telefónico con los entrevistados y se aseguró el anonimato de los participantes.Los datos analizados del Vigitel fueron del año 2014, con la participación de 40,853 entrevistados con edad media de 48.3 ± 17.6 años, compuesto por 15,521 hombres con la edad media de 45.9 ± 17.5 años y 25,332 mujeres con la edad media de 49.7 ± 17.5 años. La mayoría de la población se declaró blanco (44.9%) o moreno (40.9%). Solamente el 1.6% de los entrevistados se declararon indígenas y el 9.8% se declararon negros. Las regiones del país con el mayor número de estados tienen mayor participación, pero los pesos de post-estratificación equilibra la muestra a cada ciudad.p = 0.001). La ciudad de Palmas presentó la menor prevalencia de hipertensión (15.2%) y Porto Alegre, la mayor (29.2%).Fueron excluidos de este estudio 1,405 participantes (3.4%) qué no reportaron la AF sobre la frecuencia semanal o la duración. Por lo tanto, la base para el cálculo consideró 39,448 participantes. Entre los que confirmaron el diagnóstico de la hipertensión , hubo más mujeres  que hombres  . Mulatos tenían una menor prevalencia de hipertensión (4.7%) y los de origen asiático la mayor (10.4%) (p= 0.01). En ambos sexos, la prevalencia de hipertensión fue mayor con la edad avanzada. Ha caído desde 4.6% en las personas entre 18-24 años de edad, a 59.9% en las personas mayores de 65 años.La distribución de la prevalencia de la hipertensión es desigual en cuanto a la escolaridad. Las personas más afectadas tenían ocho años de escolaridad (38.1%: IC 95%: 36.6-40.8); 19.3% (IC 95%: 17.5-21.7) a partir de 9 a 11 años y 14,6% (IC 95%: 11.9-16.6) tenían más de 12 años  se presentó como una barrera para que este grupo de hipertensos lograra alcanzará el nível recomendado.El aumento de los casos debido a complicaciones de la hipertensión afecta a la gestión del sistema de salud con aumento de los costes para su control y tratamiento ,,La frecuencia semanal y la duración de la AF determinan el volumen semanal para estimar el alcance de la meta. En este estudio, la duración de la AF se presentó en la mayoría de acuerdo a las recomendaciones, es decir, tiene una duración de 30 min o más. Las políticas deben centrarse en fomentar el aumento y la regularidad de las actividades. Muchos hipertensos que no alcanzaron la meta participan en la AF sólo durante 1-2 veces a la semana. Generalmente, el nivel de AF de los hipertensos fue bajo, sólo el 35% alcanzaron la meta. Sin embargo, la situación más preocupante encontrada para la salud de los hipertensos fue la ausencia completa de AF para el 60% de ellos. Aunque hay algunas diferencias entre los diferentes recomendaciones de AF, en particular en relación con la forma ideal para obtener el volumen mínimo, es de consenso que la relación de la dosis-respuesta es más pronunciada cuando los inactivos incorporan un cierto grado de AF, mas que que por el incremento de la actividad entre los moderadamente activos et al.,Las barreras a la participación en la AF pueden ser diferentes según el sexo, tamaño de la ciudad, el entorno físico, la disposición y el estado de salud del individuo. De acuerdo con los datos presentados por Andrade La práctica de caminata se alcanzó em cerca del 67% de los hipertensos como la principal forma de AF practicada. Esta adhesión por los hipertensos fue mayor que la observada para el público en general (43%) El conocimiento del diagnóstico previo de hipertensión y la información sobre los beneficios de la AF sobre la enfermedad puede reforzar la idea en los hipertensos de mantenerse activos, contribuyendo indirectamente a la protección de las complicaciones de la enfermedad o la protección de enfermedades asociadas con hábitos sedentarios. Por lo tanto, vale la pena añadir los esfuerzos de los programas de salud pública intersectoriales para fomentar la participación y la de los hipertensos en AF.Este estudio tiene algunas limitaciones que deben ser abordadas. La encuesta del Vigitel sólo incluye datos acerca de lo principal deporte practicado en los últimos tres meses y no permite capturar información de otras prácticas complementarias. La medida indirecta de la AF no permite comprobar el nivel real de esfuerzo de cada individuo. Las mediciones directas, más precisas, son costosas y logísticamente difíciles en muestras grandes como es el caso de este estudio.in situ. Otra limitación se refiere a la utilización de las entrevistas telefónicas fijas, ya que no tienen en cuenta las personas que no tienen teléfono fijo. El uso de pesos post-estratificado minimiza la diferencia potencial entre la población total y población del estudio.La AF está diseñada para la población como una práctica deseable, así se debe considerar la posibilidad de la renuencia de la inactividad física. Sin embargo, Monteiro et al. Los puntos fuertes de este estudio incluyen el gran tamaño de la muestra de los adultos brasileños con hipertensión y su participación en la AF, detallando el tipo de AF practicado, su frecuencia semanal y duración del esfuerzo. El estudio proporciona evidencias pertinentes, en particular para los profesionales de la salud y agentes interesados en la planificación y la promoción de la AF en hipertensos, para intensificar las medidas, para animar a las personas a ser más activas, reducir las desigualdades en el acceso, entre los sexos y grupos de edad y asegurar espacios públicos adecuados y seguros para la AF. Igualmente importante a destacar es la importancia de los servicios de atención primaria de salud en un sistema de salud pública y universal, como un lugar apropiado para asesorar sobre los beneficios de la AF, dada su proximidad y su influencia en la población general, especialmente entre los hipertensos.Concluimos que, en Brasil, los hipertensos inactivos representan a la mayoría (60%), especialmente entre las mujeres. La frecuencia de AF semanal es reducida y es la característica más llamativa de los pacientes hipertensos que no alcanzan la meta propuesta por la OMS. Por lo tanto, es importante entender cómo la participación en la AF está incluida en los distintos segmentos de la población, lo que requiere de los profesionales de la salud y de los políticos, la tarea de fomentar hábitos regulares de AF entre los hipertensos inactivos.


Cryptococcus neofromans / C. gattii, complex which affects immunocompromised patients mainly. Meningeal infection is one of the most common presentations, but cerebellar affection is rare. Cryptococcosis is an opportunistic fungal infection whose etiology is  Male patient with 65 old years, from an area of subtropical climate with chronic exposure to poultry, without pathological antecedents, who presented clinical picture consistent with headache, fever, seizures and altered mental status.Initially without menigeal signs or intracranial hypertension and normal neurological examination. Later, the patient developed ataxia, dysdiadochokinesia and limb loss. By lumbar punction and image of nuclear magnetic resonance (NMR) cerebellitis cryptococcal was diagnosticated. Antifungal therapy with amphotericin B and fluconazole was performed, however the patient died. The cryptococcosis has different presentations, it´s a disease whose incidence has been increasing since the advent of the HIV / AIDS pandemy, however the commitment of the encephalic parenchyma and in particular the cerebellum is considered rare. In this way we are facing the first case of cryptococcal cerebellitis in our midst. Cryptococcus neofromans / C. Gattii. It is considered a sentinel disease, and Human immunodeficiency Virus (HIV) is the most common coinfection Cryptococcosis is a fungal infection, whose etiology is the complex C. gattii infection is more frequent, which is considered to be highly adaptive to changes in ecological conditions Global incidence varies between 0.04-12.0% annually and Sub-Saharan Africa is considered the region with the highest number of estimated cases in the world The following is a case of cryptococcus cerebellitis, in a patient without history of importance that presented a diagnostic challenge due to its nonspecific clinical manifestations.A 65-year-old male, a farmer, from a subtropical area south of the department of Cauca, located in the Colombian Massif, with an average environmental temperature of 19° C. He works in continuous contact with poultry and has no previous history of importance. He consulted for intense holocranial headache of four months of evolution that yielded partially with NSAIDs. Forty-eight hours before admission he was exacerbated with nausea and generalized clonic seizures of the subintrant type. He was treated with a dose of intravenous loading of Valproic Acid, continued with 500 mg every 8 hours, which controlled the seizures during the time of hospitalization. Cryptococcus spp that were confirmed in cultures in blood agar, chocolate and Sabouraud, where C. neoformans var. Grubii NIV in the Laboratory of the National Institute of Health of Colombia. Antifungal therapy with Amphotericin B at 50 mg daily and Fluconazole at 400 mg every 12 hours was initiated, with improved mental status, decreased febrile episodes, headache, ataxia and dysmetria. On the ninth day of hospitalization, the results of the MRI were reported: in the T1 segment diffuse hypointense cerebellar lesion with contrast enhancement without evidence of nodule or abscess; In the T2 Flair sequence, a predominantly right bilateral diffuse hyperintense cerebellar lesion corresponding to inflammatory changes was evidenced.  