Opioides, sobredosis y los desafíos de la reducción de daños como estrategia eficiente en el campo de la salud pública / Opioids, Overdose and Harm Reduction as an Efficient Strategy for Public Healt

Resumen El tráfico y el consumo de drogas es un desafío global que afecta a todas las sociedades en diferentes formas y dimensiones; su carácter multidimensional tiene un alto impacto en la salud de las poblaciones y en la economía de los países. Tan solo en 2021, se estimó que 296 millones de personas q q q consumieron drogas. Durante años, la política mundial de salud en materia de drogas estuvo centrada en la prohibición; sin embargo, en la actualidad se sabe que un enfoque de reducción de riesgos y daños, lejos de rechazar la abstinencia, reduce los efectos negativos del consumo de sustancias legales e ilegales, incluidas las muertes por sobredosis, lo cual trae grandes beneficios a la salud y al funcionamiento social de quienes las consumen. Este artículo brinda una comprensión integral del consumo de opioides, específicamente fentanilo, y recalca la necesidad de abordarlo a través de un enfoque integral que combine estrategias basadas en la evidencia, bajo el reconocimiento de que la salud es un derecho humano fundamental y una condición indispensable para el desarrollo.

Abstract Drug trafficking and use is a global challenge that affects all societies in different forms and dimensions. Its multidimensional nature has a high impact on the health of populations and the economies of countries. In 2021, it was estimated that 296 million people used drugs. For years, global health policy on drugs was focused on prohibition, however, we now know that a harm reduction approach, far from rejecting abstinence, reduces the negative effects of legal and illegal substance use, including overdose-related deaths. Harm reduction brings great health benefits and improves social functioning of those engaged in substance use. This article provides a comprehensive understanding of opioid use, specifically fentanyl, and emphasizes the need to address it through a comprehensive approach that combines evidence-based strategies, recognizing that health is a fundamental human right and an essential condition for development.

Effectiveness of decentralizing outpatient acute malnutrition treatment with community health workers and a simplified combined protocol: a cluster randomized controlled trial in emergency settings of Mali.

Background: Outpatient treatment of acute malnutrition is usually centralized in health centers and separated into different programs according to case severity. This complicates case detection, care delivery, and supply chain management, making it difficult for families to access treatment. This study assessed the impact of treating severe and moderate cases in the same program using a simplified protocol and decentralizing treatment outside health centers through community health workers (CHWs). Methods: A three-armed cluster randomized controlled trial under a non-inferiority hypothesis was conducted in the Gao region of Mali involving 2,038 children between 6 and 59 months of age with non-complicated acute malnutrition. The control arm consisted of 549 children receiving standard treatment in health centers from nursing staff. The first intervention arm consisted of 800 children treated using the standard protocol with CHWs added as treatment providers. The second intervention arm consisted of 689 children treated by nurses and CHWs under the ComPAS simplified protocol, considering mid-upper arm circumference as the sole anthropometric criterion for admission and discharge and providing a fixed dose of therapeutic food for severe and moderate cases. Coverage was assessed through cross-sectional surveys using the sampling evaluation of access and coverage (SLEAC) methodology for a wide area involving several service delivery units. Results: The recovery rates were 76.3% in the control group, 81.8% in the group that included CHWs with the standard protocol, and 92.9% in the group that applied the simplified protocol, confirming non-inferiority and revealing a significant risk difference among the groups. No significant differences were found in the time to recovery (6 weeks) or in anthropometric gain, whereas the therapeutic food expenditure was significantly lower with the simplified combined program in severe cases (43 sachets fewer than the control). In moderate cases, an average of 35 sachets of therapeutic food were used. With the simplified protocol, the CHWs had 6% discharge errors compared with 19% with the standard protocol. The treatment coverage increased significantly with the simplified combined program (SAM +42.5%, MAM +13.8%). Implications: Implementing a simplified combined treatment program and adding CHWs as treatment providers can improve coverage while maintaining non-inferior effectiveness, reducing the expenditure on nutritional intrants, and ensuring the continuum of care for the most vulnerable children.

