[Sociodemographic risk factors of hantavirus cardiopulmonary syndrome]. / Factores de riesgo socio-demográficos del síndrome cardiopulmonar por hantavirus.

BACKGROUND: Hantavirus cardiopulmonary syndrome (HCPS) is caused by new world hantaviruses, among which Andes hantavirus (ANDV) is endemic to Chile and Southern Argentina. The disease caused by ANDV produces plasma leakage leading to enhanced vascular permeability and has a high case fatality rate (35%), mainly due to respiratory failure, pulmonary edema and myocardial dysfunction, hypoperfusion and shock. Host sociodemographic and genetic factors might influence the course and outcome of the disease. Yet, they have not been thoroughly characterized. AIM: To evaluate sociodemographic factors as risk factors in severity of HCPS. PATIENTS AND METHODS: Study period: 2004-20013, attending in eight collaborative centers, etiological diagnosis was performed by serology or molecular biology, mild and severe HCPS were compared.139 Chilean patients were analyzed, 64 (46%) with severe disease among which 12 (19 %) died. RESULTS: European ethnicity had 5,1 times higher risk than Amerindian ethnic group to develop a severe HCPS, greater seriousness that was also associated with an urban residence. CONCLUSION: It was observed that ethnicity and type of residence were significant risk factors for HCPS severity. Hypotheses explaining these findings are discussed.

Factores de riesgo socio-demográficos del síndrome cardiopulmonar por hantavirus / Sociodemographic risk factors of hantavirus cardiopulmonary syndrome

Resumen Introducción: El síndrome cardiopulmonar por hantavirus (SCPH) es causado en Chile y en el sur de Argentina por el Andes hantavirus (ANDV), el que es endémico en esta zona. La enfermedad causada por ANDV produce un aumento de permeabilidad vascular y filtración de plasma con una alta tasa de letalidad (35%), debido principalmente a insuficiencia respiratoria por edema pulmonar y al desarrollo en los casos graves de compromiso miocárdico, hipoperfusión y shock. Aunque se sabe que los factores socio-demográficos del hospedero pueden influir en el curso y el resultado de la enfermedad, estos no se han caracterizado previamente en la población chilena. Objetivo: Evaluar la relación entre los factores socio-demográficos y la gravedad del SCPH. Pacientes y Métodos: Período de análisis 2004-20013, pacientes atendidos en ocho centros colaboradores, diagnóstico etiológico serológico o por biología molecular, se comparan SCPH leve y grave. Se analizaron 139 pacientes chilenos, 64 (46%) con enfermedad grave, entre los cuales 12 murieron (19%). Resultados: La etnia europea tuvo un riesgo 5,1 veces mayor de desarrollar un SCPH grave que la etnia amerindia, gravedad mayor que también se asoció a una residencia urbana. Conclusiones: Se observó una asociación estadísticamente significativa entre etnia, lugar de residencia y evolución de SCPH. Se discuten hipótesis que expliquen estos hallazgos.

Background: Hantavirus cardiopulmonary syndrome (HCPS) is caused by new world hantaviruses, among which Andes hantavirus (ANDV) is endemic to Chile and Southern Argentina. The disease caused by ANDV produces plasma leakage leading to enhanced vascular permeability and has a high case fatality rate (35%), mainly due to respiratory failure, pulmonary edema and myocardial dysfunction, hypoperfusion and shock. Host sociodemographic and genetic factors might influence the course and outcome of the disease. Yet, they have not been thoroughly characterized. Aim: To evaluate sociodemographic factors as risk factors in severity of HCPS. Patients and Methods: Study period: 2004-20013, attending in eight collaborative centers, etiological diagnosis was performed by serology or molecular biology, mild and severe HCPS were compared.139 Chilean patients were analyzed, 64 (46%) with severe disease among which 12 (19 %) died. Results: European ethnicity had 5,1 times higher risk than Amerindian ethnic group to develop a severe HCPS, greater seriousness that was also associated with an urban residence. Conclusion: It was observed that ethnicity and type of residence were significant risk factors for HCPS severity. Hypotheses explaining these findings are discussed.