scan of the brain was requested and showed no signs of endocranial hypertension, expansive lesions, or other relevant lesions. A lumbar puncture was performed demonstrating hypoglycemia and hyperproteinorraquia , so it widenced. A, B, C. ,Due to the relationship between this mycosis, HIV / AIDS infection and other forms of immunosuppression, cryptococcosis in immunocompetent patients can be considered exceptional ,In the presented case, the integrity of the patient's immune system could be affected by age (immunosenescence) In this case the infection occurred in a rare anatomical site, the cerebellum. This type of compromise is rare and poorly reported, despite this being the most frequent mycosis of the central nervous system. Compared with other reports this case has many similarities. Most were in immunocompetent patients, chronic and progressive headache associated with nausea and vomiting was the main symptom during the onset of the disease. One case had cerebellar symptoms such as ataxia and dysdiadochokinesia The clinical presentation of this case differs, due to the absence of cryptococomas, which are solid lesions, mainly located in basal ganglia or cerebral white matter, corresponding to abscesses or granulomas, which can be detected by NMR; Meningeal cryptococcosis is manifested clinically by headache, nausea, vomiting, fever and only one-third of those affected show signs of spinal root irritation, this is more frequent in immunocompetent patients. Neurological examination may include: alteration of the mental sphere, decreased strength in extremities, convulsions, involvement of cranial nerves . In the fundus of the eye you may see optic atrophy and often papilledema. The most frequent sequels are visual alterations such as blindness, which is the most common, besides deafness, paresis of extremities and language disorder. Meningeal signs such as occurred in our case are not very eloquent, this causes the diagnosis to be avoided and a clinical synergy is necessary with the contribution of neuroimaging, laboratory findings and epidemiological considerations. In this sense, authors such as Brizendine et al. Cryptococcus Spp, and also the subsequent typing of the therapeutic responses of each of these, which may contribute to improve the prognosis of this infection ,New molecular biology techniques such as the enzyme immunoenzyme (EIA) and Polymerase Chain Reaction (PCR) with sensitivity and specificity of 100% for both tests, which allow to classify 8 new serotypes of Cryptococcus spp of the CNS has higher mortality than other presentations of this disease and being even higher by C. gatti. The factors most associated with poor prognosis are: altered mental status, CSF opening pressure greater than 25 cm of water, cryptococcal antigen in CSF greater than 1: 512, culture positive for cryptococcus in organs other than the CNS, and absence of meningeal enhancement Infection by In this case, an immunocompetent patient presents with signs of cerebellar compromise. The lack of specificity of the clinical manifestations and the low detection rate of Cryptococcus in the CSF pose difficulties for its diagnosis, so it is necessary to perform multiple CSF studies for its identification, in addition to a radiological study, especially by magnetic resonance imaging, to make a definitive diagnosis. Cryptococcus neofromans/C. gattii. Se considera una enfermedad centinela, y la coinfección más frecuente es con el Virus de la Inmunodeficiencia Humana (VIH) La criptococosis es una infección micótica cuya etiología es el complejo La incidencia global varía entre 0.04-12.0% anual y se considera el África Subsahariana como la región con mayor número de casos estimados a nivel mundial A continuación se presenta un caso de cerebelitis criptocococica, en un paciente sin antecedentes de importancia que supuso un gran reto diagnóstico por sus manifestaciones clínicas inespecíficas.Cryptococcus spp que fueron confirmadas en cultivos en agar sangre, chocolate y Sabouraud, donde se aisló C. neoformans var. grubii VNI en el Laboratorio del Instituto Nacional de Salud de Colombia. Se inició terapia antifúngica con Anfotericina B a 50 mg día y Fluconazol a 400 mg cada 12 horas, con mejoría del estado mental, disminución de los episodios febriles, cefalea, ataxia y dismetría. Al noveno día de hospitalización se reportaron los resultados de la RMN: en la secuencia T1 lesión cerebelosa hipointensa difusa con realce al contraste, sin evidencia de nódulo ni absceso; en la secuencia T2 Flair se evidenció una lesión cereberelosa hiperintensa difusa bilateral de predominio derecho que corresponden a cambios inflamatorios.  de cerebro que no mostró signos de hipertensión endocraneana, lesiones expansivas, ni otras lesiones relevantes. Se realizó una punción lumbar que demostró hipoglucorraquia e hiperproteinorraquia , por lo atorios.  A, B, C.C. neoformans,Debido a la relación existente entre esta micosis, la infección por VIH/SIDA y otras formas de inmunosupresión, la criptococosis en pacientes inmunocompetentes se puede considerar excepcional ,En el caso presentado la integridad del sistema inmune del paciente pudo afectarse por la edad (inmunosenescencia) En este caso la infección ocurrió en un sitio anatómico poco frecuente, el cerebelo. Este tipo compromiso es raro y escasamente reportado, a pesar de ser esta entidad la micosis más frecuente del sistema nervioso central. Comparado con otros reportes este caso tiene muchas similitudes. La mayoría se presentaron en pacientes inmunocompetentes, la cefalea crónica y progresiva asociada a nausea y vómito, fue el principal síntoma durante el debut de la enfermedad. Un caso presentó síntomas cerebelosos como ataxia y disdiadococinesia La presentación clínica de este caso difiere, por la ausencia de criptococomas, que son lesiones sólidas, localizados principalmente en ganglios basales o sustancia blanca cerebral, que corresponden a abscesos o granulomas, que pueden detectarse por RMN; en algunos casos se plantearon diagnósticos diferenciales como malformaciones vasculares et al. et al. et al. La criptococosis meníngea se manifiesta clínicamente por cefalea, náuseas, vómito, fiebre y solo un tercio de los afectados presenta signos de irritación de raíces raquídeas, esto es más frecuente en pacientes inmunocompetentes. La exploración neurológica puede encontrar: alteración de la esfera mental, disminución de la fuerza en extremidades, convulsiones, compromiso de pares craneales . En el fondo de ojo se puede ver atrofia óptica y con frecuencia papiledema. Las secuelas más frecuentes son alteraciones visuales como ceguera, la cual es la más común, además de sordera, paresia de extremidades y trastorno del lenguaje. Los signos meníngeos tal como ocurrió en nuestro caso son poco elocuentes, esto hace que el diagnóstico se soslaye y es necesaria una sinergia clínica con el aporte de neuroimágenes, hallazgos de laboratorio y las consideraciones epidemiológicas. En este sentido, autores como Brizendine Cryptococcus spp, y además la posterior tipificación de las respuestas terapéuticas de cada una de éstas, lo cual podrá contribuir a mejorar el pronóstico de ésta infección ,Nuevas técnicas de biología molecular como el inmunoenzayo enzimático (EIA por sus siglas en inglés) y Reacción en Cadena de Polimerasa (PCR por sus siglas en inglés) con sensibilidad y especificidad del 100% para ambos test, que permiten clasificar 8 nuevos serotipos de Cryptococcus spp tiene mayor mortalidad que otras presentaciones de esta enfermedad y siendo aún más alta por C. gatti. Los factores más asociados a peor pronóstico son: alteración del estado mental, presión de apertura LCR mayor a 25 cm de agua, antígeno criptocócico en LCR mayor a 1:512, cultivo positivo para criptococo en órganos diferentes al SNC y ausencia de realce meníngeo La infección del SNC por En este caso, un paciente inmunocompetente se presenta con signos de compromiso cerebelar. La falta de especificidad de las manifestaciones clínicas y la baja tasa de detección del Criptococo en el LCR plantean dificultades para su diagnóstico, por lo que es necesario realizar múltiples estudios del LCR para su identificación, además de un estudio radiológico, especialmente por resonancia magnética, para hacer un diagnóstico definitivo.


The following information is missing from the Funding section: This work was partially supported by grant 207462 from the Fondo Cooperación Bilateral-Consejo Nacional de Ciencia y Tecnología (CONACyT)- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).