Impact of a simplified treatment protocol for moderate acute malnutrition with a decentralized treatment approach in emergency settings of Niger.

Introduction: Of the 45.4 million children under five affected by acute malnutrition in the world, the majority (31.8 million) are affected by moderate acute malnutrition (MAM). Its treatment is particularly complex in emergency settings such as the Diffa region in Niger. This study aims to evaluate the effectiveness and coverage of a simplified treatment protocol with Community Health Workers (CHWs) as treatment providers. Methods: This study is a non-randomized controlled trial. The control group (n = 181) received the standard protocol currently used in country, delivered by nursing staff only in health centres and health posts, while the intervention group (n = 483) received the simplified protocol which included nursing at health centres and CHWs at health post as treatment providers. Results: The recovery rate was higher in the simplified protocol group (99.6% vs. 79.56%, p < 0.001) recording lower time to recover and higher anthropometric gain. Treatment coverage in the intervention group increased from 28.8% to 84.9% and reduced in the control group (25.3% to 13.6%). No differences were found in the recovery rate of children treated by CHWs and nursing staff. Conclusion: The outcomes using the simplified protocol exceeded humanitarian requirements and demonstrated improvements compared to the standard protocol showing that the simplified protocol could be safely provided by CHWs in an emergency context. Further research in other contexts is needed to scale up this intervention.

RS3480 Polymorphism of FNDC5/Irisin Is Associated with Type 2 Diabetes Mellitus in Maya-Mestizo Women.

Objective: To investigate the possible association between rs3480 and rs16835198 of the fibronectin type III domain containing 5 (FNDC5)/Irisin and their haplotypes with the presence of type 2 diabetes mellitus (T2DM) in Maya-Mestizo women. Methods: We studied 547 postmenopausal women of Maya-Mestizo origin. The diagnosis of T2DM was based on the criteria of the American Diabetes Association. DNA was obtained from blood leukocytes. rs3480 and rs16835198 of FNDC5/Irisin were studied using real-time polymerase chain reaction allelic discrimination. Deviations from Hardy-Weinberg equilibrium and alleles differences, as well as genotype frequencies between groups, were assessed by χ2 tests. Using logistic regression analysis, the odds ratio and 95% confidence intervals were calculated to estimate the association between both polymorphisms of FNDC5/Irisin and the presence of T2DM. Pairwise linkage disequilibrium between polymorphisms was calculated by direct correlation r2, and haplotype analysis was conducted. Results: We found that the G-allele of rs3480, as well as under a dominant model, this polymorphism was significantly associated with T2DM (P = 0.028 and P = 0.003, respectively). Besides, one haplotype was associated with T2DM (P = 0.035). Conclusions: Our results suggest that the FNDC5/Irisin rs3480, and one haplotype formed by rs3480 and rs16835198 were associated with the risk of presenting T2DM in Maya-Mestizo women.

Differential histological features and myogenic protein levels in distinct muscles of d-sarcoglycan null muscular dystrophy mouse model.

Skeletal muscle (SkM) comprises slow and fast-twitch fibers, which differ in molecular composition, function, and systemic energy consumption. In addition, muscular dystrophies (DM), a group of diverse hereditary diseases, present different patterns of muscle involvement, progression, and severity, suggesting that the regeneration-degeneration process may differ depending on the muscle type. Therefore, the study aimed to explore the expression of proteins involved in the repair process in different muscles at an early stage of muscular dystrophy in the δ-sarcoglycan null mice (Sgcd-null), a limb-girdle muscular dystrophy 2 F model. Hematoxylin & Eosin (H&E) Staining showed a high number of central nuclei in soleus (Sol), tibialis (Ta), gastrocnemius (Gas), and extensor digitorum longus (Edl) from four months Sgcd-null mice. However, fibrosis, determined by trichrome of Gomori modified staining, was only observed in Sgcd-null Sol. In addition, the number of Type I and II fibers variated differentially in the Sgcd-null muscles vs. wild-type muscles. Besides, the protein expression level of ß-catenin, myomaker, MyoD, and myogenin also presented different expression levels in all the Sgcd-null muscles studied. In summary, our study reveals that muscles with different metabolic characteristics showed distinct expression patterns of proteins involved in the muscle regeneration process. These results could be relevant in designing therapies for genetic and acquired myopathy.