Therapeutic enquiries about biological agents as a tool to identify safety aspects and patterns of use.

BACKGROUND: Biotechnological agents (BA) are increasingly being used in clinical practice. We aimed to determine, whether enquiries about them to a therapeutic consultation service have also become more frequent, and to describe the information requested in these consultations. METHODS: We retrospectively reviewed 14 104 therapeutic consultations collected in a computerised database between 2000 and 2014. Enquiries about BA (monoclonal antibodies, fusion proteins or cytokine antagonists) were chosen. Information on the type of BA, underlying condition, type of enquiry and affiliation of the enquirer was retrieved and compared with data from consultations about other agents. RESULTS: During the study period, 365 enquiries about 30 different BA were received. Only 4% of them were received before 2004, while 48.8% were received after 2010. Rituximab, infliximab, adalimumab and etanercept were most frequently enquired about. Agent selection (n=184) and/or adverse effects (n=174) were the most frequent reasons for making an enquiry. Most enquiries about an agent selection were made about an off-label use (n=164), mainly for systemic autoimmune diseases (n=61). Over half of the enquiries about adverse effects were about their teratogenic potential (n=96). Enquiries about BA more often requested an opinion (87.7% vs 77.7%) were made by physicians (89.9% vs 76.9%), from a hospital (81.6% vs 44.5%) and regarded a specific patient (87.4% vs 74.5%). CONCLUSIONS: Therapeutic consultations about BA are increasing. Most of them are related to uncertainties of health professionals regarding any new medicine: their off-label use, actual adverse effects or the teratogenic potential of the involved agents.

[Combination of DRD4 and DAT1 genotypes is an important risk factor for attention deficit disorder with hyperactivity families living in Santiago, Chile]. / Combinación de genotipos DRD4 y DAT1 constituye importante factor de riesgo en miembros de familias de Santiago de Chile con déficit atencional.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. AIM: To search for possible associations between dopamine receptor D4 (DRD4) and dopamine transponder 1 (DATl) polymorphisms and ADHD in Chilean families. MATERIAL AND METHODS: We extended a previous family-based discordant sib pair analysis that included 26 cases diagnosed according to DSM-IV criteria and 25 controls (healthy siblings of cases), adding 14 cases and 11 controls. RESULTS: Both loci, individually classified as homozygotes or heterozygotes for the DRD4 7-repeat and DATl 10-repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings. However, the simultaneous presence of both DRD4 7-repeat heterozygosity and DATl 10 allele homozygosity was significantly higher (22.5%) in cases (40), compared with (2.8%) unaffected siblings (36), with an odds-ratio of 10.16. CONCLUSIONS: The genotype combination DRD4/7 heterozygotes and DAT1/10 homozygotes is a high risk factors in Chilean families for ADHD. Increased density of dopamine transporters in ADHD brains, along with abundance of 7-repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene-gene interaction worthy of studies to understand the functional basis of ADHD.

Combinación de genotipos DRD4 y DAT1 constituye importante factor de riesgo en miembros de familias de Santiago de Chile con déficit atencional / Combination of DRD4 and DAT1 genotypes is an important risk factor for attention déficit disorder with hyperactivity families living in Santiago, Chile

Background: Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. Aún: To search forpossible associations between dopamine receptor D4 (DRD4) and dopamine transponer 1 (DATl) polymorphisms and ADHD in Chilean families. Material and methods: We extended a previous family-based discordant sib pair analysis that included 26 cases diagnosed according to DSM-IV entena and 25 controls (healthy siblings of cases), adding 14 cases and 11 controls. Results: Both loci, individually classified as homozygotes or heterozygotes for the DRD4 7-repeat and DATl 10-repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings. However, the simultaneous presence of both DRD4 7-repeat heterozygosity and DATl 10 allele homozygosity was significantly higher (22.5 percent) in cases (40), compared with (2.8 percent) unaffected siblings (36), with an odds-ratio of 10.16. Conclusions: The genotype combination DRD4/7 heterozygotes and DAT1/10 homozygotes is a high risk factors in Chilean families for ADHD. Increased density of dopamine transporters in ADHD brains, along with abundance of 7-repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene-gene interaction worthy of studies to understand the functional basis ofADHD.

