The genetic origin of familial combined hyperlipidemia (FCH) is not well understood. We used microarray profiling of peripheral blood monocytes to search novel genes and pathways involved in FCH.
...Fasting plasma for determination of lipid profiles, inflammatory molecules and adipokines was obtained and peripheral blood monocytes were isolated from male FCH patients basally and after 4 weeks of atorvastatin treatment. Sex-, age- and adiposity-matched controls were also studied. Gene-expression profiles were analyzed using Affymetrix Human Genome U133A 2.0 GeneChip arrays.
Analysis of gene expression by cDNA microarrays showed that 82 genes were differentially expressed in FCH monocytes compared with controls. Atorvastatin treatment modified the expression of 86 genes. Pathway analysis revealed the over-representation of the complement and coagulation cascades, the hematopoietic cell lineage and the arachidonic acid metabolism pathways. Changes in the expression of some genes, confirmed by real-time RT-PCR, (CD36, leucine-rich repeats and immunoglobulin-like domains-1, tissue factor pathway inhibitor 2, myeloid cell nuclear differentiation antigen, tumor necrosis factor receptor superfamily, member 25, CD96 and lipoprotein lipase), may be related to a proinflammatory environment in FCH monocytes, which is partially reversed by atorvastatin. Higher plasma levels of triglycerides and free fatty acids and lower levels of adiponectin in FCH patients could also trigger changes in gene expression that atorvastatin cannot modify.
Our results show clear differences in gene expression in FCH monocytes compared with those of matched healthy controls, some of which are influenced by atorvastatin treatment.
BACKGROUND.Hyperlactatemia and lactic acidosis occur in HIV-infected adults receiving antiretroviral treatment. Our objective was to determine the incidence, course and risk factors for ...hyperlactatemia in our HIV-infected pediatric patients.
DESIGN.A prospective observational study of venous lactate concentrations during a 28-month period in 80 HIV-infected children, most of whom were receiving antiretrovirals.
METHODS.Venous blood lactate concentrations were measured every 6 months under optimal sample-obtaining conditions. Alanine values from the same blood sample were performed when lactate concentrations were elevated. Hyperalaninemia is observed only when mitochondrial oxidative phosphorylation is chronically disturbed.
RESULTS.Twenty-three patients (29%) were identified with hyperlactatemia, in 9 of the cases with normal alaninemia, probably caused by difficult venous punctures. The other 14 children (17%) had pathologic alanine concentrations with a mean lactate peak of 2.67 mmol/l (range, 2.05 to 4.9 mmol/l); none of them showed metabolic acidosis, and they were all symptom-free. Treatment was continued in all cases, and lactate has progressed spontaneously to normal values in 5 patients.
CONCLUSIONS.Symptom-free hyperlactatemia was observed in HIV-infected children receiving nucleoside analog reverse transcriptase inhibitors. In our study, only a younger age at the beginning of antiretroviral treatment was a statistically significant risk factor for hyperlactatemia. Random measurements of blood lactate concentrations should be included in the clinical follow-up of those HIV-infected children <3 years of age who are treated with nucleoside analog reverse transcriptase inhibitors, symptomatic or not.
Wolfram syndrome is a progressive neurodegenerative disorder transmitted in an autosomal recessive mode. We report two Wolfram syndrome families harboring multiple deletions of mitochondrial DNA. The ...deletions reached percentages as high as 85-90% in affected tissues such as the central nervous system of one patient, while in other tissues from the same patient and from other members of the family, the percentages of deleted mitochondrial DNA genomes were only 1-10%. Recently, a Wolfram syndrome gene has been linked to markers on 4p16. In both families linkage between the disease locus and 4p16 markers gave a maximum multipoint lod score of 3.79 at theta = 0 (P<0.03) with respect to D4S431. In these families, the syndrome was caused by mutations in this nucleus-encoded gene which deleteriously interacts with the mitochondrial genome. This is the first evidence of the implication of both genomes in a recessive disease.