Effectiveness and Coverage of Severe Acute Malnutrition Treatment with a Simplified Protocol in a Humanitarian Context in Diffa, Niger.

BACKGROUND: the aim of this study is to evaluate the effectiveness and coverage of a simplified protocol that is implemented in health centers (HCs) and health posts (HPs) for children who are suffering from severe acute malnutrition (SAM) in the humanitarian context of Diffa. METHODS: We conducted a non-randomized community-controlled trial. The control group received outpatient treatment for SAM, without medical complications, at HCs and HPs with the standard protocol of community management of acute malnutrition (CMAM). Meanwhile, with respect to the intervention group, the children with SAM received treatment at the HCs and HPs through a simplified protocol wherein the mid-upper arm circumference (MUAC) and the presence of edema were used as the admission criteria, and the children with SAM were administered doses of fixed ready-to-use therapeutic food (RUTF). RESULTS: A total of 508 children, who were all under 5 years and had SAM, were admitted into the study. The cured proportion was 87.4% in the control group versus 96.6% in the intervention group (p value = 0.001). There was no difference between the groups in the length of stay, which was 35 days, but the intervention group used a lower quantity of RUTF-70 sachets versus 90 sachets, per child cured. Coverage increases were observed in both groups. DISCUSSION: the simplified protocol used at the HCs and HPs did not result in worse recovery and resulted in fewer discharge errors compared to the standard protocol.

Bond strength comparison among 10-MDP-containing and non-10-MDP-Containing adhesives in different degrees of dental fluorosis / Comparación de fuerza de unión entre adhesivos que contienen y no contienen 10-MDP en diferentes grados de fluorosis dental

Dental fluorosis can cause changes in the enamel surface, conditioning its functionality and esthetics. The application of dental adhesives is a treatment option; however, their use on fluorotic teeth can result in limitations. The aim of this study was to compare the shear bond strength of two different adhesives, one with 10-MDP and one without 10-MDP, in different degrees of dental fluorosis.This is an in vitro study on dental enamel samples, a total of 180 samples with the inclusion criteria were treated, randomly divided into two groups of 90, according to the type of dental adhesive, where each group was again divided into three groups of 30 samples, representing different degrees of dental fluorosis according to the Thylstrup-Fejerskov index (Group I: TF1 and TF2; Group II: TF3; Group III: TF4). Normality tests, two-factor ANOVA, and post-hoc tests were used to determine differences between the groups, with a significance level of 95%. As results, a statistically significant difference was shown between the use of dental adhesive with 10-MDP and the three groups of dental fluorosis (p=0.011), in addition, a Tukey post-hoc test on the groups treated with 10-MDP adhesive revealed a statistically significant difference between group I versus group II, and group I versus group III, (p=<0.05). It is concluded that the use of adhesive systems with 10-MDP presents a better shear bond strength on enamel with dental fluorosis grades I and II in the Thylstrup-Fejerskov index.

