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1.  Peridomestic Infection as a Determining Factor of Dengue Transmission 
PLoS Neglected Tropical Diseases  2015;9(12):e0004296.
The study of endemic dengue transmission is essential for proposing alternatives to impact its burden. The traditional paradigm establishes that transmission starts around cases, but there are few studies that determine the risk.
To assess the association between the peridomestic dengue infection and the exposure to a dengue index case (IC), a cohort was carried out in two Mexican endemic communities. People cohabitating with IC or living within a 50-meter radius (exposed cohort) and subjects of areas with no ICs in a 200-meter radius (unexposed cohort) were included.
Exposure was associated with DENV infection in cohabitants (PRa 3.55; 95%CI 2.37–5.31) or neighbors (PRa 1.82; 95%CI 1.29–2.58). Age, location, toilets with no direct water discharge, families with children younger than 5 and the House Index, were associated with infection. Families with older than 13 were associated with a decreased frequency. After a month since the IC fever onset, the infection incidence was not influenced by exposure to an IC or vector density; it was influenced by the local seasonal behavior of dengue and the age. Additionally, we found asymptomatic infections accounted for 60% and a greater age was a protective factor for the presence of symptoms (RR 0.98; 95%CI 0.97–0.99).
The evidence suggests that dengue endemic transmission in these locations is initially peridomestic, around an infected subject who may be asymptomatic due to demographic structure and endemicity, and it is influenced by other characteristics of the individual, the neighborhood and the location. Once the transmission chain has been established, dengue spreads in the community probably by the adults who, despite being the group with lower infection frequency, mostly suffer asymptomatic infections and have higher mobility. This scenario complicates the opportunity and the effectiveness of control programs and highlights the need to apply multiple measures for dengue control.
Author Summary
The study of dengue transmission is essential for proposing alternatives to diminish the cases and the cost of dengue treatment and control. The traditional paradigm establishes that transmission chain starts around a case, but there are few studies that determine the risk, therefore, we studied if to live around a dengue case increases the risk to get infected by Dengue virus. We interviewed and took blood samples from people cohabitating with dengue cases and neighbors in two Mexican communities, to compare we interviewed and took blood samples from subjects of areas without dengue cases in these communities. We found that people cohabitating and neighbors had more risk to get infected. Younger and older person, the workers, families with children younger than 5, houses with toilets with no direct water discharge, and areas with more mosquitoes, also had increased infection risk until one month after the fever onset of dengue case. After this month the frequency of dengue infections was only influenced by the seasonal behavior of dengue and the age of the subjects. Also, we found that 60% of infections are asymptomatic and older people have less risk to develop symptoms. This study suggests that dengue transmission in these locations is initially peridomestic, around the houses of infected subject who may be asymptomatic (without symptoms), and it is influenced by other characteristics of the individual, the neighborhood and the community. After this peridomestic transmission, dengue spreads in the community probably by adults who mostly suffer asymptomatic infections and have higher mobility, which complicates the application and affects the results of vector control programs.
PMCID: PMC4684393  PMID: 26671573
2.  Physical activity intervention (Movi-Kids) on improving academic achievement and adiposity in preschoolers with or without attention deficit hyperactivity disorder: study protocol for a randomized controlled trial 
Trials  2015;16:456.
The prevention of obesity and improvement of academic achievement in children are concerns of industrialized societies. Obesity has been associated with psychological disorders, including attention deficit hyperactivity disorder, whose prevalence has been estimated at 6.8 % in Spanish children and adolescents. It is known that physical activity is positively related to academic achievement and negatively related to the risk of obesity in children. However, studies to test the effectiveness of physical activity interventions in improving academic achievement in preschool children are scarce and have some weaknesses that threaten their validity. Moreover, very few studies have examined their effectiveness in improving symptoms of attention deficit hyperactivity disorder. This paper outlines a two-year multidimensional preschool intervention (Movi-Kids) aimed at preventing obesity and improving academic achievement in children with or without attention deficit hyperactivity disorder.