Exemplos triviais são calibragem de instrumentos, fidedignidade de escala/medida, avaliação de equivalência entre ferramentas de mensuração, julgamento em provas de habilidades, avaliação de repetitividade ou reprodutibilidade, e análise diagnóstica  e psicométrica -Com frequência, demandas de análise de concordância são avaliadas, erroneamente, por técnicas estatísticas de correlação , que pressupõem apenas que a variação dos valores de uma variável acompanhe a variação dos valores de outra. No entanto, para a análise de concordância, além de correlação, deve haver coincidência entre os valores. Por essa razão, as medidas de efeito de concordância costumam ser menores que os coeficientes de correlação, quando aplicadas ao mesmo conjunto de dadosA definição do modelo analítico de concordância deve ser idealizada precocemente, na elaboração do projeto, de forma que seja contemplado um desenho que favoreça a coleta, a análise e a interpretação de dados. Nessa fase, contatar um estatístico experiente aumenta a chance de sucesso.Em princípio, a análise de concordância pode depender unicamente da definição predeterminada do pesquisador, que deve definir um limite tolerável para satisfazer suas necessidades. Isso ocorre comumente em calibragem e equivalência de ferramentas de mensuração, nas quais as aferições devem obedecer a uma variação percentual máxima em comparação a uma medida-padrão ou um instrumento específico. Entretanto, a existência inerente de erro aleatório de medidas ligada ao instrumento e/ou aos avaliadores inclui uma variação intrínseca das medidas, que interfere na estimativa de concordância. Para avaliar esses aspectos, foram desenvolvidos diversos testes estatísticos específicos, e os principais serão discutidos a seguir.kappa de Cohen. O valor, o intervalo de confiança e a significância estatística de kappa devem ser interpretados como a dimensão da concordância que ultrapassa a coincidência de avaliações que ocorrem ao acasoA situação mais simples ocorre quando a variável de interesse é dicotômica , e a estimativa ocorre por dois avaliadores ou dois instrumentos; nesse caso, classicamente se emprega a estatística versus transvaginal para a identificação de varizes pélvicas , p < 0,01 –, apesar de estatisticamente significativa.Como exemplo, a investigação de Barros et al.pélvicas , evidenckappa com pesos quadráticos (Fleiss-Cohen),Uma situação mais elaborada ocorre quando uma variável ordinal  é estimada por dois avaliadores. Nesse caso, além das concordâncias totais, um peso pode ser atribuído para classificações próximas, em detrimento das maiores divergências. Para essa análise, utiliza-se, classicamente, a estatística kappa com pesos apresenta maior magnitude que a medida de concordância completa, por incorporar o conceito de concordância parcial. Há uma variedade de formas de estabelecer pesos para as concordâncias parciais. Usualmente, kappa com pesos quadráticos apresenta o mesmo resultado do coeficiente de correlação intraclasse (CCI), discutido adiante,Quando a mesma amostra é analisada, o estimador kappa com pesos resultou em uma concordância substancial – 0,66  –, devido ao fato de que o avaliador 1 classificara sistematicamente as imagens em um nível maior que o avaliador 2, gerando alta concordância parcial. Outrossim, quando se dispõem de múltiplos níveis ordinais, as classificações dos valores extremos  costumam resultar em maior concordância do que as categorias intermediárias.Por exemplo, utilizando os dados brutos do trabalho de Brianezi et al.ranks) e ocorre a estimativa por dois avaliadores (interobservador), dois instrumentos ou as variáveis são estimadas em momentos diferentes (teste-reteste), emprega-se comumente o CCI para completa concordância, que é robusto inclusive para violações de normalidade das distribuições-,Quando as variáveis de interesse são quantitativas  é convencionada como: 0 (ausência), 0-0,19 (pobre), 0,20-0,39 (fraca), 0,30-0,59 (moderada), 0,60-0,79 , e ≥ 0,80 (quase completa),,Além da cuidadosa descrição metodológica do processo de seleção de sujeitos e avaliadores, e de coleta dos dados e das técnicas analíticas empregadas, os resultados de investigações de concordância devem ser expressos pelos dados percentuais de concordância , além dos estimadores, com seus intervalos de confiança de 95% e sua significância estatística. Somente assim é possível interpretar em que circunstâncias as variáveis divergem. A interpretação da magnitude dos estimadores de concordância , do poder do teste e da homogeneidade das categorias avaliadas. Esse assunto é adequadamente explorado em literatura específica,,O dimensionamento amostral para testes de concordância depende da dimensão de 1/n). São essenciais o treinamento prévio e o controle do rigor das estimativas dos avaliadores, porque podem resultar em discordância entre as estimativas, o que adiciona um erro sistemático, em detrimento da dimensão das medidas aferidas,Os indicadores de concordância são influenciados pela representatividade de cada classe analisada, o que exige a máxima homogeneidade dos subgrupos, mas também pela modificação da escala original das medidas , for the same subject/phenomenon, using different instruments, using the same instrument at different times or when performed by different examiners, or some combination of these conditions. Trivial examples include calibration of instruments, testing reliability of scales/measures, assessment of the equivalence of measurement tools, judgment in tests of ability, tests of repeatability or reproducibility, and diagnostic analysis  and psychometric agreement .-It is common for the need to analyze agreement to be, erroneously, met using statistical techniques for measurement of correlation , which are only testing the assumption that the variation in the values of one variable follows the variation in the values of another. However, for analysis of agreement, in addition to correlation, there must also be coincidence of values. This is why measures of the effect size of agreement tend to be smaller than correlation coefficients, when applied to the same dataset.The model of agreement analysis should be defined early on in the project design phase so that a study design is chosen to favor collection, analysis and interpretation of the data. Being able to count on an experienced statistician during this phase will increase the likelihood of success.In principle, analysis of agreement can depend exclusively on a definition predetermined by the researcher, who should define a tolerance limit that satisfies the research requirements. This is generally the case with calibration and equivalence of measurement instruments, in which measurements must conform to a maximum percentage variation in comparison with a standard measure or a specific instrument. However, the existence of an inherent random error of measurement linked to the instrument and/or the examiners includes an intrinsic variation in measurements, which interferes with estimation of agreement. Several different specific statistical tests have been developed to evaluate these aspects and the most important of them will be discussed below.The simplest situation occurs when the variable of interest is dichotomous , and estimation is made by two examiners or with two instruments. In such cases, Cohen’s kappa statistic is classically employed. The kappa value, confidence interval and statistical significance should all be interpreted as the magnitude of agreement that exceeds the degree of coincidence of assessments that would occur by chance.For example, an investigation conducted by Barros et al.,A more elaborate situation occurs when an ordinal variable  is estimated by two examiners. In such cases, in addition to total agreement, a weighting can be attributed to similar classifications, favoring them over larger degrees of disagreement. For this type of analysis, the classical choice is the kappa statistic with quadratic weighting (Fleiss-Cohen).,When the same sample is analyzed, the weighted kappa estimator returns a higher magnitude than the measure of complete agreement, since it incorporates the concept of partial agreement. There are several ways of establishing the weights assigned to partial agreements. Usually, kappa with quadratic weightings will return the same result as the Intraclass Correlation Coefficient (ICC), which is discussed below.For example, using the crude data from the study published by Brianezi et al.,-,When the variables of interest are quantitative  and two examiners make estimates (interobserver agreement), there are two instruments, or the variables are estimated at different times (test-retest reliability), then the ICC for complete agreement is generally used, which is even robust to violations of normal distribution.As an example, the crude data will be used from Ianhez et al.,Interobserver agreement is usually less than intraobserver agreement for estimates from the same sample, because the first includes sources of variability that are inherent to the different examiners. Additionally, the ICC estimate for single measures generates smaller magnitude estimators than the estimate for mean measures, which justifies the use of multiple measures to reduce the random error.,,In addition to careful methodological description of the process of selecting the subjects and the examiners, of the data collection and of the analytical techniques employed, the results of tests of agreement should be expressed in the form of percentage agreement data , in addition to providing the estimators and their 95% confidence intervals and statistical significance. This is the only way that enables interpretation of the circumstances under which variables diverge. The magnitude of estimators of agreement (kappa or ICC) is conventionally interpreted as follows: 0 (absent), 0-0.19 (poor), 0.20-0.39 (weak), 0.30-0.59 (moderate), 0.60-0.79 , and ≥ 0.80 .,There are generalizations of the algorithms for calculation of the kappa and ICC for multiple assessments and also for different combinations of subjects and examiners. However, these methods are beyond the scope of this text.Agreement between variables of a quantitative nature can be represented graphically, in pairs, using a Bland-Altman plot, which projects the absolute difference between the measures of each data point on the ordinate axis and the mean of the two measurements on the abscissa axis.Returning once more to the crude data collected by Ianhez et al.,,,Choice of the sample size for tests of agreement is dependent on the dimension of the kappa (or ICC), on the test power and on the homogeneity of the categories under analysis. This subject is covered adequately in specialized literature.1/n transformation). Prior training and control of the rigor of the examiners’ estimates are essential, because their absence could introduce disagreement between estimates, which would add a systematic error, in detriment to the magnitude of the measurements taken.,Indicators of agreement are influenced by the representativeness of each class analyzed, which demands maximum homogeneity of subsets, and also by the modification imposed on the original measurement scale (for example, Log or xFinally, even a good estimate of agreement, with an adequate confidence interval and statistical significance, may not be confirmed when applied to other populations, other examiners, other instruments or to measures not contained in the original sample, respecting the inferential principles of generalization of samples.


