Publications by authors named "Carlos Maldonado"

22 Publications

  • Page 1 of 1

Microcephaly Outcomes among Zika Virus-Infected Pregnant Women in Honduras.

Am J Trop Med Hyg 2021 Mar 15. Epub 2021 Mar 15.

5Instituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina.

The impact of Zika virus (ZIKV) infection on pregnancies shows regional variation emphasizing the importance of studies in different geographical areas. We conducted a prospective study in Tegucigalpa, Honduras, recruiting 668 pregnant women between July 20, 2016, and December 31, 2016. We performed Trioplex real-time reverse transcriptase-PCR (rRT-PCR) in 357 serum samples taken at the first prenatal visit. The presence of ZIKV was confirmed in seven pregnancies (7/357, 2.0%). Nine babies (1.6%) had microcephaly (head circumference more than two SDs below the mean), including two (0.3%) with severe microcephaly (head circumference [HC] more than three SDs below the mean). The mothers of both babies with severe microcephaly had evidence of ZIKV infection. A positive ZIKV Trioplex rRT-PCR was associated with a 33.3% (95% CI: 4.3-77.7%) risk of HC more than three SDs below the mean.
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http://dx.doi.org/10.4269/ajtmh.20-1483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103474PMC
March 2021

Haplotype- and SNP-Based GWAS for Growth and Wood Quality Traits in Trees under Arid Conditions.

Plants (Basel) 2021 Jan 13;10(1). Epub 2021 Jan 13.

Institute of Biological Sciences, University of Talca, 1 Poniente 1141, Talca 3460000, Chile.

The agricultural and forestry productivity of Mediterranean ecosystems is strongly threatened by the adverse effects of climate change, including an increase in severe droughts and changes in rainfall distribution. In the present study, we performed a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNPs) and haplotype blocks associated with the growth and wood quality of , a tree species suitable for low-rainfall sites. The study was conducted in a progeny-provenance trial established in an arid site with Mediterranean patterns located in the southern Atacama Desert, Chile. A total of 87 SNPs and 3 haplotype blocks were significantly associated with the 6 traits under study (tree height, diameter at breast height, slenderness coefficient, first bifurcation height, stem straightness, and pilodyn penetration). In addition, 11 loci were identified as pleiotropic through Bayesian multivariate regression and were mainly associated with wood hardness, height, and diameter. In general, the GWAS revealed associations with genes related to primary metabolism and biosynthesis of cell wall components. Additionally, associations coinciding with stress response genes, such as and , were detected. The findings of this study provide valuable information regarding genetic control of morphological traits related to adaptation to arid environments.
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http://dx.doi.org/10.3390/plants10010148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828368PMC
January 2021

A Deep Learning Approach to Population Structure Inference in Inbred Lines of Maize.

Front Genet 2020 24;11:543459. Epub 2020 Nov 24.

Departamento de Agronomia, Universidade Estadual de Maringá, Maringá, Brazil.

Analysis of population genetic variation and structure is a common practice for genome-wide studies, including association mapping, ecology, and evolution studies in several crop species. In this study, machine learning (ML) clustering methods, K-means (KM), and hierarchical clustering (HC), in combination with non-linear and linear dimensionality reduction techniques, deep autoencoder (DeepAE) and principal component analysis (PCA), were used to infer population structure and individual assignment of maize inbred lines, i.e., dent field corn ( = 97) and popcorn ( = 86). The results revealed that the HC method in combination with DeepAE-based data preprocessing (DeepAE-HC) was the most effective method to assign individuals to clusters (with 96% of correct individual assignments), whereas DeepAE-KM, PCA-HC, and PCA-KM were assigned correctly 92, 89, and 81% of the lines, respectively. These findings were consistent with both Silhouette Coefficient (SC) and Davies-Bouldin validation indexes. Notably, DeepAE-HC also had better accuracy than the Bayesian clustering method implemented in InStruct. The results of this study showed that deep learning (DL)-based dimensional reduction combined with ML clustering methods is a useful tool to determine genetically differentiated groups and to assign individuals into subpopulations in genome-wide studies without having to consider previous genetic assumptions.
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http://dx.doi.org/10.3389/fgene.2020.543459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732446PMC
November 2020

Genome-Wide Prediction of Complex Traits in Two Outcrossing Plant Species Through Deep Learning and Bayesian Regularized Neural Network.