[Genetic susceptibility to Andes Hantavirus: Association between severity of disease and HLA alíeles in Chilean patients]. / Susceptibilidad genética a hantavirus Andes: Asociación entre la expresión clínica de la infección y alelos del sistema HLA en pacientes chilenos.

Andes hantavirus (ANDV) infection in Chile has a variable clinical expression, and infected individuals may present with different grades of disease severity. This study aimed to determine if clinical expression of ANDV infection in Chilean patients is associated with the HLA system. HLA alíeles A, B, DRB1 and DQB1, were studied in two groups of patients with confirmed ANDV infection: 41 patients with a mild disease course (without respiratory failure and cardiovascular shock) and 46 patients with a severe disease course (with respiratory failure and shock). Molecular typing of HLA system was performed by SSP-PCR. The HLA-DRB 1*15 alíele, was significantly more common in the group of patients with mild disease (p = 0,007) and thus for possibly associated with a protective effect against ANDV infection. Conversely, HLA-B*08 was more common in patients with severe disease (p = 0,06). Although the association was marginally significant, alíele HLA-B*08 may be linked to an increased susceptibility to the severe clinical course of HCPS by ANDV.

Susceptibilidad genética a hantavirus Andes: Asociación entre la expresión clínica de la infección y alelos del sistema HLA en pacientes chilenos / Genetic susceptibility to Andes Hantavirus: Association between severity of disease and HLA alíeles in Chilean patients

En Chile, la infección por hantavirus Andes (ANDV) tiene una expresión clínica variable, reconociéndose diversos grados de severidad. El presente estudio se realizó con el objeto de analizar la posible asociación entre la constitución genética de pacientes chilenos para el sistema HLA y la expresión clínica de la infección por ANDV. Se analizaron los alelos HLA A, B, DRB1 y DQB1, en dos grupos de pacientes con infección por ANDV: 41 pacientes con evolución clínica leve (sin insuficiencia respiratoria severa y sin requerimientos de ventilación mecánica) y 46 pacientes con evolución clínica grave (con insuficiencia respiratoria grave y/o shock). La determinación molecular del sistema HLA se realizó mediante SSP-PCR. El alelo HLA DRB1 * 15, se encontró en una frecuencia significativamente más alta en los pacientes leves (p = 0,007). Por lo tanto, el alelo DRB 1*15 se asociaría al curso clínico leve de la enfermedad. El alelo HLA-B*08, se encontró en una frecuencia mayor en los pacientes graves, la diferencia alcanzó una significación estadística marginal (p = 0,06). Así, el alelo HLA-B*08, podría estar asociado al curso clínico grave de síndrome cardiopulmonar ocasionado por hantavirus Andes.

Andes hantavirus (ANDV) infection in Chile has a variable clinical expression, and infected individuals may present with different grades of disease severity. This study aimed to determine if clinical expression of ANDV infection in Chilean patients is associated with the HLA system. HLA alíeles A, B, DRB1 and DQB1, were studied in two groups of patients with confirmed ANDV infection: 41 patients with a mild disease course (without respiratory failure and cardiovascular shock) and 46 patients with a severe disease course (with respiratory failure and shock). Molecular typing of HLA system was performed by SSP-PCR. The HLA-DRB 1*15 alíele, was significantly more common in the group of patients with mild disease (p = 0,007) and thus for possibly associated with a protective effect against ANDV infection. Conversely, HLA-B*08 was more common in patients with severe disease (p = 0,06). Although the association was marginally significant, alíele HLA-B*08 may be linked to an increased susceptibility to the severe clinical course of HCPS by ANDV.