The diagnosis of pleural tuberculosis requires an invasive and time-consuming reference method. Polymerase chain reaction (PCR) is rapid, but validation in pleural tuberculosis is still weak. To establish the operating characteristics of real-time polymerase chain reaction (RT-PCR) hybridization probes for the diagnosis of pleural tuberculosis.Mycobacterium tuberculosis culture in fluid or pleural tissue, or pleural biopsy with granulomas. Pleural tuberculosis was ruled out (in 31 patients) if all three tests were negative. The operating characteristics of the RT-PCR, using the Mid-P Exact Test, were determined using the OpenEpi 2.3 Software (2009). The validity of the RT-PCR hybridization probes was evaluated compared to a composite reference method by a cross-sectional study at the Hospital Universitario de la Samaritana. 40 adults with lymphocytic pleural effusion were included. Pleural tuberculosis was confirmed (in 9 patients) if the patient had at least one of three tests using the positive reference method: Ziehl-Neelsen or  The RT-PCR hybridization probes showed a sensitivity of 66.7% (95% CI: 33.2%-90.7%) and a specificity of 93.5% (95% CI: 80.3%-98.9%). The PPV was 75.0% (95% CI: 38.8%-95.6%) and a NPV of 90.6% (95% CI: 76.6%-97.6%). Two false positives were found for the test, one with pleural mesothelioma and the other with chronic pleuritis with mesothelial hyperplasia.  The RT-PCR hybridization probes had good specificity and acceptable sensitivity, but a negative value cannot rule out pleural tuberculosis. Tuberculosis (TB) has been a major public health disease for decades Epidemiologically, TB has a worldwide distribution and the mortality rate of 2014 was reduced to about half that of 1990 Mycobacterium tuberculosis is isolated in culture in only 20% to 40% of cases of confirmed tuberculous pleuritis, the diagnostic yield of the culture being low in pleural fluid, but may be increased if a sample of pleural tissue is also cultured ,,,The detection of bacillus by culture, staining of histopathological studies or body fluids is essential for the diagnosis of TB, but it is necessary to take into account that less than 5% of the cases of TBP show a positive smear microscopy in the liquid Pleural due to the paucibacillary naturalization of this entity Adenosine deaminase (ADA) nonspecific inflammatory marker is an enzyme the activity of which is involved in the differentiation and proliferation of lymphocytes and the activation of macrophages and neutrophils, being indicative of active local inflammatory response ,Consequently, a combination of several tests, including cultures and Ziehl-Neelsen (ZN) staining of the fluid or pleural tissue, has been recommended as a reference method for the diagnosis of TBP, and the histopathological study of the pleural tissue M. tuberculosis in culture has led to the search for rapid diagnostic tests and new methods that detect it directly in clinical samples, without the need to wait for the result of such cultures The slow growth of Therefore, other diagnostic methods have been used, including the real-time polymerase chain reaction (RT-PCR) of the qualitative type, which is a molecular biology test, which identifies the DNA of the mycobacteria, using a technique where the amplification and detection processes occur simultaneously in the same closed vial, with no need for any subsequent action, emitting results in less time and with a high specificity (98%), but with a low or variable sensitivity (62%) not being useful to exclude the disease hot-start PCR), which significantly reduces the risk of nonspecific amplifications The fluorescence detection systems used in RT-PCR can be of two types: intercalators and specific probes labeled with fluorochromes Specific hybridization probes are probes labeled with two types of fluorochromes, a donor and an acceptor. The process is based on the transfer of fluorescent energy by resonance (FRET) between the two molecules. The most used are 1. Hydrolysis probes, also referred to as TaqMan probes2. Molecular beacons.3. FRET probes. The system consists of two probes that bind to adjacent sequences of the target DNA. One of the probes carries a donor at the 3' end and the other an acceptor at the 5' end. When the probes are hybridized, the two fluorochromes are close. Upon being energized, the donor transfers its energy to the acceptor which, in turn, emits the fluorescence that the reader of the equipment detects.In all these systems, the increase of DNA in each cycle corresponds to an increased hybridization of the probes, which leads to an increase in the same proportion of emitted fluorescence. The use of probes guarantees specificity of the detection and it allows the identification of polymorphisms or point mutations, but the cost is higher than SYBR Green and optimization of the reaction conditions is more difficult M. tuberculosis Real-TM (RT-PCR kit for M. tuberculosis complex detection) which is a real-time amplification test for the qualitative detection of M. tuberculosis complex in biological materials (the result is obtained in an average of 3.5 days). DNA is extracted from the samples, amplified and detected by fluorescent probes specific for M. tuberculosis and M. tuberculosis . M. tuberculosis  is an IS6110 insertion DNA fragment of MTb modified and cloned into the bacteriophage , in patients with lymphocytic exudate pleural effusion (according to light criteria and with a higher proportion of lymphocytes than neutrophils). Study of cross-sectional diagnostic tests to determine the validity of pleural fluid RT-PCR for the diagnosis of TBP.The population under study were all patients over 18 years of age evaluated for lymphocytic exudate pleural effusion during the period from September 1, 2009 to September 30, 2012, in the HUS internal medicine hospitalization service, where the patient and the attending physician agree to participate in the study of pleuritis with the standard methods used by them.M. tuberculosis and/or histology of pleural tissue with granulomas and where RT-PCR was performed with liquid or pleural tissue hybridization probes for M. tuberculosis.Inclusion criteria were: Patients older than 18 years of age hospitalized in the HUS internal medicine service during the study period, with lymphocytic exudate-type pleural effusion .Exclusion criteria were: Transudated pleural effusion (does not meet any of the exudate criteria discussed above) M. tuberculosis performed in pleural liquid or tissue during the years of the study and with this information we arranged to search  in the medical records of these patients the other inclusion criteria required.Initially we used the molecular biology laboratory database where we had all the RT-PCR hybridation probes for Once the information was collected, we prepared to perform their respective coding and tabulation by double entry, using an instrument designed for data collection.M. tuberculosis; 2. Ziehl-Neelsen (ZN) of pleural fluid or tissue; and 3. Histology of pleural tissue. A combined reference method was defined as follows: 1. Culture of pleural fluid or tissue for M. tuberculosis pleuritis and it was ruled out if all three were negative. It was considered a probable case if the reference method was negative but the RT-PCR hybridization probes for M. tuberculosis was positive and the ADA greater than 47 UI/L One of these three positive tests diagnosed M. tuberculosis were performed simultaneously once the diagnosis was made from lymphocyte exudate initially in pleural fluid and if these were inconclusive for a definitive diagnosis, these tests were made simultaneously in a sample of pleural biopsy. At the beginning of the study, there was no diagnosis of the etiology of the pleural effusion or previous history of TB or cancer, although this was not an exclusion criterion. Both the reference method tests and the ADA and the RT-PCR hybridization probes for M. tuberculosis, M. Africanum, M. bovis, M. bovis BCG, M. microti). Under the following amplification conditions: 1 Cycle: 95° C for 15 min, 40 Cycles: 95° C for 15 s, 65° C for 30 s, 72° C for 15 s. In order to discard the false negatives by the presence of amplification reaction inhibitors, an internal control (IC) of amplification (JOE emission) was added to all the samples. The assembly of the RT-PCR and the analysis of the results was carried out using the STRATAGENE MX 3005P equipment in the MxPro program. Samples were considered positive or negative based on increased fluorescence above the threshold established in the FAM and JOE channels. Thus, a sample was considered positive for M. tuberculosis if the fluorescence exceeded the limit of the established threshold in the FAM (green) channel, whereas a sample was considered negative if it did not show fluorescence in the FAM channel and presented positive fluorescence in the JOE channel. It is important to clarify that the results obtained for each patient with this technique were obtained in a maximum time of four hours.The complete extraction of the DNA in the pleural fluid of the patients, as well as the assembly of the RT-PCR hybridization probes was performed according to the recommendations of the kit manufacturer . In order to remove inhibitors from the RT-PCR reaction, initially all the pleural fluids obtained were treated with 250 mg of N-acetyl-L-Cysteine (Sigma), 4% NaOH and sodium citrate at 2.94%. The DNA subsequently obtained was used to assemble the RT-PCR using hybridization probes (FAM Emission) for the qualitative detection of the IS6110 gene specifically present in the Mycobacteria DNA of the tuberculous complex , for a 95% expected sensitivity, a 95% expected specificity, a 50% prevalence of pleural tuberculosis in the studied population, expecting an amplitude of the confidence interval of 95% of 0.1 on each side, using the equation proposed by Duffau Sensitivity, specificity, positive and negative predictive values, and respective confidence intervals were calculated for RT-PCR, ZN coloration and culture in pleural fluid, compared to the reference method. Confidence intervals were determined using the Mid-P Exact Test. The software OpenEpi version 2.3 (2009) was used.A population of 60 patients with pleural effusion in the HUS was included during the study period, of whom 40 met the inclusion criteria and of these nine  were confirmed the diagnosis of TBP with the method reference. Of these nine patients confirmed