Front Plant Sci 2020 27;11:593897. Epub 2020 Nov 27.

Departamento de Agronomia, Universidade Estadual de Maringá, Maringá, Brazil.

Genomic selection models were investigated to predict several complex traits in breeding populations of L. and Labill. For this, the following methods of Machine Learning (ML) were implemented: (i) Deep Learning (DL) and (ii) Bayesian Regularized Neural Network (BRNN) both in combination with different hyperparameters. These ML methods were also compared with Genomic Best Linear Unbiased Prediction (GBLUP) and different Bayesian regression models [Bayes A, Bayes B, Bayes Cπ, Bayesian Ridge Regression, Bayesian LASSO, and Reproducing Kernel Hilbert Space (RKHS)]. DL models, using Rectified Linear Units (as the activation function), had higher predictive ability values, which varied from 0.27 (pilodyn penetration of 6 years old eucalypt trees) to 0.78 (flowering-related traits of maize). Moreover, the larger mini-batch size (100%) had a significantly higher predictive ability for wood-related traits than the smaller mini-batch size (10%). On the other hand, in the BRNN method, the architectures of one and two layers that used only the pureline function showed better results of prediction, with values ranging from 0.21 (pilodyn penetration) to 0.71 (flowering traits). A significant increase in the prediction ability was observed for DL in comparison with other methods of genomic prediction (Bayesian alphabet models, GBLUP, RKHS, and BRNN). Another important finding was the usefulness of DL models (through an iterative algorithm) as an SNP detection strategy for genome-wide association studies. The results of this study confirm the importance of DL for genome-wide analyses and crop/tree improvement strategies, which holds promise for accelerating breeding progress.
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http://dx.doi.org/10.3389/fpls.2020.593897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728740PMC
November 2020

Delayed Enucleation With Neoadjuvant Chemotherapy in Advanced Intraocular Unilateral Retinoblastoma: AHOPCA II, a Prospective, Multi-Institutional Protocol in Central America.

J Clin Oncol 2019 11 19;37(31):2875-2882. Epub 2019 Sep 19.

St Jude Children's Research Hospital, Memphis, TN.

Purpose: Treatment abandonment because of enucleation refusal is a limitation of improving outcomes for children with retinoblastoma in countries with limited resources. Furthermore, many children present with buphthalmos and a high risk of globe rupture during enucleation. To address these unique circumstances, the AHOPCA II protocol introduced neoadjuvant chemotherapy with delayed enucleation.

Patients And Methods: Patients with advanced unilateral intraocular disease (International Retinoblastoma Staging System [IRSS] stage I) were considered for upfront enucleation. Those with diffuse invasion of the choroid, postlaminar optic nerve, and/or anterior chamber invasion received six cycles of adjuvant chemotherapy (vincristine, carboplatin, and etoposide). Patients with buphthalmos and those with a perceived risk for enucleation refusal and/or abandonment were given two to three cycles of chemotherapy before scheduled enucleation followed by adjuvant chemotherapy to complete six cycles, regardless of pathology.

Results: A total of 161 patients had unilateral IRSS stage I disease; 102 underwent upfront enucleation, and 59 had delayed enucleation. The estimated 5-year abandonment-sensitive event-free and overall survival rates for the group were 0.81 ± 0.03 and 0.86 ± 0.03, respectively. The 5-year estimated abandonment-sensitive event-free survival rates for patients undergoing upfront and delayed enucleation were 0.89 ± 0.03 and 0.68 ± 0.06, respectively ( = .001). Compared with AHOPCA I, abandonment for patients with IRSS stage I retinoblastoma decreased from 16% to 4%.

Conclusion: AHOPCA describes the results of advanced intraocular retinoblastoma treated with neoadjuvant chemotherapy. In eyes with buphthalmos and patients with risk of abandonment, neoadjuvant chemotherapy can be effective when followed by enucleation and adjuvant chemotherapy. Our study suggests that this approach can save patients with buphthalmos from ocular rupture and might reduce refusal of enucleation and abandonment.
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http://dx.doi.org/10.1200/JCO.18.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823891PMC
November 2019

SNP and Haplotype-Based Genomic Selection of Quantitative Traits in .

Plants (Basel) 2019 Sep 5;8(9). Epub 2019 Sep 5.