Twenty-one schools from Ciudad Real and Cuenca, Spain, were randomized to intervention and control groups. In the first academic year, children in the third grade of preschool and the first grade of primary school in the intervention group received the Movi-Kids intervention. In the second academic year, schools were crossed over to the other group. The intervention included children, parents and teachers, and the school environment, and consisted of: (i) three hour-long sessions of recreational non-competitive physical activity after school, weekly, (ii) educational materials for parents and teachers addressing sedentary lifestyle risks and (iii) playground modifications to promote physical activity during breaks. Primary outcome measures of this study were academic achievement (intelligence, cognition, memory, attention and perception), assessed by the Battery of General and Differential Aptitudes, and adiposity measures (body mass index, waist circumference, triceps skinfold thickness and body fat percentage). Secondary outcome measures were: attention deficit hyperactivity disorder risk, motor skills, health-related quality of life and sleep quality. These variables will all be measured in both groups at baseline and at the end of the first and second academic years.
It seems reasonable that an intervention to promote physical activity based on playground games will be useful for simultaneously improving academic achievement and controlling obesity.
Trial registration NCT01971827.
PMCID: PMC4603580  PMID: 26458986
academic achievement; attention deficit hyperactivity disorder; children; health-related quality of life; motor skill; Movi-Kids; obesity; physical activity; quality of sleep
3.  Elimination of Onchocerciasis from Mexico 
PLoS Neglected Tropical Diseases  2015;9(7):e0003922.
Mexico is one of the six countries formerly endemic for onchocerciasis in Latin America. Transmission has been interrupted in the three endemic foci of that country and mass drug distribution has ceased. Three years after mass drug distribution ended, post-treatment surveillance (PTS) surveys were undertaken which employed entomological indicators to check for transmission recrudescence.
Methodology/Principal findings
In-depth entomologic assessments were performed in 18 communities in the three endemic foci of Mexico. None of the 108,212 Simulium ochraceum s.l. collected from the three foci were found to contain parasite DNA when tested by polymerase chain reaction-enzyme-linked immunosorbent assay (PCR-ELISA), resulting in a maximum upper bound of the 95% confidence interval (95%-ULCI) of the infective rate in the vectors of 0.035/2,000 flies examined. This is an order of magnitude below the threshold of a 95%-ULCI of less than one infective fly per 2,000 flies tested, the current entomological criterion for interruption of transmission developed by the international community. The point estimate of seasonal transmission potential (STP) was zero, and the upper bound of the 95% confidence interval for the STP ranged from 1.2 to 1.7 L3/person/season in the different foci. This value is below all previous estimates for the minimum transmission potential required to maintain the parasite population.
The results from the in-depth entomological post treatment surveillance surveys strongly suggest that transmission has not resumed in the three foci of Mexico during the three years since the last distribution of ivermectin occurred; it was concluded that transmission remains undetectable without intervention, and Onchocerca volvulus has been eliminated from Mexico.
Author Summary
Onchocerciasis, or river blindness, is one of the neglected tropical diseases targeted by the international community for elimination. In Mexico, onchocerciasis was historically endemic in three foci, which included Northern Chiapias, Southern Chiapas and Oaxaca. Both the criteria for verification of elimination and for post-treatment surveillance developed by the international community rely heavily on the use of entomological metrics. The absence of evidence of ongoing transmission of the parasite three years after mass drug distribution has been halted is considered to be evidence that elimination efforts have been successful. In the present study, we report entomological assessments carried out in the three endemic foci in Mexico that were performed three years following the end of mass drug distribution in each focus. None of the over 100,000 Simulium ochraceum s.l. vector black flies collected from sentinel and extra-sentinel communities in these foci were found to contain parasite DNA, suggesting vector parasite contact was non-existent. This data suggest that elimination of onchocerciasis from Mexico has been achieved.
PMCID: PMC4498594  PMID: 26161558
4.  Common Cell Shape Evolution of Two Nasopharyngeal Pathogens 
PLoS Genetics  2015;11(7):e1005338.