with TBP, six were positive and three negative for RT-PCR, the latter were considered false negatives of the RT-PCR, since they presented resolution of the picture with antituberculous treatment. There were no patients with probable TBP (probable TBP: negative reference method with positive RT-PCR and ADA greater than 47 IU/L). There were two false positives for RT-PCR, one with pleural mesothelioma and the other with chronic pleuritis with mesothelial hyperplasia. In patients diagnosed with TPB, we found an average of 47.4 years of age with a standard deviation of . The PPV was 75% (95% CI: 38.8%-95.6%) and the NPV was 90.6% (95% CI: 76.6%-97.6%) (A sensitivity of 66.7% (95% CI: 33.2%-90.7%) and a specificity of 93.5% (95% CI: 80.3%-98.9%) were calculated for the test under study  .M. tuberculosis in pleural fluid, a sensitivity of 55.6% (95% CI: 39.7%-89.2%) was found with a specificity of 100% (95% CI: 87.1-100%); and for ZN in pleural fluid a sensitivity of 22.2% (95% CI: 39.7%-89.2%) was calculated with a specificity of 100% (95% CI: 87.1%-100%) (With regard to culture for 1%-100%) .M. tuberculosis in pleural fluid in the HUS were established. A sensitivity (66.7%) was found, similar to that found in previously referenced studies .With these results, the operating characteristics of the RT-PCR for the diagnosis of M. tuberculosis in pleural fluid a sensitivity of 55.6% was found while ZN in pleural fluid was 22.2%; both had a specificity of 100%. These values show lower sensitivities than the RT-PCR, confirming once again the need to have a combined reference method since these tests alone could not rule out the presence of pleural tuberculosis. Additionally, in the case of cultures, the time required to obtain the diagnosis is extended to 8 weeks in such a way that a rapid test is required, such as RT-PCR, to define the initial management of the patient in a maximum time of four hours which is what this test would take to generate a result.In culture for , et al., commercial and artisanal PCR were evaluated, reporting a sensitivity of 62% and 71%, with a specificity of 98% and 93%, respectively, which is similar to that found in our research for RT-PCR. The studies included in this meta-analysis had small sample sizes and were heterogeneous; the reference method used included culture for M. tuberculosis, clinical findings, microbiology or biopsy, so that these reference methods lack precision to make a definitive diagnosis and make validation of the test under study difficult. Later in 2005, Chakravorty et al.et al.et al. In the meta-analysis performed by PaiAccording to our reference method, there were 9 cases of TBP in our study and 31 cases with lymphocytic pleuritis due to causes other than TB, which gives us a prevalence of TBP of 23%. This prevalence is similar to that found in TBP studies in Spain The operating characteristics of the PCR vary depending on the technique used and the association of other diagnostic tests and clinical characteristics of the patient. It can be observed that the use of RT-PCR requires less time, with high specificity but with low sensitivity. This makes the test insufficient to rule out TBP if the RT-PCR is negative and there is no alternative diagnosis and it requires performing the complete combined reference method. By having sensitivity and specificity values superior to those obtained with the other tests individually and yielding results much more quickly, it is a useful test to define early on the treatment to follow with a patient with lymphocyte exudate: if it is positive there would be valid reasons to start anti-tuberculosis treatment and if it is negative, not do so. However, these results should be analyzed in the clinical context of the patient and should be confirmed with reference method , since the predictive values are not good enough (PPV: 75.0% and NPV: 90.6%) for the use of RT-PCR as a definitive diagnostic method. In fact, two false positives were presented with a diagnosis of mesothelioma and chronic pleuritis with mesothelial hyperplasia, respectively.For this study, a combined reference method was used, which allowed for a definitive and objective diagnosis of TBP and, therefore, to assess a more precisely the operating characteristics of the test under study, becoming a strength for this research. However, we should note that a weakness of the study is the sample size, which was low for the findings finally found, which increased confidence intervals and decreased study accuracy. This forces us to suggest conducting studies of validation of the RT-PCR with larger sample sizes, to increase the precision of the results.M. tuberculosis in pleural fluid has good specificity for the diagnosis of TBP, but because its predictive values are not high enough, it should not be used for the definitive diagnosis of the disease. Its greatest use would be as a method to quickly define the behavior to follow with a patient, while the reports of the definitive diagnostic tests arrive. Cultures for M. tuberculosis and ZN of pleural fluid and tissue have a lower diagnostic yield than RT-PCR and it is necessary to continue using the combined reference method to establish the definitive diagnosis of lymphocytic pleuritis. The RT-PCR for It is necessary to carry out new studies with a larger sample size in order to increase the precision of the previously established results. La tuberculosis (TB) es una enfermedad de gran impacto en salud pública desde hace décadas Epidemiológicamente, la TB tiene distribución mundial, la tasa de mortalidad de 2014 se redujo a cerca de la mitad de la de 1990 Mycobacterium tuberculosis se aísla en cultivo sólo en un 20 a 40% de los casos de una pleuritis tuberculosa confirmada, siendo el rendimiento diagnóstico del cultivo en líquido pleural bajo, pero puede aumentar si también se cultiva una muestra de tejido pleural ,,,Para el diagnóstico de la TB es fundamental la detección del bacilo por cultivo, coloraciones de estudios histopatológicos o de líquidos corporales, pero hay que tener en cuenta que en menos del 5% de los casos de TBP se logra obtener una baciloscopia positiva en el líquido pleural debido a la naturaliza paucibacilar de esta entidad La Adenosin deaminasa (ADA) marcador inflamatorio no específico, es una enzima cuya actividad está involucrada en la diferenciación y proliferación de los linfocitos y la activación de los macrófagos y neutrófilos, siendo indicativa de respuesta inflamatoria local activa ,Por estos motivos se ha recomendado utilizar como método de referencia para hacer el diagnóstico de TBP la combinación de varias pruebas, incluyendo los cultivos y la tinción de Ziehl-Neelsen (ZN) del líquido o del tejido pleural; y el estudio histopatológico del tejido pleural M. tuberculosis en cultivo ha llevado a la búsqueda de pruebas rápidas de diagnóstico y de nuevos métodos que lo detecten directamente en muestras clínicas, sin la necesidad de esperar el resultado de dichos cultivos El lento crecimiento del Por esta razón se han venido utilizando otros métodos diagnósticos, entre los cuales está la reacción en cadena de la polimerasa en tiempo real (RT-PCR) de tipo cualitativa, que es una prueba de biología molecular, que identifica el ADN de la micobacteria, utilizando una técnica donde los procesos de amplificación y detección se producen de manera simultánea en el mismo vial cerrado, sin necesidad de ninguna acción posterior, emitiendo resultados en menor tiempo y con una alta especificidad (98%), pero con una baja o variable sensibilidad (62%) no siendo útil para excluir la enfermedad (hot-start PCR) lo cual disminuye de forma notable el riesgo de amplificaciones inespecíficas Los sistemas de detección por fluorescencia empleados en la RT-PCR pueden ser de dos tipos: agentes intercalantes y sondas específicas marcadas con fluorocromos Las sondas de hibridación específicas, son sondas marcadas con dos tipos de fluorocromos, un donador y un aceptor. El proceso se basa en la transferencia de energía fluorescente mediante resonancia (FRET) entre las dos moléculas. Las más utilizadas son 1. Sondas de hidrólisis, denominadas también sondas TaqMan.2. Molecular beacons3. Sondas FRET. El sistema se compone de dos sondas que se unen a secuencias adyacentes del ADN diana. Una de las sondas lleva un donador en el extremo 3' y la otra un aceptor en el extremo 5'. Cuando las sondas están hibridadas, los dos fluorocromos están próximos. Al ser excitado, el donador transfiere su energía al aceptor que, a su vez, emite la fluorescencia que detecta el lector del equipo.En todos estos sistemas, el incremento de ADN en cada ciclo se corresponde con un aumento de hibridación de las sondas, lo que conlleva un aumento en la misma proporción de fluorescencia emitida. El empleo de sondas garantiza la especificidad de la detección y permite identificar polimorfismos o mutaciones puntuales, pero su coste es más elevado que el SYBR Green y la optimización de las condiciones de la reacción resulta más difícil M. tuberculosis Real-TM (Equipo de RT-PCR para la detección del complejo M. tuberculosis) la cual es un test de amplificación en tiempo real para la detección cualitativa del complejo M. tuberculosis en materiales biológicos (se obtiene el resultado en un promedio de 3.5 días). El ADN es extraído de las muestras; amplificado y detectado mediante sondas fluorescentes específicas para M. tuberculosis y control interno (M. tuberculosis). Mycobacterium tuberculosis (control interno) es un fragmento de ADN de inserción IS 6110 de MTb modificado y clonado en el bacteriófago , en pacientes con derrame pleural tipo exudado linfocitario (según los criterios de light y con mayor proporción de linfocitos que de neutrófilos). Estudio de pruebas diagnósticas de corte transversal, para determinar la validez de la RT-PCR en líquido pleural para el diagnóstico de TBP.La población en estudio fueron todos los pacientes mayores de 18 años evaluados por derrame pleural tipo exudado linfocitario, durante el periodo comprendido entre el primero de septiembre de 2009 hasta el 30 de septiembre de 2012, en el servicio de hospitalización de medicina interna del HUS, donde el paciente y el médico tratante aceptaran participar en el estudio de la pleuritis con los métodos estándares por ellos utilizados., cultivo de líquido o tejido pleural para M. tuberculosis y/o histología de tejido pleural con granulomas y en quienes se haya realizado RT-PCR con sondas