Institute of Biological Sciences, University of Talca, 2 Norte 685, Talca 3460000, Chile.

(Labill.) is one of the most important cultivated eucalypts in temperate and subtropical regions and has been successfully subjected to intensive breeding. In this study, Bayesian genomic models that include the effects of haplotype and single nucleotide polymorphisms (SNP) were assessed to predict quantitative traits related to wood quality and tree growth in a 6-year-old breeding population. To this end, the following markers were considered: (a) ~14 K SNP markers (SNP), (b) ~3 K haplotypes (HAP), and (c) haplotypes and SNPs that were not assigned to a haplotype (HAP-SNP). Predictive ability values (PA) were dependent on the genomic prediction models and markers. On average, Bayesian ridge regression (BRR) and Bayes C had the highest PA for the majority of traits. Notably, genomic models that included the haplotype effect (either HAP or HAP-SNP) significantly increased the PA of low-heritability traits. For instance, BRR based on HAP had the highest PA (0.58) for stem straightness. Consistently, the heritability estimates from genomic models were higher than the pedigree-based estimates for these traits. The results provide additional perspectives for the implementation of genomic selection in breeding programs, which could be especially beneficial for improving traits with low heritability.
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http://dx.doi.org/10.3390/plants8090331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783840PMC
September 2019

SNP-based mixed model association of growth- and yield-related traits in popcorn.

PLoS One 2019 25;14(6):e0218552. Epub 2019 Jun 25.

Universidad de Talca, Talca, Chile.

The identification of the genes responsible for complex traits is highly promising to accelerate crop breeding, but such information is still limited for popcorn. Thus, in the present study, a mixed linear model-based association analysis (MLMA) was applied for six important popcorn traits: plant and ear height, 100-grain weight, popping expansion, grain yield and expanded popcorn volume per hectare. To this end, 196 plants of the open-pollinated popcorn population UENF-14 were sampled, selfed (S1), and then genotyped with a panel of 10,507 single nucleotide polymorphisms (SNPs) markers distributed throughout the genome. The six traits were studied under two environments [Campos dos Goytacazes-RJ (ENV1) and Itaocara-RJ (ENV2)] in an incomplete block design. Based on the phenotypic data of the S1 progenies and on the genetic characteristics of the parents, the MLMA was performed. Thereafter, genes annotated in the MaizeGDB platform were screened for potential linkage disequilibrium with the SNPs associated to the six evaluated traits. Overall, seven and eight genes were identified as associated with the traits in ENV1 and ENV2, respectively, and proteins encoded by these genes were evaluated for their function. The results obtained here contribute to increase knowledge on the genetic architecture of the six evaluated traits and might be used for marker-assisted selection in breeding programs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592533PMC
February 2020

Genome-wide haplotype-based association analysis of key traits of plant lodging and architecture of maize identifies major determinants for leaf angle: hapLA4.

PLoS One 2019 6;14(3):e0212925. Epub 2019 Mar 6.

Universidade Estadual de Maringá, Departamento de Agronomia, Maringá, PR, Brazil.

Traits related to plant lodging and architecture are important determinants of plant productivity in intensive maize cultivation systems. Motivated by the identification of genomic associations with the leaf angle, plant height (PH), ear height (EH) and the EH/PH ratio, we characterized approximately 7,800 haplotypes from a set of high-quality single nucleotide polymorphisms (SNPs), in an association panel consisting of tropical maize inbred lines. The proportion of the phenotypic variations explained by the individual SNPs varied between 7%, for the SNP S1_285330124 (located on chromosome 9 and associated with the EH/PH ratio), and 22%, for the SNP S1_317085830 (located on chromosome 6 and associated with the leaf angle). A total of 40 haplotype blocks were significantly associated with the traits of interest, explaining up to 29% of the phenotypic variation for the leaf angle, corresponding to the haplotype hapLA4.04, which was stable over two growing seasons. Overall, the associations for PH, EH and the EH/PH ratio were environment-specific, which was confirmed by performing a model comparison analysis using the information criteria of Akaike and Schwarz. In addition, five stable haplotypes (83%) and 15 SNPs (75%) were identified for the leaf angle. Finally, approximately 62% of the associated haplotypes (25/40) did not contain SNPs detected in the association study using individual SNP markers. This result confirms the advantage of haplotype-based genome-wide association studies for examining genomic regions that control the determining traits for architecture and lodging in maize plants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212925PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402688PMC
December 2019

Fertilization using sewage sludge in unfertile tropical soils increased wood production in Eucalyptus plantations.

