A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone.

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/ß-catenin pathway were more frequently mutated and negative regulators of Wnt/ß-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/ß-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Response to pneumococcal polysaccharide vaccine in children with asthma, and children with recurrent respiratory infections, and healthy children

BACKGROUND: To analyse specific immune response to the 23-valent pneumococcal polysaccharide vaccine by measuring pneumococcal antibodies in children with asthma and with respiratory recurrent infection (RRI) as compared to healthy children. METHODS: The study included 60 children, divided into three groups: 20 with asthma, 20 with RRI, and 20 healthy controls. Post-vaccination specific IgG antibodies against 10 pneumococcal serotypes (S1, S3, S4, S5, S6B, S9V, S14, S18C, S19F, and S23F) contained in the 23-valent pneumococcal polysaccharide vaccine (PPV) were measured. A specific IgG concentration ≥1.3μg/mL was considered a protective response to the vaccine. For statistical analysis, levels of specific IgG antibodies against each of the 10 pneumococcal serotypes were compared across the three groups of children using the x2 test. RESULTS: All of the children showed antipneumococcal antibody levels >1.3μg/mL for over 70% of the serotypes, considered within the normal range of response. Average IgG antibody levels and percentages of children protected were statistically comparable among the three groups studied. CONCLUSION: The asthmatic children without RRI had pneumococcal antibody levels and percentages of serotype-specific protection to PPV comparable to those of healthy children. Asthmatic children with recurrent infections should be evaluated for specific antibody deficiency (SAD). Because asthma patients are at high risk for invasive pneumococcal infections, it would be worthwhile to explore systematic administration of PPV in children over the age of two years who have not received a pneumococcal conjugate vaccine, considering the positive response to PPV reported here

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Response to pneumococcal polysaccharide vaccine in children with asthma, and children with recurrent respiratory infections, and healthy children.

BACKGROUND: To analyse specific immune response to the 23-valent pneumococcal polysaccharide vaccine by measuring pneumococcal antibodies in children with asthma and with respiratory recurrent infection (RRI) as compared to healthy children. METHODS: The study included 60 children, divided into three groups: 20 with asthma, 20 with RRI, and 20 healthy controls. Post-vaccination specific IgG antibodies against 10 pneumococcal serotypes (S1, S3, S4, S5, S6B, S9V, S14, S18C, S19F, and S23F) contained in the 23-valent pneumococcal polysaccharide vaccine (PPV) were measured. A specific IgG concentration ≥1.3µg/mL was considered a protective response to the vaccine. For statistical analysis, levels of specific IgG antibodies against each of the 10 pneumococcal serotypes were compared across the three groups of children using the x(2) test. RESULTS: All of the children showed antipneumococcal antibody levels >1.3µg/mL for over 70% of the serotypes, considered within the normal range of response. Average IgG antibody levels and percentages of children protected were statistically comparable among the three groups studied. CONCLUSION: The asthmatic children without RRI had pneumococcal antibody levels and percentages of serotype-specific protection to PPV comparable to those of healthy children. Asthmatic children with recurrent infections should be evaluated for specific antibody deficiency (SAD). Because asthma patients are at high risk for invasive pneumococcal infections, it would be worthwhile to explore systematic administration of PPV in children over the age of two years who have not received a pneumococcal conjugate vaccine, considering the positive response to PPV reported here.

Therapeutic effects of the anti-tumor necrosis factor monoclonal antibody, infliximab, in four children with refractory juvenile idiopathic arthritis / Efectos terapéuticos del anticuerpo monocloral factor de necrosis tumoral, infliximab, en cuatro niños con artritis idiopática juvenil refractaria

Objective: To report the results of treatment with infliximab in patients with refractory juvenile idiopathic arthritis (JIA). Patients and methods: A prospective study of four children with refractory JIA was carried out. Infliximab (100 mg) was administered in weeks 0, 2 and 6. Subsequently, the drug was administered every 8 weeks. The following parameters were assessed at the beginning and at the end of the follow-up period: number of joints with active arthritis, number of joints with a limited range of motion, physician overall assessment of disease activity, parent assessment of the child's overall well-being, pain assessment scores, and erythrocyte sedimentation rate. Improvement was rated according to the definition of the American College of Rheumatology (ACR 30). Paired sample tests were used for statistical analysis. Results: Three girls and one boy aged between 10 and 16 years old with a history of JIA ranging from 1 to 9 years were included. The patients received infliximab for a period of 11 to 33 months (average 22 months). There was a significant decrease in the number of swollen joints (p < 0.05), joints with a limited range of movement (p < 0.04), pain score assessment (p < 0.005), physician overall assessment (p = 0.002), maternal evaluation (p < 0.001), the patient's own evaluation (p < 0.001), and duration of morning stiffness (p < 0.001). Both steroids and methotrexate dosages were reduced and no adverse effects or infections were registered. Conclusions: Infliximab improved joint inflammatory indexes and clinical assessments. This improvement increased the quality of life of the patients and their families, suggesting that the use of biological therapy is a good option in refractory JIA