[Molecular characterization of ABO*O alleles at the ABO group locus in three chilean populations]. / Caracterización molecular de alelos ABO*O del locus de grupo sanguíneo ABO en tres poblaciones chilenas.

BACKGROUND: Among the allelic variants of blood groups, the molecular characterization of ABO blood group has clinical and anthropological importance. AIM: To perform a characterization of the molecular variants of the allele ABO*O of the ABO blood group. MATERIAL AND METHODS: Eighty four subjects of Aymara origin, living in Northern Chile, 75 individuals of Huilliche origin, living in Southern Chile and 82 subjects living in Santiago (Central Chile), were studied. All individuals were of group O, homozygotes for G261- deletion, that defines O1 alleles. Mutations G188A, G261-, G542A, T646A and C771T, described for alleles O1, O1variant and G542A were determined by PCR-RFLP (polymerase chain reaction-restriction fragment lenght polymorphism). RESULTS: Allele O1variant has frequencies of 0.65, 0.81 and 0.6 in Aymara, Huilliche and Santiago subjects, respectively. The figures for allele O1 are 0.35, 0.19 and 0.4, respectively and those for the allele with G542A mutation are 0.119, 0.113 and 0.079, respectively. CONCLUSIONS: These results are concordant with the reported higher frequency of allele O1variant in South American aboriginal populations. The frequencies of G542A allele in these Chilean individuals are lower than those described for Amazon aborigines.

Caracterización molecular de alelos ABO*O del locus de grupo sanguíneo ABO en tres poblaciones chilenas / Molecular Characterization of ABO*O Alleles at the ABO Group Locus in Three Chilean Populations

Background: Among the allelic variants of blood groups, the molecular characterization of ABO blood group has clinical and anthropological importance. Aim: To perform a characterization of the molecular variants of the allele ABO*O of the ABO blood group. Material and methods: Eighty four subjects of Aymara origin, living in Northern Chile, 75 individuals of Huilliche origin, living in Southern Chile and 82 subjects living in Santiago (Central Chile), were studied. All individuals were of group O, homozygotes for G261- deletion, that defines O1 alleles. Mutations G188A, G261-, G542A, T646A and C771T, described for alleles O1, O1variant and G542A were determined by PCR-RFLP (polymerase chain reaction-restriction fragment lenght polymorphism). Results: Allele O1variant has frequencies of 0.65, 0.81 and 0.6 in Aymara, Huilliche and Santiago subjects, respectively. The figures for allele O1 are 0.35, 0.19 and 0.4, respectively and those for the allele with G542A mutation are 0.119, 0.113 and 0.079, respectively. Conclusions: These results are concordant with the reported higher frequency of allele O1variant in South American aboriginal populations. The frequencies of G542A allele in these Chilean individuals are lower than those described for Amazon aborigines.

Actualización en el tratamiento farmacológico de la demencia / Updating of the pharmacological treatment of dementia

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Caracterización genético molecular de habitantes de Caleta Paposo, último reducto Chango en Chile / Molecular and genetic characterization of Changos descendants living in Paposo Cove

Background: There are geographic and ethno historic evidences that relate Paposo cove, located 150 km south of the city of Antofagasta, with old fishermen-collector populations known as Changos, that lived in that zone in the XVII and XVIII centuries. Aim: To perform a genetic and molecular characterization of current Paposo inhabitants, through mitochondrial DNA polymorphism analysis and molecular analysis of classical ABO and Duffy blood groups. Material and methods: Forty unrelated individuals were studied. The presence of restriction polymorphisms that define A, B, C, and D Amerindian founder mitochondrial haplogroups was studied and molecular determination of classical blood groups were done by PCR. Results: One individual had A haplogroup (2.5 percent), 19 had B haplogroup (47.5 percent), six had C haplogroup (15 percent) and 11 had D haplogroup (27.5 percent). Three subjects (7.5 percent) did not have any of these haplogroups. Among ABO blood groups, the frequency of O101 allele was 0.39, that of allele O201 was 0.53 and that of A allele was 0.08. Duffy blood group frequencies were 0.58 for FY*A and 0.42 for FY*B. FY null allele was not found. Conclusions: The frequency distribution of Amerindian mitochondrial haplogroups in Paposo inhabitants suggest that these individuals are related with Aymara and Atacameño Amerindians that can be considered culturally and geographically close populations. This proposal is supported by the results of the molecular determination of classical blood groups. Our findings in Paposo cove may represent the distribution of these markers in Chango Indians, of whom there is limited physical evidence and that became extinct near 1890 (Rev Méd Chile 2004; 132: 663-72).