La fluorosis dental puede ocasionar cambios en la superficie del esmalte, condicionando su funcionalidad y estética, la aplicación de adhesivos dentales es una opción de tratamiento, sin embargo, su uso en dientes fluoroticos puede resultar en limitaciones. El objetivo de este estudio consistió en comparar la fuerza de adhesión a la cizalladura de dos diferentes adhesivos, uno con 10-MDP y otro sin 10-MDP, en diferentes grados de fluorosis dental. Se trata de un estudio in vitro en muestras de esmalte dental, un total de 180 muestras con los criterios de inclusión fueron tratadas, aleatoriamente divididas en dos grupos de 90, de acuerdo al tipo de adhesivo dental, donde cada grupo fue dividido nuevamente en tres grupos de 30 muestras, representando diferentes grados de fluorosis dental según el índice de Thylstrup- Fejerskov (Grupo I: TF1 y TF2; Grupo II: TF3; Grupo III: TF4). Para determinar diferencias entre los grupos se utilizaron pruebas de normalidad, ANOVA de dos factores, y pruebas post-hoc, con un nivel de significancia de 95%. Como resultados, se mostró una diferencia estadísticamente significativa entre el uso de adhesivo dental con 10- MDP y los tres grupos de fluorosis dental (p=0.011), además, una prueba post hoc de Tukey sobre los grupos tratados con adhesivo 10-MDP revelaron una diferencia estadísticamente significativa entre el grupo I frente al grupo II, y el grupo I frente al grupo III, (p=<0.05) Se concluye que el uso de sistemas adhesivos con 10-MDP presentan una mejor resistencia de adhesión al cizallamiento en esmalte con grados de fluorosis dental I y II en el índice de Thylstrup-Fejerskov

(-)-Epicatechin modulates the expression of myomiRs implicated in exercise response in mouse skeletal muscle.

The flavanol (-)-epicatechin has exercise-mimetic properties. Besides, several miRNAs play a role in modulating the adaptation of the muscle to different training protocols. However, notwithstanding all information, few studies aimed to determine if (-)-epicatechin can modify the expression of miRNAs related to skeletal muscle development and regeneration. Mice were treated for fifteen days by oral gavage with the flavanol (-)-epicatechin. After treatment, the quadriceps of the mice was dissected, and total RNA was extracted. The expression level of miR-133, -204, -206, -223, -486, and -491 was analyzed by qRT-PCR. We also used bioinformatic analysis to predict the participation of these miRNAs in different skeletal muscle signal transduction pathways. Additionally, we analyzed the level of the myogenic proteins MyoD and myogenin by Western blot and measured the cross-sectional area of muscle fibers stained with E&H. (-)-Epicatechin upregulated the expression of miR-133, -204, -206, -223, and -491 significantly, which was associated with an increase in the level of the myogenic proteins MyoD and Myogenin and an augment in the fiber size. The bioinformatics analysis showed that the studied miRNAs might participate in different signal transduction pathways related to muscle development and adaptation. Our results showed that (-)-epicatechin upregulated miRNAs that participate in skeletal exercise muscle adaptation, induced muscle hypertrophy, and increased the level of myogenic proteins MyoD and MyoG.

Association of polymorphisms rs2303729, rs10880, and rs1131620 of LTBP4 with sarcopenia in elderly patients with type 2 diabetes mellitus.

BACKGROUND: Latent TGFß binding protein 4 (LTBP4) modifies skeletal muscle function, and polymorphisms in this gene have been associated with a longer ambulation time in patients with Duchenne muscular dystrophy. However, no studies associate these polymorphisms with an acquired muscle condition. AIM: The study aims to determine whether three functional variants within the LTBP4 were associated with sarcopenia in patients with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: We performed an analysis with 144 elderly individuals with T2DM, including 101 without sarcopenia and 43 with sarcopenia. Polymorphism frequency was determined by real-time PCR allelic discrimination TaqMan assay. RESULTS: Under different genetic models, the univariant analysis did not show a significant association of any polymorphism with sarcopenia. But the multivariate model analysis showed that variant rs1131620 (OR 7.852, 95% CI 1.854-33.257, p = 0.005) was significantly associated with sarcopenia under a dominant model. Under the same analysis, the variants rs2303729 and rs10880 had a more discrete association (OR 3.537 95% CI 1.078-11.607, p = 0.037; OR 5.008, 95% CI 1.120-22.399, p = 0.035, respectively). CONCLUSIONS: Our study highlights the importance of studying LTBP4 polymorphisms associated with sarcopenia. These findings suggest that the rs1131620 polymorphism of the LTBP4 may be part of the observed sarcopenia process in patients with T2DM.