de hibridación en líquido o tejido pleural buscando M. tuberculosis.Los criterios de inclusión fueron: Pacientes mayores de 18 años de edad hospitalizados en el servicio de medicina interna del HUS durante el periodo del estudio, con derrame pleural tipo exudado linfocitario Los criterios de exclusión fueron: Derrame pleural tipo transudado  en las historias clínicas de estos pacientes los demás criterios de inclusión requeridos.Inicialmente se utilizó la base de datos del laboratorio de biología molecular donde contamos con todas las RT-PCR sondas de hibridación para Una vez recolectada la información, nos dispusimos a realizar su respectiva codificación y tabulación por doble entrada, para lo que se utilizó un instrumento diseñado para la recolección de datos.M. tuberculosis; 2. Ziehl-Neelsen (ZN) de líquido o tejido pleural; e 3. Histología de tejido pleural. Se definió un método de referencia combinado de la siguiente forma: 1. Cultivo de líquido o tejido pleural para M. tuberculosis y dicha entidad se descartó si las tres fueron negativas. Se consideró como caso probable si el método de referencia era negativo pero la RT-PCR sondas de hibridación para M. tuberculosis positiva y el ADA mayor de 47 UI/L Con una de estas tres pruebas diagnósticas positiva se diagnosticó la pleuritis por M. tuberculosis fueron realizadas en paralelo una vez se hizo el diagnóstico a partir del exudado linfocitario inicialmente en líquido pleural y si estas no eran concluyentes para generar un diagnóstico definitivo se realizaron dichas pruebas de forma paralela en muestra de biopsia pleural. Al inicio del estudio no se tenía el diagnóstico de la etiología de dicho derrame pleural ni tampoco antecedente previo de TB ni cáncer, aunque esto no era un criterio de exclusión. Tanto las pruebas del método de referencia como el ADA y la RT-PCR sondas de hibridación para M. tuberculosis, M. africanum, M. bovis, M. bovis BCG, M. microti). Bajo las siguientes condiciones de amplificación: 1 Ciclo: 95° C por 15 min, 40 Ciclos: 95° C por 15 s, 65° C por 30 s, 72° C por 15 s. Con el fin de descartar los falsos negativos por presencia de inhibidores de la reacción de amplificación, a todas las muestras se les adicionó un control interno (CI) de amplificación (Emisión JOE). El montaje de la RT-PCR y el análisis de los resultados se llevó acabo utilizando el equipo STRATAGENE MX 3005P en el programa MxPro. Las muestras fueron consideradas positivas o negativas basados en el aumento de la fluorescencia por encima del umbral establecido en los canales FAM y JOE. De esta forma, una muestra se consideró positiva para M. tuberculosis si la fluorescencia superó el límite del umbral establecido en el canal FAM (verde), mientras que una muestra se consideró negativa si no presentó fluorescencia en el canal FAM y presentó fluorescencia positiva en el canal JOE. Es importante aclarar que los resultados obtenidos para cada paciente con esta técnica se obtuvieron en un tiempo máximo de cuatro horas.La extracción total del ADN presente en el líquido pleural de los pacientes, así como el montaje de la RT-PCR sondas de hibridación se realizó según las recomendaciones del fabricante del kit . Para ello y con el fin de remover inhibidores de la reacción de la RT-PCR, inicialmente todos los líquidos pleurales obtenidos, fueron tratados con 250 mg de N-acetil-L Cisteina (Sigma), NaOH al 4% y citrato de sodio al 2.94%. El ADN posteriormente obtenido fue utilizado en el montaje de la RT-PCR, utilizando sondas de hibridación (Emisión FAM) para la detección cualitativa del gen IS6110 presente de forma específica en el ADN de las Micobacterias pertenecientes al complejo tuberculoso , para una sensibilidad esperada del 90%, una especificidad esperada del 95% una prevalencia de tuberculosis pleural en la población estudiada del 50%, esperando una amplitud del intervalo de confianza del 95% de 0.1 a cada lado, utilizando la ecuación propuesta por Duffau Se calcularon la sensibilidad, especificidad, valores predictivos positivo y negativo, y los respectivos intervalos de confianza, para la RT-PCR, cultivo y coloración de ZN en líquido pleural, comparados con el método de referencia. Los intervalos de confianza se determinaron mediante la Prueba Mid-P Exact. Se utilizó el software OpenEpi versión 2.3 (2009).Se obtuvo una población de 60 pacientes con derrame pleural en el HUS durante el periodo del estudio, de los cuales 40 cumplieron con los criterios de inclusión y de estos a nueve  se les confirmó el diagnóstico de TBP con el método de referencia. De estos nueve pacientes confirmados con TBP, 6 fueron positivos y 3 negativos para la RT-PCR, estos últimos, se consideraron como falsos negativos de la RT-PCR, ya que presentaron resolución del cuadro con el manejo antituberculoso. No hubo pacientes con TBP probable (TBP probable: método de referencia negativo con RT-PCR positiva y ADA mayor de 47UI/L). Se presentaron dos falsos positivos para la RT - PCR, uno con un mesotelioma pleural y el otro con una pleuritis crónica con hiperplasia mesotelial. En los pacientes con diagnóstico de TBP encontramos una media de 47.4 años de edad con una desviación estándar de  se calculó una sensibilidad del 66.7% (IC 95%: 33.2%-90.7%) y una especificidad del 93.5% (IC 95%: 80.3%-98.9%). El VPP fue 75% (IC 95%: 38.8%-95.6%) y el VPN fue 90.6% (IC 95%: 76.6%-97.6%)  .M. tuberculosis en líquido pleural se encontró una sensibilidad del 55.6% (IC 95%: 39.7%-89.2%) con una especificidad del 100% (IC 95%: 87.1-100%); y para el ZN en líquido pleural se calculó una sensibilidad del 22.2% (IC 95%: 39.7%-89.2%) con una especificidad del 100% (IC 95%: 87.1% - 100%)  .M. tuberculosis en líquido pleural en el HUS. Se determinó una sensibilidad (66.7%) similar a lo encontrado en estudios previamente referenciados -,Con estos resultados se establecieron las características operativas de la RT -PCR para el diagnóstico de M. tuberculosis en líquido pleural se encontró una sensibilidad del 55.6% mientras que para el ZN en líquido pleural fue del 22.2%, ambos tuvieron una especificidad del 100%. Estos valores muestran sensibilidades menores a la de la RT-PCR, confirmando una vez más la necesidad de tener un método de referencia combinado ya que estas pruebas por si solas no podrían descartar la presencia de tuberculosis pleural. Adicionalmente, en el caso de los cultivos, el tiempo necesario para obtener el diagnóstico se alarga hasta 8 semanas de tal manera que obliga a recurrir a una prueba rápida, como la RT-PCR, para definir el manejo inicial del paciente en un tiempo máximo de cuatro horas que es lo que esta prueba se tardaría en generar un resultado.En el cultivo para , et al., se evaluó PCR comerciales y artesanales, reportando una sensibilidad del 62% y 71%, con una especificidad del 98% y 93%, respectivamente, lo cual es similar a lo encontrado en nuestra investigación para RT-PCR. Los estudios incluidos en este meta-análisis tenían tamaños muestrales pequeños y eran heterogéneos, los método de referencia utilizados incluían cultivo para M. tuberculosis, hallazgos clínicos, microbiología o biopsia, de tal forma que estos método de referencia carecen de precisión para dar un diagnóstico definitivo y dificultan la validación de la prueba en estudio. Posteriormente en el año 2005, Chakravorty et al. et al.et al. En el meta-análisis realizado por PaiDe acuerdo con nuestro método de referencia, en nuestro estudio tuvimos 9 casos de TBP y 31 casos con pleuritis linfocitaria por causas diferentes a TB, lo cual nos da una prevalencia de TBP de 23%, esta prevalencia es similar a la encontrada en estudios de TBP en España Las características operativas de la PCR varían dependiendo de la técnica utilizada y de la asociación de otras pruebas diagnósticas y características clínicas del paciente. Se puede observar que el uso de la RT-PCR requiere menor tiempo, con alta especificidad pero con baja sensibilidad. Esto hace que la prueba resulte insuficiente para descartar TBP si la RT-PCR es negativa y no existe otro diagnóstico alterno, y exige realizar el método de referencia combinado completo. Al tener unos valores de sensibilidad y especificidad superiores a los obtenidos con las otras pruebas en forma individual y arrojar resultados en forma mucho más rápida, resulta una prueba útil para definir tempranamente el manejo a seguir con un paciente que tenga exudado linfocitario: si es positiva habría razones válidas para comenzar el tratamiento anti -tuberculoso y si es negativa para no hacerlo. Sin embargo estos resultados deben ser analizados en el contexto clínico del paciente y deben confirmarse con el método de referencia , ya que los valores predictivos no son suficientemente buenos (VPP: 75.0% y VPN: 90.6%) para usar la RT-PCR como un método diagnóstico definitivo; y, de hecho, se presentaron dos falsos positivos en donde el diagnóstico fue mesotelioma y pleuritis crónica con hiperplasia mesotelial, respectivamente.Para el presente estudio se utilizó un método de referencia combinado lo que permitió tener un diagnóstico definitivo y objetivo de TBP, y de esta manera hacer una evaluación más precisa de las características operativas de la prueba en estudio, convirtiéndose en una fortaleza para la presente investigación. Sin embargo, debemos señalar que como debilidad del estudio está el tamaño muestral, que resultó bajo para los hallazgos finalmente encontrados, lo cual aumentó los intervalos de confianza y disminuyó la precisión del estudio. Esto nos obliga a sugerir la realización de estudios de validación de la RT-PCR con mayores tamaños muestrales, para aumentar la precisión de los resultados.M. tuberculosis en líquido pleural tiene una buena especificidad para el diagnóstico de TBP, pero debido a que sus valores predictivos no son suficientemente altos, no debe utilizarse para el diagnóstico definitivo de la enfermedad. Su mayor utilidad sería como método para definir rápidamente la conducta a seguir con un paciente, mientras llegan los reportes de las pruebas diagnósticas definitivas. Los cultivos para M. tuberculosis y los ZN de líquido y tejido pleural tienen menor rendimiento diagnóstico que la RT-PCR y es necesario seguir usando el método de referencia combinado para establecer el diagnóstico definitivo de la pleuritis linfocitaria. La RT-PCR para Es necesario realizar nuevos estudios con un mayor tamaño muestral con el fin de aumentar la precisión de los resultados previamente establecidos.