Respiratory infectious diseases are the third cause of worldwide death. The nasopharynx is the portal of entry and the ecological niche of many microorganisms, of which some are pathogenic to humans, such as Neisseria meningitidis and Moraxella catarrhalis. These microbes possess several surface structures that interact with the actors of the innate immune system. In our attempt to understand the past evolution of these bacteria and their adaption to the nasopharynx, we first studied differences in cell wall structure, one of the strongest immune-modulators. We were able to show that a modification of peptidoglycan (PG) composition (increased proportion of pentapeptides) and a cell shape change from rod to cocci had been selected for along the past evolution of N. meningitidis. Using genomic comparison across species, we correlated the emergence of the new cell shape (cocci) with the deletion, from the genome of N. meningitidis ancestor, of only one gene: yacF. Moreover, the reconstruction of this genetic deletion in a bacterium harboring the ancestral version of the locus together with the analysis of the PG structure, suggest that this gene is coordinating the transition from cell elongation to cell division. Accompanying the loss of yacF, the elongation machinery was also lost by several of the descendants leading to the change in the PG structure observed in N. meningitidis. Finally, the same evolution was observed for the ancestor of M. catarrhalis. This suggests a strong selection of these genetic events during the colonization of the nasopharynx. This selection may have been forced by the requirement of evolving permissive interaction with the immune system, the need to reduce the cellular surface exposed to immune attacks without reducing the intracellular storage capacity, or the necessity to better compete for adhesion to target cells.
Author Summary
The nasopharynx hosts an important microbial community that comprises some well-known pathogens such as Neisseria meningitidis and Moraxella catarrhalis. In some circumstances, it also represents the portal of entry of systemic infections such as septicemia and meningitis, or infections of the respiratory system, middle ear, eye, central nervous system and joints of humans, caused by N. meningitidis and M. catarrhalis, respectively. In this article, we demonstrated that both bacteria underwent a similar cell shape evolution that resulted in a transition from a bacillus to a coccus. This was consequently accompanied by a change, similar for both bacteria, in the structure of the PG, the major bacterial cell shape determinant and also a strongly recognized molecule by the immune system. In our efforts in understanding the evolutionary events that led to the cell shape transition in N. meningitidis, we identified two genetic deletion events required for the shape transition, i.e. of yacF (zapD) and the cell elongation machinery. Furthermore, we delineated the importance of YacF (ZapD) in the coordination of the cell elongation and division. Finally, we suggest that this transition was selected to reduce the cell surface sensible to immune attacks and to redistribute surface appendages, such as pili, to acquire new properties of cell adhesion or movement necessary for the proper colonization of the nasopharynx.
PMCID: PMC4498754  PMID: 26162030
5.  Complete Genome Sequences of Chikungunya Virus Strains Isolated in Mexico: First Detection of Imported and Autochthonous Cases 
Genome Announcements  2015;3(3):e00300-15.
The mosquito-borne chikungunya virus, an alphavirus of the Togaviridae family, is responsible for acute polyarthralgia epidemics. Here, we report the complete genome sequences of two chikungunya virus strains, InDRE04 and InDRE51, identified in the Mexican states of Jalisco and Chiapas in 2014. Phylogenetic analysis showed that both strains belong to the Asian genotype.
PMCID: PMC4424286  PMID: 25953170
6.  Economic and Disease Burden of Dengue in Mexico 
PLoS Neglected Tropical Diseases  2015;9(3):e0003547.
Dengue imposes a substantial economic and disease burden in most tropical and subtropical countries. Dengue incidence and severity have dramatically increased in Mexico during the past decades. Having objective and comparable estimates of the economic burden of dengue is essential to inform health policy, increase disease awareness, and assess the impact of dengue prevention and control technologies.