(-) - Epicatechin improves Tibialis anterior muscle repair in CD1 mice with BaCl2-induced damage.

Several studies have shown the beneficial effect that Epicatechin (Epi) has on the skeletal muscle of murine models and patients with muscular dystrophy and in the muscles of patients with diabetes or murine sarcopenia models. This flavanol has been shown to enhance antioxidant pathways and improve muscle architecture. However, the repair process during muscle regeneration has not been analyzed. To address this, we characterize the effect of Epi in the repair process of the Tibialis anterior in a murine model with BaCl2-induced damage. CD1 mice of 10 weeks of age were randomly selected and injured with BaCl2. One hour later, they were divided into four groups (n=6 for histology groups and n=12 for western blot groups). Epi was administered every 12h, until the time of sacrifice. Histological and morphological analysis showed that Epi significantly reduced the area of damage and hypertrophy at 15 days in the damaged muscle. Furthermore, western blot assays showed that the treatment increases ß-catenin (active) and myogenic proteins such as MyoD and Myogenin. These results show that Epi exerts therapeutic effects accelerating skeletal muscle repair after induced damage chemically, thus highlighting the therapeutic potential of this flavanol in different myopathies.

Low prevalence of chewing lice (Phthiraptera) in wintering populations of the reed bunting Emberiza schoeniclus (Aves: Passeriformes: Emberizidae) in the Iberian Peninsula.

The reed bunting is a passerine bird of the Palearctic region, some subspecies suffer a decline in their populations. Four species of lice have been cited in reed bunting, but lice studies have not been carried out in the Iberian Peninsula. Between 2018 and 2020 a wintering population of the reed bunting is sampled in the center of the Iberian Peninsula through mist nets. Lice were collected directly from birds by a visual body examination. Of the 208 reed buntings sampled, only four individuals were parasitized. We find two species: Menacanthus chrysophaeus, which is the first record in Iberian lice, and Brueelia blagovescenskyi. Lice are not associated with the sex or age of the birds. The prevalence obtained is low compared to other European populations. This difference can be explained by the phenology of the subspecies, the migratory populations have a lower load of lice than sedentary populations.

Prevalencia de trastornos temporomandibulares mediante el índice anamnésico simplificado de Fonseca en estudiantes de odontología de la Universidad Juárez del Estado de Durango, México / Prevalence of temporomandibular disorders according to the simplified Fonseca anamnestic index in dentistry students of the Juárez University of the State of Durango, Mexico

Objetivo. Estimar la prevalencia de trastornos temporomandibulares (TTM) en estudiantes de Odontología de la Universidad Juárez del Estado de Durango, México. Material y métodos. Se trata de un estudio descriptivo, observacional, prospectivo y transversal. El universo de estudio contempló a la población estudiantil de la Facultad de Odontología, de la Universidad Juárez del Estado de Durango (México). Se incluyeron alumnos que cursaron del 1.o al 8.o semestre durante el ciclo escolar 2018-A, con edades entre los 18 y 28 años, a quienes se les aplicó un instrumento (índice anamnésico simplificado de Fonseca) que permitió caracterizar los TTM. El tamaño de la muestra se determinó utilizando el software Epi InfoTM y se obtuvo un tamaño de muestra total de 263 individuos. Para describir los datos, se utilizó el paquete estadístico R Studio Team (2019). Resultados. La prevalencia total de TTM en la población estudiada fue del 63% y el TTM más prevalente fue el leve, con un 44%. La prueba Ji2 entre el sexo y el TTM muestra significancia estadística (p = 0,001), igual que entre el sexo y los ítems del índice simplificado de Fonseca: ítem 4 (p = 0,001), ítem 7 (p = 0,021), ítem 8 (p = 0,021), ítem 9 (0,001) y el ítem 10 (p = 0,001). Conclusiones. Existe una alta prevalencia de TTM en la población estudiantil de la Facultad de Odontología de la Universidad Juárez del Estado de Durango (México), y el sexo femenino tiene una relación con la presencia y la manifestación de síntomas en estos trastornos. (AU)