Objetivo: mostrar los resultados del tratamiento con infliximab en pacientes con Artritir Idiopática Juvenil (AIJ) refractaria. Pacientes y métodos: Estudio prospectivo de cuatro niños con AIJ refractaria. El infliximab se administró a dosis de 100 mg en las semanas 0, 2 y 6. Después se administró cada 8 semanas. Se valoraron los siguientes parámetros al inicio y al final del periodo de seguimiento: número de articulaciones con artritis activa, número de articulaciones con limitada capacidad de movimiento, valoración clínica global de la enfermedad, valoración de los padres del bienestar del niño, puntuación para valorar el dolor, y velocidad de sedimentación eritrocitaria. La mejoría se estimó de acuerdo con la definición de la American College of Rheumatology (ACR 30). El análisis estadístico se baso en tests de muestras emparejadas. Resultados: Se incluyeron tres niñas y un varón entre 10 y 16 años de edad, con historia de AIJ desde 1 a 9 años. Recibieron infliximab por un periodo de 11 a 33 meses (media 22 meses). Hubo un significativo descenso en el número de articulaciones hinchadas (p<0.001), de articulaciones con limitación del movimiento (p<0.04), valoración por la madre (p<0.001) y de los propios pacientes (p<0.001) y de la duración de rigidez matutina (p<0.001). Se redujeron tanto la dosis de esteroides como de metotrexato, y no se registraron efectos adversos ni infecciones. Conclusiones: El infliximab mejoró los índices de inflamación articular y la valoración clínica. Esta mejoría permitió una mejor calidad de vida personal y familiar, lo que sugiere que el uso de la terapéutica biológica es una buena opción en la AIJ refractaria

Spanish validation of the Syndrom Kurztest (SKT).

There is an urgent need in multinational studies for efficient and sensitive tests for the evaluation of dementias. These tests are used to investigate the regional characteristics of dementias, providing possible insight into the different etiologies of the disorders. These tests are also utilized to assess the outcome of treatment interventions at multinational levels. We validated and standardized the Syndrom Kurztest, a brief European neuropsychological test, in a population of elderly Chileans, possessing high levels of illiteracy. In our sample, the SKT was found to be an effective instrument for the diagnosis of dementias, and for differentiating mild-moderate from severe degrees of the disease. There was a good correlation between the scores on the SKT and the age of the participants, but the gender and the years of schooling had no effect. The test is a useful contribution to the study of dementias, found in the aging developing world, particularly because it can be used in illiterate populations.

Morphine-induced ventilatory failure after spinal cord compression.

We describe a patient who required large doses of parenteral morphine for severe pain secondary to epidural spinal cord compression caused by metastatic cancer. The pain improved suddenly after neurological progression to a complete cord compression. Shortly afterwards, the patient developed acute respiratory depression caused by an apparent relative overdose of morphine. Our hypothesis is that the cord compression relieved the pain by interrupting the nociceptive pathway. The dose of morphine was then physiologically excessive once the neurologic damage was completed and the pain had been relieved. We advise caution in patients receiving high doses of opioids in which a change in disease status or a pain-relieving intervention may produce rapid pain relief.

[Risk of transmission of cholera by fish products: regional perspective in South America]. / Riesgos de transmisión del cólera por productos pesqueros: perspectiva regional en Sudamérica.

Cholera returned to South America in January 1991, after almost a century of absence. The hygienic status of the countries affected, aggravated by economic and political difficulties, allowed the disease to spread rapidly. In Peru, fishery products were incriminated from the outset, although without conclusive evidence. However, epidemiological and laboratory findings in other countries have confirmed the transmission of the disease by these products. The authors discuss the effects of the recent cholera epidemic on the trade and consumption of fishery products in countries of South America. The actual risk of cholera transmission by food and in particular by the consumption of fishery products is discussed, and a basis for conducting an accurate evaluation of these risks is proposed. Finally, the authors summarise the measures recommended to prevent the transmission of cholera by fishery products.

[Evaluation of long term care institutions for the aged in the Federal District. A critical viewpoint]. / Evaluación de instituciones de cuidados prolongados para ancianos en el Distrito Federal. Una visión crítica.