Methods and Findings
We estimated the annual economic and disease burden of dengue in Mexico for the years 2010–2011. We merged multiple data sources, including a prospective cohort study; patient interviews and macro-costing from major hospitals; surveillance, budget, and health data from the Ministry of Health; WHO cost estimates; and available literature. We conducted a probabilistic sensitivity analysis using Monte Carlo simulations to derive 95% certainty levels (CL) for our estimates. Results suggest that Mexico had about 139,000 (95%CL: 128,000–253,000) symptomatic and 119 (95%CL: 75–171) fatal dengue episodes annually on average (2010–2011), compared to an average of 30,941 symptomatic and 59 fatal dengue episodes reported. The annual cost, including surveillance and vector control, was US$170 (95%CL: 151–292) million, or $1.56 (95%CL: 1.38–2.68) per capita, comparable to other countries in the region. Of this, $87 (95%CL: 87–209) million or $0.80 per capita (95%CL: 0.62–1.12) corresponds to illness. Annual disease burden averaged 65 (95%CL: 36–99) disability-adjusted life years (DALYs) per million population. Inclusion of long-term sequelae, co-morbidities, impact on tourism, and health system disruption during outbreaks would further increase estimated economic and disease burden.
With this study, Mexico joins Panama, Puerto Rico, Nicaragua, and Thailand as the only countries or areas worldwide with comprehensive (illness and preventive) empirical estimates of dengue burden. Burden varies annually; during an outbreak, dengue burden may be significantly higher than that of the pre-vaccine level of rotavirus diarrhea. In sum, Mexico’s potential economic benefits from dengue control would be substantial.
Author Summary
During the past decades, dengue fever has become the most common arthropod-borne viral disease, imposing a substantial economic and disease burden in most tropical and subtropical countries, including Mexico. Dengue incidence and severity have dramatically increased in Mexico, with transmission regularly reported in 28 of 32 states. Objective estimates of the burden of dengue are important to inform policy decisions and priorities. We merged multiple data sources to estimate (i) total episodes, (ii) costs per episode, (iii) surveillance and vector control costs, and (iv) disease burden (2010–2011). Results suggest that Mexico had about 139,000 symptomatic and 119 fatal dengue episodes per year on average. The annual cost, including surveillance and vector control, was about US$170 million, or $1.56 per capita, comparable to other countries in the Americas. Annual disease burden averaged 65 disability-adjusted life years per million population, with most of the years lost to disability corresponding to ambulatory episodes. The results show a substantial burden of dengue on the health care system and economy of Mexico. This quantification of the economic burden should help public health officials make informed decisions about current and promising new preventive and control measures to reduce dengue infections.
PMCID: PMC4364886  PMID: 25786225
7.  Systems Biology Approaches to Understand Natural Products Biosynthesis 
Actinomycetes populate soils and aquatic sediments that impose biotic and abiotic challenges for their survival. As a result, actinomycetes metabolism and genomes have evolved to produce an overwhelming diversity of specialized molecules. Polyketides, non-ribosomal peptides, post-translationally modified peptides, lactams, and terpenes are well-known bioactive natural products with enormous industrial potential. Accessing such biological diversity has proven difficult due to the complex regulation of cellular metabolism in actinomycetes and to the sparse knowledge of their physiology. The past decade, however, has seen the development of omics technologies that have significantly contributed to our better understanding of their biology. Key observations have contributed toward a shift in the exploitation of actinomycete’s biology, such as using their full genomic potential, activating entire pathways through key metabolic elicitors and pathway engineering to improve biosynthesis. Here, we review recent efforts devoted to achieving enhanced discovery, activation, and manipulation of natural product biosynthetic pathways in model actinomycetes using genome-scale biological datasets.
PMCID: PMC4673338  PMID: 26697425
actinomycetes; genome mining; genomics; transcriptomics; proteomics; metabolomics; genome-scale metabolic reconstructions
8.  Gender differences on effectiveness of a school-based physical activity intervention for reducing cardiometabolic risk: a cluster randomized trial 
Studies that have examined the impact of a physical activity intervention on cardiometabolic risk factors have yielded conflicting results. The objective of this study was to assess the impact of a standardized physical activity program on adiposity and cardiometabolic risk factors in schoolchildren.
Cluster randomized trial study of 712 schoolchildren, 8–10 years, from 20 public schools in the Province of Cuenca, Spain. The intervention (MOVI-2) consisted of play-based and non-competitive activities. MOVI-2 was conducted during two 90-minute sessions on weekdays and one 150-minute session on Saturday mornings every week between September 2010 and May 2011. We measured changes in adiposity (overweight/obesity prevalence, body mass index [BMI], triceps skinfold thickness [TST], body fat %, fat-free mass, waist circumference) and other cardiometabolic risk factors (LDL-cholesterol, triglycerides/HDL-cholesterol ratio, insulin, C-reactive protein and blood pressure). The analyses used mixed regression models to adjust for baseline covariates under cluster randomization.