J Environ Manage 2017 Dec 1;203(Pt 1):51-58. Epub 2017 Aug 1.

Dipartimento di Architettura, Design e Urbanistica, Università degli Studi di Sassari, Via Colombo no 1, 08100, Nuoro, Italy; Desertification Research Centre, Università degli Studi di Sassari, Viale Italia no 39, 07100, Sassari, Italy. Electronic address:

Fertilization of Eucalyptus plantations using sewage sludge on unfertile tropical soils represents an alternative to using mineral N and P fertilizers. A 44-month field experiment was conducted to study the effects of increasing application of sludge, and its interactions with mineral N and P fertilizers, on wood volume. Four rates of sludge (0, 8, 15 and 23 Mg ha, dry base), N (0, 47, 95 and 142 kg ha) and P (0, 28, 56 and 84 kg ha of PO) were combined in a 4 × 4 × 4 factorial scheme in a totally randomized block design. Response surface and age-shift modeling was used to establish an initial recommendation for mineral fertilization of the Eucalyptus plantations treated with sludge and to analyze the implications of increased growth on the duration of the forest cycle in a tropical climate. The results showed that from 8 to 44 months after planting, the sludge application (with or without N and P) yielded a statistically larger wood volume (P < 0.05), compared to application of N and P fertilizers only. The response surface modeling showed the following outcomes: i) application of sludge based on N criterion reduced the need for N and P fertilizers by 100%; and ii) an increase in wood volume by 7% could be achieved, compared to NPK fertilizers only, if 2/3 of the recommended P was applied. The cultivation time to produce 150 m ha of wood volume was 45 months for the control and was reduced by two, three, four, or five months, respectively, through application of recommended P, sludge dose, sludge plus one third of P, and sludge plus two thirds of P. On the whole, sewage sludge could represent an excellent unconventional N and P fertilizer source for wood production on unfertile tropical soils.
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http://dx.doi.org/10.1016/j.jenvman.2017.07.074DOI Listing
December 2017

Building two indica rice reference genomes with PacBio long-read and Illumina paired-end sequencing data.

Sci Data 2016 Sep 13;3:160076. Epub 2016 Sep 13.

National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan 430070, China.

Over the past 30 years, we have performed many fundamental studies on two Oryza sativa subsp. indica varieties, Zhenshan 97 (ZS97) and Minghui 63 (MH63). To improve the resolution of many of these investigations, we generated two reference-quality reference genome assemblies using the most advanced sequencing technologies. Using PacBio SMRT technology, we produced over 108 (ZS97) and 174 (MH63) Gb of raw sequence data from 166 (ZS97) and 209 (MH63) pools of BAC clones, and generated ~97 (ZS97) and ~74 (MH63) Gb of paired-end whole-genome shotgun (WGS) sequence data with Illumina sequencing technology. With these data, we successfully assembled two platinum standard reference genomes that have been publicly released. Here we provide the full sets of raw data used to generate these two reference genome assemblies. These data sets can be used to test new programs for better genome assembly and annotation, aid in the discovery of new insights into genome structure, function, and evolution, and help to provide essential support to biological research in general.
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http://dx.doi.org/10.1038/sdata.2016.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020871PMC
September 2016

Extensive sequence divergence between the reference genomes of two elite indica rice varieties Zhenshan 97 and Minghui 63.

Proc Natl Acad Sci U S A 2016 08 17;113(35):E5163-71. Epub 2016 Aug 17.