Objective: The objective was to estimate the prevalence of temporomandibular disorders (TMD), in students of the Faculty of Dentistry. Material and Methods: This was a descriptive, observational, prospective, cross-sectional study. The study included 18 to 28-year-old students from the Faculty of Dentistry of the Universidad Juárez del Estado de Durango, México, attending the 1st to 8th semester of the 2018-A school year in whom the simplified Fonseca anamnestic index (sFAI) was applied to characterize TMD. The sample size was determined using the Epi InfoTM software, obtaining a total sample size of 263 individuals. The R Studio (2019) statistical package was used to describe the data. Results: The prevalence of TMD in the study population was 63%, with a mild disorder being the most prevalent in 44%. The Chi2 test showed statistically significant differences between sex and TMD (p = 0.001) and between sex and 5 items of the sFAI: item 4 (p= 0.001), item 7 (p= 0.001), item 8 (p = 0.021), item 9 (p= 0.001) and item 10 (p = 0.001). Conclusions: There is a high prevalence of TMD in the student population of the Faculty of Dentistry of the Universidad Juárez del Estado de Durango, Mexico, with females presenting a higher prevalence of the presence and manifestation of symptoms in these disorders. (AU)

[Prevalence of temporomandibular disorders according to the simplified fonseca anamnestic index in dentistry students of the juárez university of the state of durango, mexico]. / Prevalencia de trastornos temporomandibulares mediante el índice anamnésico simplificado de fonseca en estudiantes de odontología de la universidad juárez del estado de durango, méxico.

Objective: The objective was to estimate the prevalence of temporomandibular disorders (TMD), in students of the Faculty of Dentistry. Material and Methods: This was a descriptive, observational, prospective, cross-sectional study. The study included 18 to 28-year-old students from the Faculty of Dentistry of the Universidad Juárez del Estado de Durango, México, attending the 1st to 8th semester of the 2018-A school year in whom the simplified Fonseca anamnestic index (sFAI) was applied to characterize TMD. The sample size was determined using the Epi InfoTM software, obtaining a total sample size of 263 individuals. The R Studio (2019) statistical package was used to describe the data. Results: The prevalence of TMD in the study population was 63%, with a mild disorder being the most prevalent in 44%. The Chi2 test showed statistically significant differences between sex and TMD (p = 0.001) and between sex and 5 items of the sFAI: item 4 (p= 0.001), item 7 (p= 0.001), item 8 (p = 0.021), item 9 (p= 0.001) and item 10 (p = 0.001). Conclusions: There is a high prevalence of TMD in the student population of the Faculty of Dentistry of the Universidad Juárez del Estado de Durango, Mexico, with females presenting a higher prevalence of the presence and manifestation of symptoms in these disorders.

Expression of adipokines and their receptors in adipose tissue of women with class 3 obesity with or without hypertension.

Obesity increases the risk of developing hypertension. Since both pathological entities constitute public health problems, the aim of this study was to investigate RNA expression of adiponectin, leptin and their receptors in adipose tissue in women with class 3 obesity, with or without hypertension. Serum concentrations of these adipokines were also quantitated. Women with obesity and hypertension (n = 22) and with obesity without hypertension (n = 37) were included. All patients presented class 3 obesity, without diabetes mellitus. The expression of mRNA in: adiponectin, ADIPOR1 and ADIPOR2 was analyzed in visceral (VAT) and subcutaneous (SAT) adipose tissue; leptin and its receptor were only analyzed in SAT, by reverse transcription quantitative PCR. Measurements of adiponectin and leptin concentrations were performed using enzyme-linked immunosorbent assay kits. Analysis of mRNA expressions in VAT and SAT are presented as median and quartiles. Analysis of serum concentrations of adipokines are presented as median and percentiles 25th-75th. Women presenting a higher mean arterial pressure, had significantly higher levels of mRNA expression of adiponectin in SAT. Besides, we found several significant positive correlations of these adipokines and their receptors. In conclusion, we found that those women with a higher mean arterial pressure and receiving antihypertensive treatment, presented higher levels of mRNA expression of adiponectin in SAT.