Supportive and palliative care: experience at the Institut Jules Bordet.

The Supportive and Palliative Care Unit of the Institut Jules Bordet officially started its activities in February 1999. Our Unit comprises eight beds (four rooms with one bed each and two rooms with two beds each). We admit advanced cancer patients presenting with severe symptoms whose control is going to require all the expertise of a multidisciplinary team. Whilst these eight beds are identified geographically in the hospital, the team's mobility assures continuity of care for patients who wish to stay in another department. The infrastructure of the Unit and its rooms allow close family members who wish to sleep close to the patients to do so. Otherwise, visits are allowed round the clock, though always with due consideration for patients' comfort. Patients are referred either by a physician working in our Institution (medical oncologist, surgeon, or radiotherapist) or by their family physicians. Less frequently, patients themselves specifically ask to be admitted to our Unit. The activity of the Unit itself during its first year of functioning can be summarized as follows. We admitted 155 advanced cancer patients, for a total number of 210 hospitalizations. Patients were admitted a median of 35 months after their diagnosis and a median of 20 days before death. Stays were generally short (median 11 days). We systematically used quantitative assessment tools (MMSQ, MDAS,EFAT and various VAS) to detect and monitor their symptoms and any complications. The main symptoms on admission were pain, anorexia, asthenia, dyspnea and anxiety/depression. Pain, nausea/vomiting, constipation and cough were controlled in almost all patients, whereas control of asthenia and anorexia was most often insufficient. In 51% of our cases the patients could be discharged home; 40% died in the unit; 4% were transferred to long-term palliative care units and 1% to other units within our Institution (4% were still hospitalized at the time of this analysis).

[Survey on the needs expressed by primary care doctors for continuing education in drug therapy]. / Encuesta sobre las necesidades sentidas por médicos de atención primaria sobre la formación continuada en terapéutica farmacológica.

OBJECTIVE: To describe the aspects of continuing education in pharmacological therapeutics considered as most relevant by the primary health care physicians. DESIGN: Observational study.Setting. Physicians filled-up the questionnaires during 45 minutes at their primary health care centres. PARTICIPANTS: Primary health care physicians involved in the Fundation Institut Català de Farmacologia continuing education activities since 1997 were selected. MAIN MEASUREMENTS: A specific questionnaire was designed to collect the physicians' opinion on different topics regarding continuing education in pharmacological therapeutics. RESULTS: 180 physicians from 21 primary health care centres answered the questionnaire. 68% of the responding physicians considered that continuing education has to be useful to improve routine clinical practice. Regular seminars and methods stimulating active participation administered by primary health care professionels are preferred. Continuing education in pharmacological therapeutics should be focused to health problems rather than being drug-oriented. They referred being more interested in drug selection issues and in the role of new drug in comparison with the existing alternatives rather than in regulation and drug consumption issues. 66,3% of the responding physicians considered that continuing education in pharmacological therapeutics should be compulsory. Public health authorities and primary health care physicians should share the responsibility in setting-up continuing education in pharmacological therapeutics programs, according to the opinion of almost 70% of the physicians. CONCLUSIONS: Primary health care physicians are interested in continuing education in pharmacological therapeutics as far as it is practical and useful to solve problems of their routine clinical practice.