OBJECTIVE: To critically analyze the level and quality of infrastructure, human resources and organization of long term care institutions for the elderly in Mexico City and to describe the functional status and care requirements of their residents. MATERIAL AND METHODS: A census was made of the institutions located in the metropolitan area of Mexico City which totalled 115. These were classified according to their belonging to the public or private sector (for profit and non-profit). In each category we made a random selection of 33 institutions which were all assessed according to the methodology described by Firevicius and applied by PAHO in several countries in Latin-America. This questionnaire was applied by a single interviewer. Within the selected institutions, 30% of the residents, who were also randomly selected were assessed by means of the Kuntzman's care requirements scale. Out of a total population of 1955, 617 (34%) residents were assessed. RESULTS: The mean score obtained by the institutions was under 50% of the maximum possible score with a great deal of dispersion of the results. The lowest scores were identified in the private for profit sector and in a subgroup of public institutions. The highest scores were found among private non-profit institutions and a sector of the public institutions. The most important shortcomings identified were related to infrastructure and quality of human resources. The mean age of the institutionalized elderly is 76; 48.1% are functionally independent, 21.3% partially dependent and 30.6% totally dependent. When trying to correlate the mean functional status of the population of a given institution with its resources for care-giving we usually found no correlation. It is commonplace to find highly dependent populations living in poorly staffed or inadequately equipped institutions and vice versa CONCLUSIONS: Quality of care in long term care institutions in Mexico City is often poor and this is particularly true for private for profit institutions. Lack of norms and supervision pertaining to the functioning of such institutions contributes greatly to this reality.

Alimentos de destete contaminados: un importante factor de riesgo de diarrea y malnutrición asociada / Contaminated weaning food: a major risk factor for diarrhoea and associated malnutrition

Las infecciones y la malnutrición asociada son la causa de una proporción importante de los 13 millones de defunciones de lactantes y niños menores de 5 años que cada año se producen en el mundo. Entre las enfermedades de los lactantes y niños pequeños las infecciones respiratorias ocupan el primer lugar, seguidas por las enfermedades diarreicas, que son las más perjudiciales para el crecimiento. Las causas de las enfermedades diarreicas se han atribuido tradicionalmente a problemas de abastecimiento de agua y saneamiento. Para prevenir esas enfermedades, los gobiernos y las organizaciones no gubernamentales se han centrado y a veces se han limitado a mejorar el abastecimiento de agua y el saneamiento, así como a fomentar y proteger la lactancia materna. A partir de diversos trabajos publicados, este artículo de revisión muestra que los alimentos de destete preparados en condiciones no higiénicas muchas veces están contaminados por grandes cantidades de gérmenes patógenos y son por ello una de las causas principales de enfermedad diarreica y malnutrición asociada. De los datos presentados se deduce que las direcciones de trabajo actuales no basta para prevenir las enfermedades diarreicas. Debe considerarse prioritaria la educación de las madres en los principios de inocuidad de los alimentos, en particular de los alimentos de destete. En todos los programas nacionales de alimentación infantil o de alimentación y nutrición deberían integrarse programas educativos basados en el análisis del riesgo potencial y en la determinación de puntos críticos de control, teniendo también en cuenta los factores socioculturales

Contaminated food, a hazard for the very young.

Contaminated food is responsible for much diarrhoeal disease in young children, yet the education of mothers and care-givers about the preparation of food under hygienic conditions tends to be neglected.

PIP: Breast milk is no longer sufficient to meet the nutritional requirements of infants aged 4-6 months; thus, during weaning, complimentary foods should be introduced gradually. At this time, infants are at increased risk of getting diarrhea from food-borne pathogens resulting in reduced food intake and loss of nutrients through vomiting and fever. Diminished immunological resistance to infections causes as estimated 13 million fatalities a year among children under 5 years of age as a result of infectious diseases and malnutrition. In developing countries, preparation of weaning foods under unhygienic conditions causes up to 70% of diarrheal cases. Pathogenic strains of Escherichia coli account for up to 25% of diarrhea episodes. The sources of food contamination are night soil, polluted water, files and other pests, domestic animals, dirty utensils and pots, unwashed hands, and dust. Pathogenic bacteria can multiply if the food is prepared several hours before consumption and stored at temperatures favoring the growth of microorganisms and/or production of toxins. Insufficient cooking or reheating can also facilitate bacterial growth. Sociocultural and economic factors contribute to risks, such as short supply of food; maternal ignorance about the link between diarrhea and improper food handling; unsafe water supplies and lack of sanitation with increased risk of food contamination; shortage of fuel for cooking and lack of refrigeration; and insufficient time for food preparation. The World Health Organization Golden Rules for Safe Food Preparation need to be observed. Food should be thoroughly cooked and fed to infants once it is cool enough; food should not be stored where there are no facilities for storage below 10 degrees Celsius or for keeping food at or above 60 degrees Celsius. Mothers should be advised about food safety within the framework of educational programs.