Serum concentrations of apelin-17 isoform vary in accordance to blood pressure categories in individuals with obesity class 3.

Background: The aim of this study was to investigate if serum concentrations of apelin-36, apelin-17, apelin-13 or apelin-12 were different in obesity class 3 individuals with hypertension, when compared to those without hypertension (normal or high-normal).Subjects and Methods: Twenty six individuals with obesity class 3-related hypertension and thirty three individuals without hypertension, who were divided in individuals with normal (n = 23) or with high-normal (n = 10) blood pressure (BP) were analyzed. All individuals presented obesity class 3, without diabetes mellitus. Measurements of all apelin isoforms were performed using enzyme-linked immunosorbent assay kits. Analysis of differences between groups of Apelin isoform concentrations was performed by a One-way ANOVA, with a Tukey test post hoc.Results: The individuals of the hypertensive group presented a slightly lower serum concentration of all apelin isoforms, but these differences were not statistically significant. These results were more evident when the group of patients without hypertension were divided based in normal and high-normal BP, observing that apelin-17 isoform were higher in individuals with high-normal BP in comparison to subjects with normal BP (P = 0.018); concentrations were also higher when compared to subjects with hypertension (P = 0.004).Conclusions: To our knowledge, this is the first study regarding the differences of apelin-17 isoform concentrations in individuals pertaining to different categories of BP, who presented obesity class 3. The group of patients that presented hypertension showed a lower concentration of all isoforms. This observation could be due to the fact that these patients were taking antihypertensive medication.

Safety and Immunogenicity of a Tetravalent Dengue DNA Vaccine Administered with a Cationic Lipid-Based Adjuvant in a Phase 1 Clinical Trial.

We conducted an open label, dose escalation Phase 1 clinical trial of a tetravalent dengue DNA vaccine (TVDV) formulated in Vaxfectin® to assess safety and immunogenicity. A total of 40 dengue- and flavivirus-naive volunteers received either low-dose (1 mg) TVDV alone (N = 10, group 1), low-dose TVDV (1 mg) formulated in Vaxfectin (N = 10, group 2), or high-dose TVDV (2 mg, group 3) formulated in Vaxfectin® (N = 20). Subjects were immunized intramuscularly with three doses on a 0-, 30-, 90-day schedule and monitored. Blood samples were obtained after each immunization and various time points thereafter to assess anti-dengue antibody and interferon gamma (IFNγ) T-cell immune responses. The most common adverse events (AEs) across all groups included mild to moderate pain and tenderness at the injection site, which typically resolved within 7 days. Common solicited signs and symptoms included fatigue (42.5%), headache (45%), and myalgias (47.5%). There were no serious AEs related to the vaccine or study procedures. No anti-dengue antibody responses were detected in group 1 subjects who received all three immunizations. There were minimal enzyme-linked immunosorbent assay and neutralizing antibody responses among groups 2 and 3 subjects who completed the immunization schedule. By contrast, IFNγ T-cell responses, regardless of serotype specificity, occurred in 70%, 50%, and 79% of subjects in groups 1, 2, and 3, respectively. The largest IFNγ T-cell responses were among group 3 subjects. We conclude that TVDV was safe and well-tolerated and elicited predominately anti-dengue T-cell IFNγ responses in a dose-related fashion.

Analysis of the rs13306560 functional variant in the promoter region of the MTHFR gene in sporadic Parkinson´s disease.