The original article  is missiThis study was supported by Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and by a grant from Instituto de Salud Carlos III (PI10/00253), co-financed by the European Regional Development Fund (ERDF).


FMR1 gene has four allelic variants according to the number of repeats of the CGG triplet. Premutation carriers with between 55 and 200 repeats are susceptible to developing pathologies such as tremor and ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) syndrome.  The FMR1 premutation diagnosed by PCR and Southern Blot, complying with the clinical and radiological criteria of FXTAS, and in addition, has a history of vagal symptoms suggestive of ovarian failure and menstrual cycle disorders that led to hysterectomy at age 33 and was subsequently diagnosed with FXPOI.  The patient was a 53-year-old female farmer with severe tremor in the upper limbs at rest that worsens with movement, tremor in the jaw and tongue, and generalized cerebral atrophy. She is a carrier of the FMR1 gene.An unusual case of FXTAS and FXPOI complying with clinical and radiological criteria is reported in a premutation carrier of the  The FMR1  gene, with locus Xq27.3, has 17 exons spanning 38 kb, OMIM * 309550 The carriers of the premutation have a variable phenotype and incomplete penetrance completely different than those who have CM and are affected by Fragile X syndrome (FXS) Pathologies found in carriers have been referred to as FRAXopathies, and the most well-known are tremor and ataxia associated with FXS  and primary ovarian insufficiency syndrome associated with FXS (FXPOI) The objective of this article is to contribute to the literature by reporting a rare case of FXTAS and FXPOI in a carrier of FMR1 premutation with the appearance of symptoms at an early age and severe symptomatology. This is the first report of this association in Colombia.The patient is originally from a Colombian population north of Valle del Cauca, a region with a high prevalence of premutation and full mutation of the FMR1 gene.The patient is a 53-year-old woman, a farmer, with a 4-year history of distal tremor at rest that worsens with movement, with a greater involvement of the upper limbs, that has become increasingly severe. In the last year, the tremor involved the mandibular region and the tongue. Therefore, the patient repeatedly consulted a physician; electrolyte and thyroid function studies were performed, and cerebral structural alterations were measured by computerized axial tomography. All results were within normal limits. However, due to the tremor's worsening, a contrast-enhanced brain MRI was performed and showed significant cortical and subcortical atrophy, with greater frontotemporal involvement, and an increase in the size of the ventricular system, markedly in the third ventricle Subsequently, a molecular study was performed for the quantification of FMR1 gene triplets with PCR using a triple primer, including a CGG-specific primer and Southern Blot. Thirty and 82 repeats were found in each allele. Personal pathological antecedents included convulsive syndrome in childhood that was spontaneously resolved at 14 years old; medically managed bilateral carpal tunnel; a gestational formula G5P3C2V2Mo3; and irregular menstrual cycles characterized by persistent polymenorrhea and metrorrhagia, without improvement despite medical management that forced a hysterectomy at the age of 33 years. The living children were studied, and none had PM or MC of the FMR1 gene. In the year prior to hysterectomy and up to 2 years later, she reported perimenopausal symptoms such as hot flashes, profuse night sweats, persistent headache, and vaginal dryness. At the time of the physical examination, there was a tremor at rest that involved the upper limbs, the jaw and the tongue, which worsened during activity. In spite of the limitation for performing cerebellar tests imposed by the tremor, no alterations in gait pattern or other signs of cerebellar ataxia were documented. The Fahn-Tolosa-Marín tremor rating scale Another relevant element found in the physical examination was the presence of neuropathy in the four extremities caused by the alteration of superficial sensitivity with the presence of hypoesthesia and paresthesia.During the interview, manifestations of anxiety with affective modulation were observed. The GAD-7 Scale In addition, an evaluation of the patient's cognitive status was Fahn-Tolosa-Marín performed through the Mini-Mental test in which 25 points out of 30 were obtained, which is suggestive of a pathology.The testing was assessed by a neurologist who initiated treatment with propanolol for tremor management and also by a psychiatrist who considered psychotherapeutic management without the need for medication at that time. The prevalence of FMR1 premutation is 11.7 per 10,000 males (95% CI: 6.0-18.7) and 34.4 per 10,000 females (95% CI: 6.3-83.3), corresponding to 1 for every 855 males and 1 for every 291 females The carriers of the premutation can develop pathologies called FRAXopathy, such as FXTAS and FXPOI The phenotype of those affected by the MC of the FMR1 gene is completely different and does not have the classic features of FXS such as mild to moderate intellectual disability (ID), autistic spectrum disorders, elongated face, prognathism, large winged ears, joint hypermobility, macroorchidism, language deficit, anxiety and aggression. In females, the phenotype is usually less severe FXPOI is found in 20% of premutation carriers. Menstrual bleeding often stops for a year before the age of 40, which is a diagnosis of primary ovarian insufficiency. This frequency is increased 20-fold when compared to the general population, where primary ovarian insufficiency is approximately 1% In the patient reported here, the association of irregular menstrual cycles that led to hysterectomy at age 33, vagal symptoms (related to menopause) and the finding of FMR1 premutation led us to conclude that the patient had primary ovarian insufficiency and FXPOI.FXTAS is a progressive neurodegenerative disorder characterized by neurological deficits that include progressive intention tremor, cerebellar ataxia, cognitive deficit, parkinsonism, neuropathies, autonomic dysfunction and dementia. This syndrome occurs in 40% of male carriers at age 60 and in 75% at age 80 and occurs in 20% of females In FXTAS, the alteration in the FMR1 gene does not silence the FMR1 gene as in those affected by the FXS in which the FMRP  is diminished or absent The diagnosis of FXTAS in FMR1 premutation carriers combines clinical, radiological, neuroimaging and pathological criteria For a definitive diagnosis of FXTAS, it is necessary to have two major criteria: a major clinical criterion plus a major radiological criterion or pathological criterion; the presence of two major clinical criteria or a minor clinical criterion plus a minor radiological criterion make a probable diagnosis. Finally, a possible diagnosis of FXTAS is based on the presence of a minor clinical criterion and a minor clinical criterion The diagnosis of FXTAS in the patient reported here was made by having two major clinical criteria: intension tremor of severe intensity and sustained cognitive impairment demonstrated by a lower than expected score in the Mini-Mental test, and the minor radiological criterion being generalized and marked cortical atrophy in the frontal region. In addition, generalized anxiety was noted, and neuropathy was present as carpal tunnel syndrome. The severity of the symptoms and the early age of the FXTAS make the case infrequent and of poor prognosis.However, in this patient, the age of onset of FXPOI at approximately 33 years, the age of onset of FXTAS symptoms before age 50, the severity of symptoms such as intention tremor that prevents her from performing activities of daily living, mandibular tremor, cognitive deficits, anxiety and generalized cortical atrophy make us consider that this is a very rare case, not only because of the low prevalence of FXTAS in females but also because of the poor presentation of FXTAS and FXPOI simultaneously, with a natural history of unusual disease. Treatment of FXTAS is mainly symptomatic, with therapeutic options that seek to alleviate neuromotor and psychiatric symptoms, with beta blockers, such as propanolol, being the most used for the relief of essential tremor, followed by