Among girls, we found a reduction of adiposity in intervention versus control schools, with a decrease in TST (−1.1 mm; 95% confidence interval [CI] -2.3 to −0.7), body fat % (−0.9%; 95% CI −1.3 to −0.4), waist circumference (−2.7 cm; 95% CI −4.5 to −0.9), and an increase in fat-free mass (0.3 kg; 95% CI 0.01 to 0.6). The intervention also led to lower serum LDL-cholesterol and insulin levels. Among boys, a reduction in waist circumference (−1.4 cm; 95% CI −2.6 to −0.1; P = 0.03), and an increase in fat-free mass (0.5 kg; 95% CI 0.2 to 0.9; P = 0.003) was associated with the intervention versus control schools. The prevalence of overweight/obesity or underweight, BMI, and other cardiometabolic risk factors was not modified by the intervention. No important adverse events were registered.
An extracurricular intervention of non-competitive physical activity during an academic year, targeting all schoolchildren regardless of body weight, is a safe and effective measure to reduce adiposity in both genders and to improve cardiometabolic risk profile in girls.
Trial registration
Clinical trials NCT01277224.
Electronic supplementary material
The online version of this article (doi:10.1186/s12966-014-0154-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4295398  PMID: 25491026
Physical activity; Intervention; Obesity; Cardiometabolic risk factors; Metabolic syndrome; Children
9.  Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes 
Cardiac hypertrophy is characterized by alterations in both cardiac bioenergetics and insulin sensitivity. Insulin promotes glucose uptake by cardiomyocytes and its use as a substrate for glycolysis and mitochondrial oxidation in order to maintain the high cardiac energy demands. Insulin stimulates Ca2+ release from the endoplasmic reticulum, however, how this translates to changes in mitochondrial metabolism in either healthy or hypertrophic cardiomyocytes is not fully understood.
In the present study we investigated insulin-dependent mitochondrial Ca2+ signaling in normal and norepinephrine or insulin like growth factor–1-induced hypertrophic cardiomyocytes. Using mitochondrion-selective Ca2+-fluorescent probes we showed that insulin increases mitochondrial Ca2+ levels. This signal was inhibited by the pharmacological blockade of either the inositol 1,4,5-triphosphate receptor or the mitochondrial Ca2+ uniporter, as well as by siRNA-dependent mitochondrial Ca2+ uniporter knockdown. Norepinephrine-stimulated cardiomyocytes showed a significant decrease in endoplasmic reticulum-mitochondrial contacts compared to either control or insulin like growth factor–1-stimulated cells. This resulted in a reduction in mitochondrial Ca2+ uptake, Akt activation, glucose uptake and oxygen consumption in response to insulin. Blocking mitochondrial Ca2+ uptake was sufficient to mimic the effect of norepinephrine-induced cardiomyocyte hypertrophy on insulin signaling.
Mitochondrial Ca2+ uptake is a key event in insulin signaling and metabolism in cardiomyocytes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12964-014-0068-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4234850  PMID: 25376904
Insulin; Calcium; Mitochondria; Cardiac hypertrophy; Inositol 1,4,5-triphosphate receptor; Akt; IGF-1; Catecholamines
10.  Genome Sequence of Vibrio cholerae Strain O1 Ogawa El Tor, Isolated in Mexico, 2013 
Genome Announcements  2014;2(5):e01123-14.
We present the draft genome sequence of Vibrio cholerae InDRE 3140 recovered in 2013 during a cholera outbreak in Mexico. The genome showed the Vibrio 7th pandemic islands VSP1 and VSP2, the pathogenic islands VPI-1 and VPI-2, the integrative and conjugative element SXT/R391 (ICE-SXT), and both prophages CTXφ and RS1φ.
