Development of an Aptamer-Based Electrochemical Microfluidic Device for Viral Vaccine Quantitation.

Global deployment of vaccines poses significant challenges in the distribution and use of the accompanying immunoassays, one of the standard methods for quality control of vaccines, particularly when establishing assays in countries worldwide to support testing/release upon importation. This work describes our effort toward developing an integrated, portable device to carry out affinity assays for viral particles quantification in viral vaccines by incorporating (i) aptamers, (ii) microfluidic devices, and (iii) electrochemical detection. We generated and characterized more than eight aptamers against multiple membrane proteins of cytomegalovirus (CMV), which we used as a model system and designed and fabricated electrochemical microfluidic devices to measure CMV concentrations in a candidate vaccine under development. The aptamer-based assays provided a half maximal effective concentration, EC50, of 12 U/mL, comparable to that of an ELISA using a pair of antibodies (EC50 60 U/mL). The device measured relative CMV concentrations accurately (within ±10% bias) and precisely (11%, percent relative standard deviation). This work represents the critical first steps toward developing simple, affordable, and robust affinity assays for global deployment without the need for sensitive equipment and extensive analyst training.

Increased Ion Temperature and Neutron Yield Observed in Magnetized Indirectly Driven D_{2}-Filled Capsule Implosions on the National Ignition Facility.

The application of an external 26 Tesla axial magnetic field to a D_{2} gas-filled capsule indirectly driven on the National Ignition Facility is observed to increase the ion temperature by 40% and the neutron yield by a factor of 3.2 in a hot spot with areal density and temperature approaching what is required for fusion ignition [1]. The improvements are determined from energy spectral measurements of the 2.45 MeV neutrons from the D(d,n)^{3}He reaction, and the compressed central core B field is estimated to be ∼4.9 kT using the 14.1 MeV secondary neutrons from the D(T,n)^{4}He reactions. The experiments use a 30 kV pulsed-power system to deliver a ∼3 µs current pulse to a solenoidal coil wrapped around a novel high-electrical-resistivity AuTa_{4} hohlraum. Radiation magnetohydrodynamic simulations are consistent with the experiment.

Trade-offs between succulent and non-succulent epiphytes underlie variation in drought tolerance and avoidance.

Epiphyte communities comprise important components of many forest ecosystems in terms of biomass and diversity, but little is known regarding trade-offs that underlie diversity and structure in these communities or the impact that microclimate has on epiphyte trait allocation. We measured 22 functional traits in vascular epiphyte communities across six sites that span a microclimatic gradient in a tropical montane cloud forest region in Costa Rica. We quantified traits that relate to carbon and nitrogen allocation, gas exchange, water storage, and drought tolerance. Functional diversity was high in all but the lowest elevation site where drought likely limits the success of certain species with particular trait combinations. For most traits, variation was explained by relationships with other traits, rather than differences in microclimate across sites. Although there were significant differences in microclimate, epiphyte abundance, and diversity, we found substantial overlap in multivariate trait space across five of the sites. We found significant correlations between functional traits, many of which related to water storage (leaf water content, leaf thickness, hydrenchymal thickness), drought tolerance (turgor loss point), and carbon allocation (specific leaf area, leaf dry matter content). This suite of trait correlations suggests that the epiphyte community has evolved functional strategies along with a drought avoidance versus drought tolerance continuum where leaf succulence emerged as a pivotal overall trait.

MAOA expression predicts vulnerability for alcohol use.

The role of the monoamines dopamine (DA) and serotonin (5HT) and the monoamine-metabolizing enzyme monoamine oxidase A (MAOA) have been repeatedly implicated in studies of alcohol use and dependence. Genetic investigations of MAOA have yielded conflicting associations between a common polymorphism (MAOA-LPR) and risk for alcohol abuse. The present study provides direct comparison of tissue-specific MAOA expression and the level of alcohol consumption. We analyzed rhesus macaque MAOA (rhMAOA) expression in blood from males before and after 12 months of alcohol self-administration. In addition, nucleus accumbens core (NAc core) and cerebrospinal fluid (CSF) were collected from alcohol access and control (no alcohol access) subjects at the 12-month time point for comparison. The rhMAOA expression level in the blood of alcohol-naive subjects was negatively correlated with subsequent alcohol consumption level. The mRNA expression was independent of rhMAOA-LPR genotype and global promoter methylation. After 12 months of alcohol use, blood rhMAOA expression had decreased in an alcohol dose-dependent manner. Also after 12 months, rhMAOA expression in the NAc core was significantly lower in the heavy drinkers, as compared with control subjects. The CSF measured higher levels of DA and lower DOPAC/DA ratios among the heavy drinkers at the same time point. These results provide novel evidence that blood MAOA expression predicts alcohol consumption and that heavy alcohol use is linked to low MAOA expression in both the blood and NAc core. Together, the findings suggest a mechanistic link between dampened MAOA expression, elevated DA and alcohol abuse.