National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan 430070, China;

Asian cultivated rice consists of two subspecies: Oryza sativa subsp. indica and O. sativa subsp. japonica Despite the fact that indica rice accounts for over 70% of total rice production worldwide and is genetically much more diverse, a high-quality reference genome for indica rice has yet to be published. We conducted map-based sequencing of two indica rice lines, Zhenshan 97 (ZS97) and Minghui 63 (MH63), which represent the two major varietal groups of the indica subspecies and are the parents of an elite Chinese hybrid. The genome sequences were assembled into 237 (ZS97) and 181 (MH63) contigs, with an accuracy >99.99%, and covered 90.6% and 93.2% of their estimated genome sizes. Comparative analyses of these two indica genomes uncovered surprising structural differences, especially with respect to inversions, translocations, presence/absence variations, and segmental duplications. Approximately 42% of nontransposable element related genes were identical between the two genomes. Transcriptome analysis of three tissues showed that 1,059-2,217 more genes were expressed in the hybrid than in the parents and that the expressed genes in the hybrid were much more diverse due to their divergence between the parental genomes. The public availability of two high-quality reference genomes for the indica subspecies of rice will have large-ranging implications for plant biology and crop genetic improvement.
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http://dx.doi.org/10.1073/pnas.1611012113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024649PMC
August 2016

Efficacy of medical grade honey against multidrug-resistant organisms of operational significance: part I.

J Trauma Acute Care Surg 2014 Sep;77(3 Suppl 2):S204-7

From the Clinical Investigation Facility, David Grant Medical Center, Travis Air Force Base, Fairfield, California.

Background: MEDIHONEY (Derma Sciences, Inc., Toronto, Ontario M1S 3S4, Canada) was cleared by the Food and Drug Administration for use on tramatic wounds, diabetic ulcers, and second-degree burns against normal skin flora but not necessarily against multidrug-resistant organisms (MDROs) infecting these wounds or its associated recovery and healing rate.

Methods: Here, we report on the efficacy of this medical grade honey treatment against two MDROs (Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus [MRSA]). In this initial phase (Part I), an in-laboratory validation and characterization of the efficacy against antibiotic-resistant bacteria were performed in vitro.

Results: The antimicrobial resistance of both MDROs was confirmed in vitro using standard microbiology techniques and species' DNA signatures. The minimum inhibitory concentration of the MEDIHONEY was determined to be 3.5% for MRSA and 8.5% for A. baumannii. The minimum bactericidal concentrations determined against MRSA and multidrug-resistant A. baumannii were shown to be 9.5% and 10.5%, respectively.

Conclusion: Our in vitro findings support the efficacy of MEDIHONEY against MRSA and A. baumannii as requested by first responders. We also conducted screening assays using other "supermarket brands" of honey. All cultures from the latter showed bacterial and fungal growths. The use of supermarket brand honey for wound treatment is discouraged.
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http://dx.doi.org/10.1097/TA.0000000000000324DOI Listing
September 2014

The genome sequence of African rice (Oryza glaberrima) and evidence for independent domestication.

Nat Genet 2014 Sep 27;46(9):982-8. Epub 2014 Jul 27.

Dow AgroSciences, Indianapolis, Indiana, USA.

The cultivation of rice in Africa dates back more than 3,000 years. Interestingly, African rice is not of the same origin as Asian rice (Oryza sativa L.) but rather is an entirely different species (i.e., Oryza glaberrima Steud.). Here we present a high-quality assembly and annotation of the O. glaberrima genome and detailed analyses of its evolutionary history of domestication and selection. Population genomics analyses of 20 O. glaberrima and 94 Oryza barthii accessions support the hypothesis that O. glaberrima was domesticated in a single region along the Niger river as opposed to noncentric domestication events across Africa. We detected evidence for artificial selection at a genome-wide scale, as well as with a set of O. glaberrima genes orthologous to O. sativa genes that are known to be associated with domestication, thus indicating convergent yet independent selection of a common set of genes during two geographically and culturally distinct domestication processes.
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http://dx.doi.org/10.1038/ng.3044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036042PMC
September 2014

[Direct costs and hospital morbimortality impact from preventable adverse drug events].

Biomedica 2011 Jul-Sep;31(3):307-15

Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia, Bogotá, D.C., Colombia.

Introduction: Implementing pharmacovigilance activities consists of monitoring and assessment of activities related to medical attention. However, additional data are necessary to identify conditions where care quality can be improved. Therefore, a focus on adverse drug events analysis from a prevention and economic perspective is needed, with emphasis on its local impact.

Objective: Preventable adverse drug events were summarized to establishing their impact on morbidity and mortality, as well as to estimate the ensuing economic burden.

Materials And Methods: The data were gathered from a level 3 hospital (high complexity), located in Bogotá, Colombia, where specific pharmacovigilance activities were recorded in 2007. Patient charts were reviewed to characterize adverse drug events according to their causality, severity and preventability. Direct costs were estimated by grouping diagnostic tests, length of hospitalization, procedures and additional drugs required.