PMCID: PMC4214995  PMID: 25359919
12.  Mitochondrial metabolism and the control of vascular smooth muscle cell proliferation 
Differentiation and dedifferentiation of vascular smooth muscle cells (VSMCs) are essential processes of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. Alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of a variety of cardiovascular diseases, including atherosclerosis, hypertension, and vascular stenosis. This review provides an overview of the current state of knowledge of molecular mechanisms involved in the control of VSMC proliferation, with particular focus on mitochondrial metabolism. Mitochondrial activity can be controlled by regulating mitochondrial dynamics, i.e., mitochondrial fusion and fission, and by regulating mitochondrial calcium handling through the interaction with the endoplasmic reticulum (ER). Alterations in both VSMC proliferation and mitochondrial function can be triggered by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion and mitochondrial–ER interaction. Several lines of evidence highlight the relevance of mitochondrial metabolism in the control of VSMC proliferation, indicating a new area to be explored in the treatment of vascular diseases.
PMCID: PMC4266092  PMID: 25566542
vascular smooth muscle cell; proliferation; mitofusin-2; mitochondrial metabolism; mitochondrial dynamics
13.  Highly Pathogenic Avian Influenza A(H7N3) Virus in Poultry Workers, Mexico, 2012 
Emerging Infectious Diseases  2013;19(9):1531-1534.
We identified 2 poultry workers with conjunctivitis caused by highly pathogenic avian influenza A(H7N3) viruses in Jalisco, Mexico. Genomic and antigenic analyses of 1 isolate indicated relatedness to poultry and wild bird subtype H7N3 viruses from North America. This isolate had a multibasic cleavage site that might have been derived from recombination with host rRNA.
PMCID: PMC3810917  PMID: 23965808
influenza virus; H7N3; highly pathogenic avian influenza A virus; viruses; conjunctivitis; poultry workers; Mexico
14.  The Genome Sequence of Streptomyces lividans 66 Reveals a Novel tRNA-Dependent Peptide Biosynthetic System within a Metal-Related Genomic Island 
Genome Biology and Evolution  2013;5(6):1165-1175.
The complete genome sequence of the original isolate of the model actinomycete Streptomyces lividans 66, also referred to as 1326, was deciphered after a combination of next-generation sequencing platforms and a hybrid assembly pipeline. Comparative analysis of the genomes of S. lividans 66 and closely related strains, including S. coelicolor M145 and S. lividans TK24, was used to identify strain-specific genes. The genetic diversity identified included a large genomic island with a mosaic structure, present in S. lividans 66 but not in the strain TK24. Sequence analyses showed that this genomic island has an anomalous (G + C) content, suggesting recent acquisition and that it is rich in metal-related genes. Sequences previously linked to a mobile conjugative element, termed plasmid SLP3 and defined here as a 94 kb region, could also be identified within this locus. Transcriptional analysis of the response of S. lividans 66 to copper was used to corroborate a role of this large genomic island, including two SLP3-borne “cryptic” peptide biosynthetic gene clusters, in metal homeostasis. Notably, one of these predicted biosynthetic systems includes an unprecedented nonribosomal peptide synthetase—tRNA-dependent transferase biosynthetic hybrid organization. This observation implies the recruitment of members of the leucyl/phenylalanyl-tRNA-protein transferase family to catalyze peptide bond formation within the biosynthesis of natural products. Thus, the genome sequence of S. lividans 66 not only explains long-standing genetic and phenotypic differences but also opens the door for further in-depth comparative genomic analyses of model Streptomyces strains, as well as for the discovery of novel natural products following genome-mining approaches.
PMCID: PMC3698927  PMID: 23709624
bacterial next-generation genome sequencing; Streptomyces comparative genomics; copper homeostasis; L/F tRNA transferase; peptide biosynthesis
15.  First Draft Genome Sequence of a Strain from the Genus Citricoccus 
Journal of Bacteriology  2011;193(21):6092-6093.
Bacteria of the genus Citricoccus have been isolated from ecological niches characterized by diverse abiotic stress conditions. Here we report the first genome draft of a strain of the genus Citricoccus isolated from the extremely oligotrophic Churince system in the Cuatro Ciénegas Basin (CCB) in Coahuila, Mexico.