Alimentos de destete contaminados: un importante factor de riesgo de diarrea y malnutrición asociada / Contaminated weaning food: a major risk factor for diarrhoea and associated malnutrition

Las infecciones y la malnutrición asociada son la causa de una proporción importante de los 13 millones de defunciones de lactantes y niños menores de 5 años que cada año se producen en el mundo. Entre las enfermedades de los lactantes y niños pequeños las infecciones respiratorias ocupan el primer lugar, seguidas por las enfermedades diarreicas, que son las más perjudiciales para el crecimiento. Las causas de las enfermedades diarreicas se han atribuido tradicionalmente a problemas de abastecimiento de agua y saneamiento. Para prevenir esas enfermedades, los gobiernos y las organizaciones no gubernamentales se han centrado y a veces se han limitado a mejorar el abastecimiento de agua y el saneamiento, así como a fomentar y proteger la lactancia materna. A partir de diversos trabajos publicados, este artículo de revisión muestra que los alimentos de destete preparados en condiciones no higiénicas muchas veces están contaminados por grandes cantidades de gérmenes patógenos y son por ello una de las causas principales de enfermedad diarreica y malnutrición asociada. De los datos presentados se deduce que las direcciones de trabajo actuales no basta para prevenir las enfermedades diarreicas. Debe considerarse prioritaria la educación de las madres en los principios de inocuidad de los alimentos, en particular de los alimentos de destete. En todos los programas nacionales de alimentación infantil o de alimentación y nutrición deberían integrarse programas educativos basados en el análisis del riesgo potencial y en la determinación de puntos críticos de control, teniendo también en cuenta los factores socioculturales

Publicado en inglés en: Bull. WHO. Vol. 71(1), 1993

Contaminated weaning food: a major risk factor for diarrhoea and associated malnutrition.

Infections and the malnutrition associated with them are responsible for a significant proportion of the 13 million deaths among infants and children under 5 years of age worldwide each year. After respiratory infections, diarrhoeal diseases are the commonest illnesses and have the greatest negative impact upon the growth of infants and young children. The causes of diarrhoeal diseases have traditionally been ascribed to water supply and sanitation. In attempts to prevent such diseases, efforts by governments and nongovernmental organizations have been focused on and sometimes limited to improving water supply and sanitation as well as promoting and protecting breast-feeding. Based on studies reported in the literature, this review article demonstrates that weaning foods prepared under unhygienic conditions are frequently heavily contaminated with pathogens and thus are a major factor in the cause of diarrhoeal diseases and associated malnutrition. In the light of the evidence presented, it appears that current efforts are not sufficient to prevent diarrhoeal diseases: education of mothers in food safety principles, particularly weaning food, must also receive high priority. Educational programmes based on the hazard-analysis-critical-control-point approach, taking into consideration also sociocultural factors, should be integrated into all national infant feeding or food and nutrition programmes.

PIP: Even though contaminated foods are responsible for up to 70% of diarrheal episodes, efforts to prevent diarrheal diseases often overlook food safety. Food safety is at least as important as breast feeding or providing a safe water supply and sanitation services. In developing countries, weaning foods are often prepared in an unhygienic manner. Thus, the weaning age is an especially dangerous time for infants since they are exposed to infective doses of foodborne pathogens. Infections caused by pathogenic Escherichia coli is probably responsible for as much as 25% of all diarrheal episodes in developing countries. E coli is often linked to weaning foods. Other significant microbial infections causing diarrhea include shigellosis and cholera. Rotavirus most frequently attacks 6-24 month olds and causes 20% of all diarrheal deaths among those under 5 years old. Foodborne infections can have dangerous and longterm effects, especially on nutritional status. In fact, the resistance of infants suffering from nutritional deficiencies is suppressed, leaving them wide open to infectious diseases, particularly those causing diarrhea, which further reduces their ability to fight disease. They then become progressively more malnourished. Food contamination sources include unclean hands, feces, polluted water, flies, pests, domestic animals, unclean utensils and pots, and an unsanitary environment. Cross-contamination during food preparation is also responsible, e.g., contact between raw and cooked foods. Beliefs and practices, ignorance, taboos, poverty, insufficient food, social infrastructure, and shortage of fuel and time often make it more difficult to assure food safety. Food safety could reduce hospital costs since diarrhea is the leading reason for hospitalizations among children. Food safety education for mothers in primary health care and infant feeding programs is the most important intervention in promoting the health and nutritional status of infants and children.