OBJECTIVE: Among susceptibility genes for Sporadic Parkinson´s Disease (SPD), the MTHFR gene has been suggested as candidate. The A allele of the functional variant rs13306560 in its promoter region has been liked to decreased transactivation capacity. Therefore, we sought to determine a possible association of the rs13306560 and SPD. METHODS: In total, 237 individuals were genotyped, 113 patients with SPD diagnosed according to the Queen Square Brain Bank criteria and 124 neurologically healthy controls. Genotyping was performed using TaqMan probes for the rs13306560 and real-time PCR. RESULTS: The A allelle was associated to protection in SPD, under the dominant model, (OR=0.22, C.I.=[0.048-1.080], p=0.04), nevertheless, after logistic regression analysis with adjustment for gender, resulted only in a trend (Exp (ß)=0.211, [I.C. 95.0%, 0.042-1.057], p=0.058). CONCLUSION: Although further studies are needed, our data suggest an important role of the MTHFR gene variants in the fine-tuning regulation of one-carbon metabolism in the brain.

Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia.

Ataxia-telangiectasia is a multisystemic disease with severe neurological affectation, immunodeficiency and telangiectasia. The disorder is caused by alterations in the ATM gene, whose size and complexity make molecular diagnosis difficult. We designed a target-enrichment next-generation sequencing strategy to characterize 28 patients from several regions of Spain. This approach allowed us to identify gene variants affecting function in 54 out of the 56 alleles analyzed, although the two unresolved alleles belong to brothers. We found 28 ATM gene mutations, of which 10 have not been reported. A total of 171 gene variants not affecting function were also found, of which 22 are reported to predispose to disease. Interestingly, all Roma (Spanish Gypsies) patients are homozygous for the same mutation and share the H3 ATM haplotype, which is strong evidence of a founder effect in this population. In addition, we generated a panel of 27 primary T cell lines from A-T patients, which revealed significant expression of ATM in two patients and traces of the protein in nine more. None of them retained residual ATM activity, and almost all T cell lines show increased or intermediate radiosensitivity.

Enhanced and selective optical trapping in a slot-graphite photonic crystal.

Applicability of optical trapping tools for nanomanipulation is limited by the available laser power and trap efficiency. We utilized the strong confinement of light in a slot-graphite photonic crystal to develop high-efficiency parallel trapping over a large area. The stiffness is 35 times higher than our previously demonstrated on-chip, near field traps. We demonstrate the ability to trap both dielectric and metallic particles of sub-micron size. We find that the growth kinetics of nanoparticle arrays on the slot-graphite template depends on particle size. This difference is exploited to selectively trap one type of particle out of a binary colloidal mixture, creating an efficient optical sieve. This technique has rich potential for analysis, diagnostics, and enrichment and sorting of microscopic entities.

Polymorphisms of APLN-APLNR system are associated with essential hypertension in Mexican-Mestizo individuals.

The aim of this study was to evaluate if polymorphisms of APLN and APLNR genes may play a role as susceptibility markers for hypertension in a group of Mexican-Mestizo patients. A case-control study was carried out including normotensive and hypertensive individuals. For these, two polymorphisms of APLN (rs3761581 and rs56204867) and two of APLNR () genes were genotyped by 5' exonuclease TaqMan assay in 400 normotensive individuals and 383 patients. The results showed that, under an additive model adjusted by BMI, HDL, triglycerides, glucose and family history of essential hypertension, the rs7119375 and rs10501367 polymorphisms of APLNR gene were associated significantly with a decreased risk of essential hypertension (P=0.039 and P=0.029, respectively). Besides, the haplotypes analysis of these polymorphisms showed that H1 haplotype was associated with an increased risk of essential hypertension (P=0.026), while the H2 haplotype was associated with a decreased risk (P=0.032). Contrary, the rs3761581 and rs56204867 polymorphisms of APLN gene were not associated with essential hypertension (P=0.1707 and P=0.0769, respectively). The data suggest that APLNR rs7119375 and rs10501367 are associated with a decreased risk of essential hypertension in our Mexican-Mestizo studied group, but further studies are warranted.