PMCID: PMC3194908  PMID: 21994924
16.  Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders 
Molecular Therapy  2011;19(11):1971-1980.
Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood–brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations.
PMCID: PMC3222525  PMID: 21811247
17.  Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN 
Nature biotechnology  2010;28(3):271-274.
Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function1. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect ~60% of motor neurons when injected intravenously into neonatal mice2–4. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, neuromuscular physiology and life span. Treatment on postnatal day 5 results in partial correction, whereas postnatal day 10 treatment has little effect, suggesting a developmental period in which scAAV9 therapy has maximal benefit. Notably, we also show extensive scAAV9-mediated motor neuron transduction after injection into a newborn cynomolgus macaque. This demonstration that scAAV9 traverses the blood-brain barrier in a nonhuman primate emphasizes the clinical potential of scAAV9 gene therapy for SMA.
PMCID: PMC2889698  PMID: 20190738
18.  The influenza A(H1N1) epidemic in Mexico. Lessons learned 
Several influenza pandemics have taken place throughout history and it was assumed that the pandemic would emerge from a new human virus resulting from the adaptation of an avian virus strain. Mexico, since 2003 had developed a National Preparedness and Response Plan for an Influenza Pandemic focused in risk communication, health promotion, healthcare, epidemiological surveillance, strategic stockpile, research and development. This plan was challenged on April 2009, when a new influenza A(H1N1) strain of swine origen was detected in Mexico. The situation faced, the decisions and actions taken, allowed to control the first epidemic wave in the country. This document describes the critical moments faced and explicitly point out the lessons learned focused on the decided support by the government, the National Pandemic Influenza Plan, the coordination among all the government levels, the presence and solidarity of international organizations with timely and daily information, diagnosis and the positive effect on the population following the preventive hygienic measures recommended by the health authorities. The international community will be able to use the Mexican experience in the interest of global health.
PMCID: PMC2765941  PMID: 19785747
19.  The prevalence of chronic diseases and major disease risk factors at different ages among 150 000 men and women living in Mexico City: cross-sectional analyses of a prospective study 
BMC Public Health  2009;9:9.
While most of the global burden from chronic diseases, and especially vascular diseases, is now borne by low and middle-income countries, few large-scale epidemiological studies of chronic diseases in such countries have been performed.
From 1998–2004, 52 584 men and 106 962 women aged ≥35 years were visited in their homes in Mexico City. Self reported diagnoses of chronic diseases and major disease risk factors were ascertained and physical measurements taken. Age- and sex-specific prevalences and means were analysed.
After about age 50 years, diabetes was extremely common – for example, 23.8% of men and 26.9% of women aged 65–74 reported a diagnosis. By comparison, ischaemic heart disease was reported by 4.8% of men and 3.0% of women aged 65–74, a history of stroke by 2.8% and 2.3%, respectively, and a history of cancer by 1.3% and 2.1%. Cancer history was generally more common among women than men – the excess being largest in middle-age, due to breast and cervical cancer. At older ages, the gap narrowed because of an increasing prevalence of prostate cancer. 51% of men and 25% of women aged 35–54 smoked cigarettes, while 29% of men and 41% of women aged 35–54 were obese (i.e. BMI ≥30 kg/m2). The prevalence of treated hypertension or measured blood pressure ≥140/90 mmHg increased about 50% more steeply with age among women than men, to 66% of women and 58% of men aged 65–74. Physical inactivity was highly prevalent but daily alcohol drinking was relatively uncommon.
Diabetes, obesity and tobacco smoking are highly prevalent among adults living in Mexico City. Long-term follow-up of this and other cohorts will establish the relevance of such factors to the major causes of death and disability in Mexico.
PMCID: PMC2645387  PMID: 19134207
20.  para tu Salud: Reduction of Weight and Waistlines by Integrating Exercise Breaks into Workplace Organizational Routine 
Preventing Chronic Disease  2007;5(1):A12.