Multiparameter Particle Display (MPPD): A Quantitative Screening Method for the Discovery of Highly Specific Aptamers.

Aptamers are a promising class of affinity reagents because they are chemically synthesized, thus making them highly reproducible and distributable as sequence information rather than a physical entity. Although many high-quality aptamers have been previously reported, it is difficult to routinely generate aptamers that possess both high affinity and specificity. One of the reasons is that conventional aptamer selection can only be performed either for affinity (positive selection) or for specificity (negative selection), but not both simultaneously. In this work, we harness the capacity of fluorescence activated cell sorting (FACS) for multicolor sorting to simultaneously screen for affinity and specificity at a throughput of 107 aptamers per hour. As a proof of principle, we generated DNA aptamers that exhibit picomolar to low nanomolar affinity in human serum for three diverse proteins, and show that these aptamers are capable of outperforming high-quality monoclonal antibodies in a standard ELISA detection assay.

Integrated electrochemical microsystems for genetic detection of pathogens at the point of care.

The capacity to achieve rapid, sensitive, specific, quantitative, and multiplexed genetic detection of pathogens via a robust, portable, point-of-care platform could transform many diagnostic applications. And while contemporary technologies have yet to effectively achieve this goal, the advent of microfluidics provides a potentially viable approach to this end by enabling the integration of sophisticated multistep biochemical assays (e.g., sample preparation, genetic amplification, and quantitative detection) in a monolithic, portable device from relatively small biological samples. Integrated electrochemical sensors offer a particularly promising solution to genetic detection because they do not require optical instrumentation and are readily compatible with both integrated circuit and microfluidic technologies. Nevertheless, the development of generalizable microfluidic electrochemical platforms that integrate sample preparation and amplification as well as quantitative and multiplexed detection remains a challenging and unsolved technical problem. Recognizing this unmet need, we have developed a series of microfluidic electrochemical DNA sensors that have progressively evolved to encompass each of these critical functionalities. For DNA detection, our platforms employ label-free, single-step, and sequence-specific electrochemical DNA (E-DNA) sensors, in which an electrode-bound, redox-reporter-modified DNA "probe" generates a current change after undergoing a hybridization-induced conformational change. After successfully integrating E-DNA sensors into a microfluidic chip format, we subsequently incorporated on-chip genetic amplification techniques including polymerase chain reaction (PCR) and loop-mediated isothermal amplification (LAMP) to enable genetic detection at clinically relevant target concentrations. To maximize the potential point-of-care utility of our platforms, we have further integrated sample preparation via immunomagnetic separation, which allowed the detection of influenza virus directly from throat swabs and developed strategies for the multiplexed detection of related bacterial strains from the blood of septic mice. Finally, we developed an alternative electrochemical detection platform based on real-time LAMP, which not is only capable of detecting across a broad dynamic range of target concentrations, but also greatly simplifies quantitative measurement of nucleic acids. These efforts represent considerable progress toward the development of a true sample-in-answer-out platform for genetic detection of pathogens at the point of care. Given the many advantages of these systems, and the growing interest and innovative contributions from researchers in this field, we are optimistic that iterations of these systems will arrive in clinical settings in the foreseeable future.

Screening attendance, age group and diabetic retinopathy level at first screen.