anticonvulsants. Patients with ataxia have shown improvement with the use of memantine We present a patient with clinical and radiological criteria indicating FXTAS and FXPOI with the appearance of symptoms at an early age and severe symptomatology, showing a natural history of the rare disease in carriers of FMR1 gene premutation. El gen FMR1 , con locus Xq27.3, tiene 17 exones que abarcan 38 Kb, OMIM *309550 Los portadores de la premutación tienen un fenotipo variable y de penetrancia incompleta completamente diferente a quienes tienen la MC y son afectados por el síndrome X Frágil (SXF) A las patologías encontradas en portadores se les ha denominado FRAXOPATIAS y las más conocidas son el síndrome de temblor y ataxia asociado al SXF  y el síndrome de falla ovárica primaria asociado al SXF (FXPOI)  El objetivo de este artículo es aportar a la literatura un raro caso de FXTAS y FXPOI en una portadora de la premutación del gen FMR1, con aparición de los síntomas a edad temprana y sintomatología severa, siendo este el primer reporte de esta asociación en Colombia.La paciente es originaria y procedente de una población Colombiana al norte del Valle del Cauca, región con elevada prevalencia de premutación y mutación completa del gen FMR1.Mujer de 53 años, agricultora, con una historia de 4 años de temblor distal en reposo que empeora con el movimiento, con un mayor compromiso de los miembros superiores, el cual se hace cada vez más severo; en el último año, el temblor comprometió la región mandibular y la lengua. Por lo anterior, ella consultó en repetidas ocasiones y se realizaron estudios de electrolitos, función tiroidea y alteraciones estructurales cerebrales mediante una tomografía axial computarizada, todos los resultados dentro de los límites normales. Sin embargo, por empeoramiento del temblor le realizaron RMN contrastada de cerebro, la cual mostró una atrofia cortical y subcortical significativa, con un mayor compromiso frontotemporal, un aumento del tamaño del sistema ventricular, marcado en el tercer ventrículo; sin otros hallazgos Posteriormente, se le realizó un estudio molecular para la cuantificacion de las tripletas del gen FMR1 con PCR, usando un triple cebador, incluyendo un cebador especifico para CGG y Southern Blot. Se encontraron 30 y 82 repeticiones en cada alelo. Con los antecedentes patológicos personales que incluyeron: síndrome convulsivo en la infancia que se resolvió espontáneamente a los 14 de años, túnel de carpo bilateral en manejo médico; una fórmula gestacional G5P3C2V2Mo3; los ciclos menstruales irregulares caracterizados por polimenorreas y metrorragias persistentes, sin mejoría a pesar del manejo médico, que obligaron a la realización de una histerectomía a la edad de 33 años. Los hijos vivos fueron estudiados y ninguno presentó PM o MC del gen FMR1. Refirió, en el año previo a la histerectomía y hasta dos años después, síntomas perimenopáusicos como oleadas de calor, sudoración nocturna profusa, cefalea persistente y sequedad vaginal. Al momento del examen físico se evidenció temblor en reposo que compromete los miembros superiores, la mandíbula y la lengua, que empeora durante la actividad; a pesar de la limitación para la realización de pruebas cerebelosas impuestas por el temblor, no se documentaron alteraciones del patrón de marcha, ni otros signos de ataxia cerebelosa. Buscando una aproximación objetiva a los hallazgos del examen físico se aplicó la Escala de Temblor de Fahn, Tolosa y Marín Otro elemento relevante encontrado en el examen físico fue la presencia de una neuropatía en las cuatro extremidades, causada por la alteración de la sensibilidad superficial, con la presencia de hipoestesia y parestesias.Durante la entrevista con modulación del afecto, se observaron manifestaciones de ansiedad. Se aplicó entonces, la Escala GAD-7 Además, se realizó una evaluación del estado cognitivo de la paciente a través del test de MINIMENTAL, en el cual se obtuvieron 25 puntos de 30 posibles, siendo este resultado sugestivo de una patología.Fue valorada por neurología quien inició un tratamiento con propanolol para manejo del temblor y también por psiquiatría quien consideró un manejo psicoterapéutico sin necesidad de medicación en ese momento. La prevalencia de la premutación del gen FMR1 es de 11.7 por cada 10,000 hombres (IC 95%: 6.0-18.7) y 34.4 por cada 10,000 mujeres (IC 95%: 6.3-83.3), correspondiendo a 1 por cada 855 hombres y 1 por cada 291 mujeres Los portadores de la premutación pueden desarrollar patologías denominadas FRAXOPATIAS, como FXTAS y FXPOI El fenotipo de los afectados por la MC del gen FMR1 es completamente diferente y no tienen las características clásicas del SXF como discapacidad intelectual (DI) leve a moderada, trastornos del espectro autista, cara alargada, prognatismo, orejas grandes y aladas, articulaciones hiperextensibles, macroorquidismo, déficit del lenguaje, ansiedad y agresión; en mujeres el fenotipo suele ser menos severo El FXPOI se encuentra en el 20% de las portadoras de la premutación, tienen desaparición de sangrado menstrual por un año antes de los 40 años, lo que hace un diagnóstico de falla ovárica prematura; esta frecuencia esta aumentada 20 veces al compararlo con la población general, en la que la falla ovárica prematura esta alrededor del 1% En la paciente aquí reportada la asociación de ciclos menstruales irregulares que obligaron a la histerectomía a los 33 años, síntomas vagales (relacionados con menopausia) y el hallazgo de premutación del gen FMR1, nos llevaron a concluir que la paciente tuvo falla ovárica prematura y FXPOI.El FXTAS es un desorden neurodegenerativo progresivo caracterizado por déficits neurológicos que incluyen temblor progresivo de intención, ataxia cerebelar, déficit cognitivo, parkinsonismo, neuropatías, disfunción autonómica y demencia; este síndrome se presentan en el 40% de los hombres portadores de la premutación a los 60 años y en el 75% a los 80 años, y en el 20% de las mujeres 3En el FXTAS la alteración en el gen FMR1 no produce el silenciamiento del gen FMR1 como en los afectados por el SXF en quienes la FMRP  esta disminuida o ausente El diagnóstico de FXTAS en portadores de la premutación del gen FMR1 combina criterios clínicos, radiológicos de neuroimágenes y patológicos Para un diagnóstico definitivo del FXTAS es necesario tener dos criterios mayores: un criterio clínico mayor más uno radiológico mayor o uno patológico; la presencia de dos criterios clínicos mayores o un criterio clínico menor más un criterio radiológico menor hacen un diagnostico probable. Por último un diagnóstico posible de FXTAS se constituye a partir de la presencia de un criterio clínico menor y un criterio clínico menor El diagnóstico del FXTAS en la paciente aquí reportada se hizo por tener dos criterios clínicos mayores: temblor de intensión severo y deterioro cognitivo sustentado en un puntaje menor al esperado en el test de MINIMENTAL; y el criterio radiológico menor atrofia cortical generalizada y marcada en la región frontal; además, presentó ansiedad generalizada y neuropatía por síndrome del túnel carpiano. La severidad de los síntomas y la edad temprana aparición del FXTAS hacen que el caso sea poco frecuente y de mal pronóstico.Sin embargo, en esta paciente la edad de aparición de FXPOI alrededor de los 33 años, la edad de inicio de síntomas del FXTAS antes de los 50 años, la severidad de los síntomas como temblor de intensión que le impide realizar actividades de la vida diaria, temblor mandibular, déficit cognitivo, ansiedad y atrofia cortical generalizada nos hace considerar que se trata de un caso muy poco frecuente, no solo por la baja prevalencia del FXTAS en mujeres, sino también por la escasa presentación de FXTAS y FXPOI simultáneamente, con una historia natural de la enfermedad inusual. El tratamiento en el FXTAS es principalmente sintomático con opciones terapéuticas que buscan aliviar los síntomas neuromotores y psiquiátricos, siendo los beta bloqueadores, como el propanolol, los más usados para el alivio del temblor esencial, seguidos de los anticonvulsivantes. Pacientes con ataxia han mostrado mejoría con el uso de memantina Se aporta un paciente con criterios clínicos y radiológicos de FXTAS y FXPOI con aparición de los síntomas a edad temprana y sintomatología severa, mostrando una historia natural de la enfermedad poco frecuente en portadoras de la premutación del gen FMR1