Results: The charts of 283 patients and 448 reports were analyzed. These data indicated that 24.8% of adverse drug events were preventable and that an associated mortality of 1.1% had occurred. The associated direct costs were between USD $16,687 and $18,739. Factors more commonly associated with preventability were drug-drug interactions, as well as inappropriate doses and unsuitable frequencies at which the drugs were administrated.

Conclusions: The data recommended that actions be taken to decrease preventable adverse drug events, because of negative impact on patient´s health, and unnecessary consumption of healthcare resources.
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http://dx.doi.org/10.1590/S0120-41572011000300003DOI Listing
July 2013

Adjacent-level degeneration after cervical disc arthroplasty versus fusion.

Eur Spine J 2011 Aug 28;20 Suppl 3:403-7. Epub 2011 Jul 28.

Department of Neurosurgery, Hospital Insular of Las Palmas, Plaza Doctor Pasteur, s/n., 35016, Las Palmas de Gran Canaria, Spain.

Introduction: The principal objective of this study was to evaluate the incidence of adjacent-segment degeneration (ASD) in patients who underwent cervical disc arthroplasty (CDA) as compared with anterior cervical discectomy and fusion (ACDF).

Methods: It is a prospective cohort study of patients with a single-level cervical degenerative disc disease from C3 to C7 who underwent CDA or ACDF between January 2004 and December 2006, with a minimum follow-up of 3 years. The patients were evaluated pre- and postoperatively with the visual analog scale (VAS), the neck disability index (NDI), and a complete neurological examination. Plain radiographic assessments included sagittal-plane angulation, range of motion (ROM), and radiological signs of ASD.

Results: One hundred and five patients underwent ACDF and 85 were treated with CDA. The postoperative VAS and NDI were equivalent in both groups. The ROM was preserved in the CDA group but with a small decreased tendency within the time. Radiographic evidence of ASD was found in 11 (10.5%) patients in the ACDF group and in 7 (8.8%) subjects in the CDA group. The Kaplan-Meier survival analysis for the ASD occurrence did not reach statistically significant differences (log rank, P = 0.72).

Conclusions: Preservation of motion in the CDA patients was not associated with a reduction of the incidence of symptomatic adjacent-segment disease and there may be other factors that influence ASD.
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http://dx.doi.org/10.1007/s00586-011-1916-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175825PMC
August 2011

[Direct costs and clinical aspects of adverse drug reactions in patients admitted to a level 3 hospital internal medicine ward].

Biomedica 2006 Mar;26(1):31-41

Departamento de Farmacia, Universidad Nacional de Colombia, Bogotá, D.C., Colombia.

Introduction: Adverse drug reactions (ADRs) occur frequently in hospitals and increase costs of health care; however, few studies have quantified the clinical and economic impact of ADRs in Colombia.

Objectives: These impacts were evaluated by calculating costs associated with ADRs in patients hospitalized in the internal medicine ward of a Level 3 hospital located in Bogotá, Colombia. In addition, salient clinical features of ADRs were identified and characterized.

Material And Methods: Intensive follow-ups for a cohort of patients were conducted for a five month period in order to detect ADRs; different ways to classify them, according to literature, were considered as well. Information was collected using the INVIMA reporting format, and causal probability was evaluated with the Naranjo algorithm. Direct costs were calculated from the perspective of payer, based on the following costs: additional hospital stay, medications, paraclinical tests, additional procedures, patient displacement to intermediate or intensive care units, and other costs.

Results: Of 836 patients admitted to the service, 268 adverse drug reactions were detected in 208 patients (incidence proportion 25.1%, occurence rate 0.32). About the ADRs found, 74.3% were classified as probable, 92.5% were type A, and 81.3% were moderate. The body system most often affected was the circulatory system (33.9%). Drugs acting on the blood were most frequently those ones associated with adverse reactions (37.6%). The costs resulting from medical care of adverse drug reactions varied from COL dollar 93,633,422 (USD dollar 35,014.92) to COL dollar 122,155,406 (USD dollar 45,680.94), according to insurance type, during the study period.

Conclusions: Adverse drug reactions have a significant negative health and financial impact on patient welfare. Because of the substantial resources required for their medical care and the significant proportion of preventable adverse reactions, active programs of institutional pharmacovigilance are highly recommended.
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March 2006

Procuring hardware for your EMR system.