AIMS: To report on the relationships between age at diagnosis of diabetes, time from registration with the screening programme to first diabetic eye screening and severity of diabetic retinopathy. METHODS: Data were extracted from four English screening programmes and from the Scottish, Welsh and Northern Irish programmes. Time from diagnosis of diabetes to first screening and age at diagnosis were calculated. RESULTS: Time from registration with the screening programme to first screening episode is strongly related to age at registration. Within 18 months of registration 89% of 3958 young people under 18 years of age and 81% of 391 293 people over 35 years of age were seen. In 19 058 people between 18 and 34 years of age, 80% coverage was not reached until 2 years and 9 months. The time from diagnosis of diabetes to first screening is positively associated with severity of disease (P < 0.0001). CONCLUSIONS: This report is the first that to demonstrate that those in the 18-34 year age group are least likely to attend promptly for screening after registration with a higher risk of referable diabetic retinopathy being present at the time of first screen. Date of diagnosis should be recorded and prodigious efforts made to screen all people promptly after diagnosis. Screening programmes should collect data on those who have not attended within one year of registration.

The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories.

3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine-releaser that is widely used as a recreational drug. Preliminary work has supported the potential of MDMA in psychotherapy for post-traumatic stress disorder (PTSD). The neurobiological mechanisms underlying its putative efficacy are, however, poorly understood. Psychotherapy for PTSD usually requires that patients revisit traumatic memories, and it has been argued that this is easier to do under MDMA. Functional magnetic resonance imaging (fMRI) was used to investigate the effect of MDMA on recollection of favourite and worst autobiographical memories (AMs). Nineteen participants (five females) with previous experience with MDMA performed a blocked AM recollection (AMR) paradigm after ingestion of 100 mg of MDMA-HCl or ascorbic acid (placebo) in a double-blind, repeated-measures design. Memory cues describing participants' AMs were read by them in the scanner. Favourite memories were rated as significantly more vivid, emotionally intense and positive after MDMA than placebo and worst memories were rated as less negative. Functional MRI data from 17 participants showed robust activations to AMs in regions known to be involved in AMR. There was also a significant effect of memory valence: hippocampal regions showed preferential activations to favourite memories and executive regions to worst memories. MDMA augmented activations to favourite memories in the bilateral fusiform gyrus and somatosensory cortex and attenuated activations to worst memories in the left anterior temporal cortex. These findings are consistent with a positive emotional-bias likely mediated by MDMA's pro-monoaminergic pharmacology.

The potential roles of strigolactones and brassinosteroids in the autoregulation of nodulation pathway.

BACKGROUND AND AIMS: The number of nodules formed on a legume root system is under the strict genetic control of the autoregulation of nodulation (AON) pathway. Plant hormones are thought to play a role in AON; however, the involvement of two hormones recently described as having a largely positive role in nodulation, strigolactones and brassinosteroids, has not been examined in the AON process. METHODS: A genetic approach was used to examine if strigolactones or brassinosteroids interact with the AON system in pea (Pisum sativum). Double mutants between shoot-acting (Psclv2, Psnark) and root-acting (Psrdn1) mutants of the AON pathway and strigolactone-deficient (Psccd8) or brassinosteroid-deficient (lk) mutants were generated and assessed for various aspects of nodulation. Strigolactone production by AON mutant roots was also investigated. KEY RESULTS: Supernodulation of the roots was observed in both brassinosteroid- and strigolactone-deficient AON double-mutant plants. This is despite the fact that the shoots of these plants displayed classic strigolactone-deficient (increased shoot branching) or brassinosteroid-deficient (extreme dwarf) phenotypes. No consistent effect of disruption of the AON pathway on strigolactone production was found, but root-acting Psrdn1 mutants did produce significantly more strigolactones. CONCLUSIONS: No evidence was found that strigolactones or brassinosteroids act downstream of the AON genes examined. While in pea the AON mutants are epistatic to brassinosteroid and strigolactone synthesis genes, we argue that these hormones are likely to act independently of the AON system, having a role in the promotion of nodule formation.

Learning rate and temperament in a high predation risk environment.