Proactive worksite strategies that change the physical or sociocultural environment(s) to incorporate obligatory physical activity may be necessary to engage sedentary people. This study describes implementation and evaluation of an intervention, Pausa para tu Salud (Pause for Your Health), that integrated a brief period of group exercise into the workday.
An uncontrolled pretest–post-test study design tested the effects of integrating daily 10-minute exercise breaks during paid work time during January 2003 through January 2004. A total of 335 Mexican Ministry of Health office workers provided baseline data as a part of routine annual clinical screening examinations.
Baseline mean body mass index and waist circumferences were 27.8 kg/m2 and 87.6 cm for women and 26.6 kg/m2 and 89.7 cm for men. Complete data were available for 271 (80.9%) employees at 1-year follow-up. Two-tailed, paired t-test comparisons were used. Body mass index decreased by 0.32 kg/m2 (P = .05), and waist circumference by 1.6 cm (P = .0009) overall. The body mass index decrease, however, was significant only for men (−0.43 kg/m2, P = .03). Multivariate analyses revealed a significant decrease in diastolic blood pressure among women (z = −2.04, P = .042).
The intervention was associated with significant improvements in both measures of body composition. Substantive health and organizational benefits may result from integrating brief periods of physical activity into the workday if these findings are replicated in randomized controlled trials in other worksites.
PMCID: PMC2248785  PMID: 18082001
21.  HLA haplotypes associated with hemochromatosis mutations in the Spanish population 
BMC Medical Genetics  2004;5:25.
The present study is an analysis of the frequencies of HLA-A and -B antigens and HLA haplotypes in two groups of individuals homozygous for the two main HFE mutations (C282Y and H63D) and a group heterozygous for the S65C mutation.
The study population includes: 1123 healthy individuals, 100 homozygous for the C282Y mutation, 138 homozygous for the H63D mutation and 17 heterozygous for the S65C mutation. HFE and HLA alleles were detected using DNA-based and microlymphocytotoxicity techniques respectively.
An expected significant association between C282Y and the HLA-A3/B7 haplotype was found, but other HLA haplotypes carrying the -A3 antigen were found: HLA-A3/B62 and HLA-A3/B44. Also, a significant association between H63D mutation and HLA-A29/B44 haplotype was found, and again other HLA haplotypes carrying the HLA-A29 antigen were also found: HLA-A29/B14 and HLA-A29/B62. In addition, the S65C mutation seems to be associated with a HLA haplotype carrying the HLA-A26 antigen.
These findings clearly suggest that HLA-A3/B7 and HLA-A29/B44 are the ancestral haplotypes from which the C282Y and H63D mutations originated, respectively. The frequencies of these mutations in different populations, their geographical distribution, and the degree of the statistical association to the ancestral haplotypes, suggest that the H63D mutation must have occurred earlier than the C282Y mutation.
PMCID: PMC529258  PMID: 15498100
22.  The U.S.-Mexico Border Infectious Disease Surveillance Project: Establishing Binational Border Surveillance 
Emerging Infectious Diseases  2003;9(1):97-102.
In 1997, the Centers for Disease Control and Prevention, the Mexican Secretariat of Health, and border health officials began the development of the Border Infectious Disease Surveillance (BIDS) project, a surveillance system for infectious diseases along the U.S.-Mexico border. During a 3-year period, a binational team implemented an active, sentinel surveillance system for hepatitis and febrile exanthems at 13 clinical sites. The network developed surveillance protocols, trained nine surveillance coordinators, established serologic testing at four Mexican border laboratories, and created agreements for data sharing and notification of selected diseases and outbreaks. BIDS facilitated investigations of dengue fever in Texas-Tamaulipas and measles in California–Baja California. BIDS demonstrates that a binational effort with local, state, and federal participation can create a regional surveillance system that crosses an international border. Reducing administrative, infrastructure, and political barriers to cross-border public health collaboration will enhance the effectiveness of disease prevention projects such as BIDS.
PMCID: PMC2873746  PMID: 12533288
border health; Mexico; southwestern United States; sentinel surveillance; communicable diseases; hepatitis; viral; human; migrant health; international health; infectious diseases; research

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