Authors:
Carlos Maldonado

J Med Pract Manage 2006 Jan-Feb;Suppl:55-6

The Coker Group, Technology Division, USA.

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April 2006

Evidence that Sp1 positively and Sp3 negatively regulate and androgen does not directly regulate functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) gene expression in normal human prostate epithelial cells.

Oncogene 2004 Sep;23(41):6942-53

Department of Carcinogenesis, Science Park-Research Division, The University of Texas MD Anderson Cancer Center, 1808 Park Rd. 1C, Smithville, TX 78957, USA.

In this project, we studied the gene regulation of 15-lipoxygenase 2 (15-LOX2), the most abundant arachidonate-metabolizing LOX in adult human prostate and a negative cell-cycle regulator in normal human prostate (NHP) epithelial cells. Through detailed in silico promoter examination and promoter deletion and activity analysis, we found that several Sp1 sites (i.e., three GC boxes and one CACCC box) in the proximal promoter region play a critical role in regulating 15-LOX2 expression in NHP cells. Several pieces of evidence further suggest that the Sp1 and Sp3 proteins play a physiologically important role in positively and negatively regulating the 15-LOX2 gene expression, respectively. First, mutations in the GC boxes affected the 15-LOX2 promoter activity. Second, both Sp1 and Sp3 proteins were detected in the protein complexes that bound the GC boxes revealed by electrophoretic mobility shift assay. Third, importantly, inhibition of Sp1 activity or overexpression of Sp3 both inhibited the endogenous 15-LOX2 mRNA expression. Since 15-LOX2 is normally expressed in the prostate luminal epithelial cells, we subsequently explored whether androgen/androgen receptor may directly regulate its gene expression. The results indicate that androgen does not directly regulate 15-LOX2 gene expression. Together, these observations provide insight on how 15-LOX2 gene expression may be regulated in NHP cells.
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http://dx.doi.org/10.1038/sj.onc.1207913DOI Listing
September 2004

[Evaluation of medication side-effects from an economic perspective].

Biomedica 2003 Dec;23(4):401-7

Grupo de Farmacovigilancia, Instituto Nacional de Vigilancia de Medicamentos y Alimentos, INVIMA, Bogotá, D.C., Colombia.

Pharmacovigilance is a health sciences discipline devoted to the data collection, data analysis and decision-making related to adverse drug reactions (ADR). It has played an expanded theoretical and practical role since the 1960's. However, few studies have made a careful analysis of the decision-making costs in evaluating ADRs. Herein, the relevant literature is reviewed concerning the costs generated due to the attention of the drug adverse events in medical practice. Examples are taken from international literature which offer by extrapolation of the potential future costs of ADR in Colombia. The objective is to sensitize and generate insights about the need for implementation and development of a national pharmacovigilance system.
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December 2003

Subcellular localization and tumor-suppressive functions of 15-lipoxygenase 2 (15-LOX2) and its splice variants.

J Biol Chem 2003 Jul 18;278(27):25091-100. Epub 2003 Apr 18.

Department of Carcinogenesis, the University of Texas M. D. Anderson Cancer Center, Science Park Research Division, Smithville 78957, USA.

15-Lipoxygenase 2 (15-LOX2), the most abundant arachidonate (AA)-metabolizing enzyme expressed in adult human prostate, is a negative cell-cycle regulator in normal human prostate epithelial cells. Here we study the subcellular distribution of 15-LOX2 and report its tumor-suppressive functions. Immunocytochemistry and biochemical fractionation reveal that 15-LOX2 is expressed at multiple subcellular locations, including cytoplasm, cytoskeleton, cell-cell border, and nucleus. Surprisingly, the three splice variants of 15-LOX2 we previously cloned, i.e. 15-LOX2sv-a/b/c, are mostly excluded from the nucleus. A potential bi-partite nuclear localization signal (NLS),203RKGLWRSLNEMKRIFNFRR221, is identified in the N terminus of 15-LOX2, which is retained in all splice variants. Site-directed mutagenesis reveals that this putative NLS is only partially involved in the nuclear import of 15-LOX2. To elucidate the relationship between nuclear localization, enzymatic activity, and tumor suppressive functions, we established PCa cell clones stably expressing 15-LOX2 or 15-LOX2sv-b. The 15-LOX2 clones express 15-LOX2 in the nuclei and possess robust enzymatic activity, whereas 15-LOX2sv-b clones show neither nuclear protein localization nor AA-metabolizing activity. To our surprise, both 15-LOX2- and 15-LOX2sv-b-stable clones proliferate much slower in vitro when compared with control clones. More importantly, when orthotopically implanted in nude mouse prostate, both 15-LOX2 and 15-LOX2sv-b suppress PC3 tumor growth in vivo. Together, these results suggest that both 15-LOX2 and 15-LOX2sv-b suppress prostate tumor development, and the tumor-suppressive functions apparently do not necessarily depend on AA-metabolizing activity and nuclear localization.
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http://dx.doi.org/10.1074/jbc.M301920200DOI Listing
July 2003