Encuesta sobre las necesidades sentidas por médicos de atención primaria sobre la formación continuada en terapéutica farmacológica / Survey on the needs expressed by primary care doctors for continuing education in drug therapy

Objetivo. Describir qué aspectos de la formación en terapéutica farmacológica consideran los médicos de atención primaria como más necesarios. Diseño. Estudio observacional. Emplazamiento. Los médicos fueron citados en su centro para contestar las encuestas. Participantes. Participaron médicos de centros de atención primaria a los que habitualmente la Fundación Institut Catalá de Farmacología dirige su programa de formación. Mediciones principales. Se elaboró un cuestionario, diseñado específicamente para recoger la opinión de los médicos sobre la formación continuada en terapéutica farmacológica. Resultados. La encuesta fue realizada en 21 centros de atención primaria de Barcelona. Respondieron a la encuesta 180 médicos. El 68 por ciento de médicos considera que la formación continuada ha de ser útil para mejorar su práctica clínica habitual. Prefieren realizar seminarios periódicos, métodos docentes participativos y consideran que las personas que han de impartir habitualmente la formación han de ser cercanas a la atención primaria. Prefieren una formación dirigida al abordaje terapéutico de los problemas de salud. Con respecto a la información sobre medicamentos, están más interesados en la selección de los mismos y su lugar terapéutico que en temas de regulación o consumo farmacológico. El 66,3 por ciento de los encuestados considera que la formación continuada debería ser obligatoria. Casi un 70 por ciento considera que la responsabilidad en la elaboración de los programas de formación debería ser compartida por las instituciones sanitarias y los propios profesionales. Conclusiones. Los médicos de atención primaria están interesados en una formación continuada sobre terapéutica farmacológica de carácter práctico, que dé respuestas a las cuestiones que se le plantean en su actividad clínica habitual (AU)

From clinical trials to clinical practice: oral anticoagulation among patients with non-rheumatic, atrial fibrillation.

OBJECTIVES: The aim of the present study was to evaluate the impact of the results of clinical trials on the prophylactic treatment of non-rheumatic atrial fibrillation with oral anticoagulants. METHODS: Retrospectively, we studied a random sample of 375 patients discharged from our hospital with a diagnosis of non-rheumatic atrial fibrillation between 1991 and 1993. Information about diagnoses, other clinical variables and treatments prescribed at discharge was obtained from the hospital medical records. RESULTS: During the whole study period, 14% of patients were prescribed an oral anticoagulant agent and 17% were prescribed acetylsalicylic acid. A non-significant increase in the proportion of patients prescribed oral anticoagulant drugs, from 9% to 17%, was observed. Multivariate analysis showed that a history of stroke (OR = 5.96) and younger age were significantly associated with the prescription of oral anticoagulants. ASA prescription was strongly associated with a history of concomitant vascular disease (OR = 5.8), but not with other risk factors for stroke. Sixty-five percent of patients had one or more risk factors for stroke, did not present any contraindications to anticoagulant agents, but nevertheless were not prescribed one of these drugs. CONCLUSIONS: Anticoagulant agents and acetylsalicylic acid were largely underprescribed to patients with non-rheumatic atrial fibrillation, and oral anticoagulants were not prescribed according to the individual patients' risk of stroke.

Composición genética de la población chilena: los atacameños de la comuna de San Pedro de Atacama / Genetic composition of chilean population: the atacameños from San Pedro de Atacama

This work describes the genetic composition of atacameños from San Pedro de Atacama. The results show that a) the contribution of non-indigenous genes is relatively low, in relation to the spanish inmigration period. b) the Hardy-Weinberg genetics disequilibrium for MNSs system should have biological implications. c) the variant for esterasa D enzyme may be the same found in other chilean populations

Composición genética de la población chilena: los yamanas de Ukika / Genetic composition of chilean population: the yamanas from Ukika

The genetic composition of a group of 24 Yamana indians that survive in Puerto Williams, navarino Island, Chile (parallel 55 south of Tierra del Fuego), was studied. Results showed that these indians have a different genetic composition than Pehuenche indians, specially for HLA system and sterase D. This fact validates the hypothesis based on archeological and antropological evidence, about the paleoindian origin of Yamanas