Objective. Exposure to nudeoside analogues in fetal or early life has been associated with rare clinically significant mitochondrial toxic effects, mainly neurologic symptoms. Lactate (LA) ...measurements have been used to monitor nudeoside-related mitochondrial toxicity. Our aim was to determine the prevalence, clinical evolution, and risk factors for hyperlactatemia in our cohort of human immunodeficiency virus (HIV)-uninfected children who were exposed to antiretrovirals. Methods. We conducted a prospective observational study of 127 HIV-uninfected infants who were born to HIV-infected women. Clinical symptoms suggesting mitochondrial dysfunction were analyzed in routine follow-up, and LA and alanine plasma levels were obtained at 6 weeks, 3 months, 6 months, and 12 months in all patients. Elevated alanine levels, together with hyperlactatemia, suggest chronic mitochondrial injury. Results. Most (85%) women received highly active antiretroviral therapy (HAART) during pregnancy (mean duration: 31 weeks) and zidovudine during labor (93%). Most (96%) children received zidovudine alone. Hyperlactatemia with hyperalaninemia was detected in 63 children in at least 1 of the measurements. Mean LA levels were significantly higher in children who were exposed to nucleoside analogue reverse transcriptase inhibitors than in control subjects (2.88 vs 1.61 at 6 weeks, 2.78 vs 1.49 at 3 months, 1.89 vs 1.39 at 6 months, and 1.71 vs 1.24 at 12 months; peak levels: 8.06, 10.1, 7.28, and 4.48 mmol/L, respectively). In 44 patients, LA levels progressed spontaneously to normality within the first year of life. Three girls presented a slight and self-limited delay in psychomotor development, with LA peak levels of 7.3, 4.0, and 4.6 mmol/L. Only the gestational use of didanosine was associated with a higher risk of hyperlactatemia. Conclusions. In our series, almost half of the children (63 of 127) who were exposed to nucleuside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleuside analogue--induced toxicity affected neurologic development. Pediatrics 2004;114:e598-e603. URL: www.pediatrics.org/ cgi/doi/10.1542/peds.2004-0955; alanine, children, HAART, HIV infection, hyperlactatemia, mitochondria, vertical transmission.
Protocols for the prevention of group B streptococcal disease are being widely used with proven efficacy. The aim of this study was to assess compliance with a culture-based approach recommending ...universal culture screening at 35-37 weeks' gestation, established in our hospital. A retrospective cohort study was undertaken from January 2003 to January 2004. Compliance with the culture-based approach was considered to be good (92.1%) and only partially amenable to improvements. Effectively, there are inherent limitations to the protocol that can be resolved with the use of other strategies, such as tests for quick identification of genital carrier status.
To analyze factors related to drug-resistant pathogens (DRPs) in community-onset pneumonia (COP) and whether previously suggested criteria are useful in our emergency-department.
Prospective 1-year ...study of adults coming to the emergency department for COP. We assessed the usefulness of criteria used in health-care-associated pneumonia (HCAP), as well the Shorr index, the Barthel index, and clinical suspicion of resistant pathogens. Data were analyzed by multiple logistic regression and the area under the receiver operating characteristic curve (AUC).
We included 139 patients with a mean (SD) age of 75.9 (15.3) years; 63.3% were men. Forty-nine COP patients (35.2%) were at risk for DRP-caused pneumonia according to HCAP criteria; 43 (30.9%) according to the Shorr index, and 56 (40.3%) according to the Aliberti index. A score of less than 60 derived from the Barthel index was recorded for 25 patients (18%). Clinical suspicion of a DRP was recorded for 11 (7.9%). A DRP was isolated in 5 patients (3.6%) (3, Pseudomonas aeruginosa; 2, methicillin-resistant Staphylococcus aureus). Multiple logistic regression analysis identified 2 predictors of DRP-caused COP: hospital admission within the last 90 days (odds ratio OR, 8.92; 95% CI, 1.92-41.45) and initial arterial blood oxygen saturation (OR, 0.85; 95% CI, 0.74-0.98). The AUC was 0.91 (95% CI, 0.85-0.98). The model identified 22 patients (16.8%) at risk for DRP-caused pneumonia. The positive and negative predictive values were 20% and 99.1%, respectively, for the model 90-day period (vs 8.7% and 98.9%, respectively, for criteria used in HCAP).
Hospitalization within the 90-day period before a COP emergency and arterial blood oxygen saturation were good predictors of DRP in our setting. Criteria of DRP in HCAP, on the other hand, had lower ability to identify patients at risk in COP.