Annexin II expression is reduced or lost in prostate cancer cells and its re-expression inhibits prostate cancer cell migration.

Oncogene 2003 Mar;22(10):1475-85

Department of Carcinogenesis, The Uniersity of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957, USA.

While studying Bim, a BH3-only proapoptotic protein, we identified an approximately 36 kDa protein, which was abundantly expressed in all five strains of primary normal human prostate (NHP) epithelial cells but significantly reduced or lost in seven prostate cancer cell lines. The approximately 36 kDa protein was subsequently identified as annexin II by proteomic approach and confirmed by Western blotting using an annexin II-specific antibody. Conventional and 2D SDS-PAGE, together with Western blotting, also revealed reduced or lost expression of annexin I in prostate cancer cells. Subcellular localization studies revealed that in NHP cells, annexin II was distributed both in the cytosol and underneath the plasma membrane, but not on the cell surface. Prostate cancer cells showed reduced levels as well as altered expression patterns of annexin II. Since annexins play important roles in maintaining Ca(2+) homeostasis and regulating the cytoskeleton and cell motility, we hypothesized that the reduced or lost expression of annexin I/II might promote certain aggressive phenotypes of prostate cancer cells. In subsequent experiments, we indeed observed that restoration of annexin II expression inhibited the migration of the transfected prostate cancer cells without affecting cell proliferation or apoptosis. Hence, our results suggest that annexin II, and, likely, annexin I, may be endogenous suppressors of prostate cancer cell migration and their reduced or lost expression may contribute to prostate cancer development and progression.
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http://dx.doi.org/10.1038/sj.onc.1206196DOI Listing
March 2003

Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells.

J Biol Chem 2002 May 11;277(18):16189-201. Epub 2002 Feb 11.

Department of Carcinogenesis, the University of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, Texas 78957, USA.

15-Lipoxygenase 2 (15-LOX2) is a recently cloned human lipoxygenase that shows tissue-restricted expression in prostate, lung, skin, and cornea. The protein level and enzymatic activity of 15-LOX2 have been shown to be down-regulated in prostate cancers compared with normal and benign prostate tissues. The biological function of 15-LOX2 and the role of loss of 15-LOX2 expression in prostate tumorigenesis, however, remain unknown. We report the cloning and functional characterization of 15-LOX2 and its three splice variants (termed 15-LOX2sv-a, 15-LOX2sv-b, and 15-LOX2sv-c) from primary prostate epithelial cells. Western blotting with multiple primary prostate cell strains and prostate cancer cell lines reveals that the expression of 15-LOX2 is lost in all prostate cancer cell lines, accompanied by decreased enzymatic activity revealed by liquid chromatography/tandem mass spectrometry analyses. Further experiments show that the loss of 15-LOX2 expression results from transcriptional repression caused by mechanism(s) other than promoter hypermethylation or histone deacetylation. Subsequent functional studies indicate the following: 1) the 15-LOX2 product, 15(S)-hydroxyeicosatetraenoic acid, inhibits prostate cancer cell cycle progression; 2) 15-LOX2 expression in primary prostate epithelial cells is inversely correlated with cell cycle; and 3) restoration of 15-LOX2 expression in prostate cancer cells partially inhibits cell cycle progression. Taken together, these results suggest that 15-LOX2 could be a suppressor of prostate cancer development, which functions by restricting cell cycle progression.
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http://dx.doi.org/10.1074/jbc.M111936200DOI Listing
May 2002