Los protocolos de prevención de la enfermedad por estreptococo del grupo B se emplean ampliamente y su eficacia ha sido demostrada. El objetivo del estudio es evaluar la aplicación del cribado de EGB ...en nuestro centro de trabajo, que recomienda efectuar un cultivo vaginal y rectal a todas las embarazadas en las semanas 35-37 de gestación, mediante un estudio de cohortes retrospectivo entre enero 2003 y enero 2004. Se objetiva una Buena aplicación del cribado (92,1%), que sólo podría mejorarse parcialmente. En efecto, existen limitaciones inherentes a dicha estrategia, que podrían resolverse con la introducción de tests de detección rápida de portadoras al inicio del trabajo de parto.
Protocols for the prevention of group B streptococcal disease are being widely used with proven efficacy. The aim of this study was to assess compliance with a culture-based approach recommending universal culture screening at 35-37 weeks’ gestation, established in our hospital. A retrospective cohort study was undertaken from January 2003 to January 2004. Compliance with the culture-based approach was considered to be good (92.1%) and only partially amenable to improvements. Effectively, there are inherent limitations to the protocol that can be resolved with the use of other strategies, such as tests for quick identification of genital carrier status.
Introducción: varios estudios han relacionado la enfermedad de Alzheimer (EA) con defectos mitocondriales. Tales defectos incluyen anomalías de tipo estructural, bioquímico y genético. Entre las de ...tipo genético destacan los reordenamientos y las mutaciones puntuales descritas en el DNA mitocondrial (ADNmt). Objetivo: estudiar la incidencia de reordenamientos y cuatro mutaciones puntuales en el ADNmt de pacientes con EA y determinar las posibles diferencias respecto a individuos control. Pacientes y métodos: necropsias de cerebelo, córtex frontal e hipocampo de pacientes con EA y controles. También se dispuso de sangre de enfermos vivos diagnosticados de EA y de controles. Las muestras se analizaron mediante Southern blot, hibridando con una sonda mitocondrial. También se analizaron las mutaciones puntuales G3196A, A3397G, A4336G y G5460A/T. Resultados: no se observaron diferencias entre pacientes y controles, ni en tejidos cerebrales ni en sangre en los análisis realizados mediante southern. No se halló asociación entre las mutaciones puntuales analizadas y la EA en nuestras muestras. Conclusiones: los resultados obtenidos no apoyan la hipótesis de una implicación mitocondrial en la EA, en cuanto a reordenamientos y las cuatro mutaciones puntuales analizados en el ADNmt en nuestras muestras, lo cual no descarta la posible existencia de otras mutaciones puntuales no analizadas y/u otros defectos mitocondriales que contribuyan al desarrollo de la EA.
Introducción: varios estudios han relacionado la enfermedad de Alzheimer (EA) con defectos mitocondriales. Tales defectos incluyen anomalías de tipo estructural, bioquímico y genético. Entre las de ...tipo genético destacan los reordenamientos y las mutaciones puntuales descritas en el DNA mitocondrial (ADNmt). Objetivo: estudiar la incidencia de reordenamientos y cuatro mutaciones puntuales en el ADNmt de pacientes con EA y determinar las posibles diferencias respecto a individuos control. Pacientes y métodos: necropsias de cerebelo, córtex frontal e hipocampo de pacientes con EA y controles. También se dispuso de sangre de enfermos vivos diagnosticados de EA y de controles. Las muestras se analizaron mediante Southern blot, hibridando con una sonda mitocondrial. También se analizaron las mutaciones puntuales G3196A, A3397G, A4336G y G5460A/T. Resultados: no se observaron diferencias entre pacientes y controles, ni en tejidos cerebrales ni en sangre en los análisis realizados mediante southern. No se halló asociación entre las mutaciones puntuales analizadas y la EA en nuestras muestras. Conclusiones: los resultados obtenidos no apoyan la hipótesis de una implicación mitocondrial en la EA, en cuanto a reordenamientos y las cuatro mutaciones puntuales analizados en el ADNmt en nuestras muestras, lo cual no descarta la posible existencia de otras mutaciones puntuales no analizadas y/u otros defectos mitocondriales que contribuyan al desarrollo de la EA.
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