Living in challenging environments can influence the behavior of animals in a number of ways. For instance, populations of prey fish that experience frequent, nonlethal interactions with predators have a high proportion of individuals that express greater reaction to risk and increased activity and exploration-collectively known as temperament traits. Temperament traits are often correlated, such that individuals that are risk-prone also tend to be active and explore more. Spatial learning, which requires the integration of many sensory cues, has also been shown to vary in fish exposed to different levels of predation threat. Fish from areas of low predation risk learn to solve spatial tasks faster than fish from high predation areas. However, it is not yet known whether simpler forms of learning, such as learning associations between two events, are similarly influenced. Simple forms of associative learning are likely to be affected by temperament because a willingness to approach and explore novel situations could provide animals with a learning advantage. However, it is possible that routine-forming and inflexible traits associated with risk-prone and increased exploratory behavior may act in the opposite way and make risk-prone individuals poorer at learning associations. To investigate this, we measured temperament in Panamanian bishop fish (Brachyrhaphis episcopi) sampled from a site known to contain many predators. The B. episcopi were then tested with an associative learning task. Within this population, fish that explored more were faster at learning a cue that predicted access to food, indicating a link between temperament and basic learning abilities.

SCUAD and chronic rhinosinusitis. Reinforcing hypothesis driven research in difficult cases.

BACKGROUND: Our objective is to present recent research findings on recalcitrant chronic rhinosinusitis (CRS) in relation to "Severe Chronic Upper Airway Disease" (SCUAD). METHODOLOGY: Literature review using Medline and Em base databases (search terms 'chronic rhinosinusitis'; "chronic sinusitis" or"Severe Chronic Upper Airway Disease") limited to articles published in the English language. RESULTS: Complex pathophysiological mechanisms characterize various forms of chronic rhinitis and rhinosinusitis (CRS), where inflammation persists in spite of adequate medical treatment. In these cases, a multifactorial etiology often underlies the development of sino-nasal inflammation. The interaction between chronic upper and lower airway inflammation via neurogenic and systemic pathways may complicate the therapy of these patients, and lead to insufficient symptom control. CONCLUSION: The recently introduced definition of"Severe Chronic Upper Airway Disease" (SCUAD) increases awareness of those patients with persistent inflammation and symptoms despite guideline-driven pharmacologic treatment. The concept of SCUAD may prove helpful in directing research towards clarifying the definition, diagnosis and pathophysiology of rhinitis and rhinosinusitis,their limits and overlap. In this review, a hypothesis on SCUAD immunopathology is also presented.

Accurate zygote-specific discrimination of single-nucleotide polymorphisms using microfluidic electrochemical DNA melting curves.

We report the first electrochemical system for the detection of single-nucleotide polymorphisms (SNPs) that can accurately discriminate homozygous and heterozygous genotypes using microfluidics technology. To achieve this, our system performs real-time melting-curve analysis of surface-immobilized hybridization probes. As an example, we used our sensor to analyze two SNPs in the apolipoprotein E (ApoE) gene, where homozygous and heterozygous mutations greatly affect the risk of late-onset Alzheimer's disease. Using probes specific for each SNP, we simultaneously acquired melting curves for probe-target duplexes at two different loci and thereby accurately distinguish all six possible ApoE allele combinations. Since the design of our device and probes can be readily adapted for targeting other loci, we believe that our method offers a modular platform for the diagnosis of SNP-based diseases and personalized medicine.

Towards Harmonized Adolescent Health Measurement: Assessing Alignment Between Current Recommendations and the Global Action for Measurement of Adolescent Health-Recommended Indicators.

PURPOSE: This study identified alignment of indicators across different initiatives and data collection instruments as a foundation for future harmonization of adolescent health measurement. METHODS: Using the Global Action for Measurement of Adolescent health (GAMA) recommended indicators as the basis for comparison, we conducted a desk review of 14 global-level initiatives, such as the Sustainable Development Goals and the Global Strategy for Women's, Children's and Adolescents' Health, and five multicountry survey programs, such as the Multiple Indicator Cluster Surveys and the Global school-based Student Health Survey. We identified initiative and survey indicators similar to a GAMA indicator, deconstructed indicators into standard elements to facilitate comparison, and assessed alignment to the corresponding GAMA indicator across each of the elements. RESULTS: A total of 144 initiative indicators and 90 survey indicators were identified. Twenty-four initiative indicators (17%) and 14 survey indicators (16%) matched the corresponding GAMA indicators across all elements. Population of interest was the most commonly discrepant element; whereas GAMA indicators mostly refer to ages 10-19, many survey and initiative indicators encompass only part of this age range, for example, 15-19-year-olds as a subset of adults ages 15-49 years. An additional 53 initiative indicators (39%) and 44 survey indicators (49%) matched on all elements except the population of interest. DISCUSSION: The current adolescent measurement landscape is inconsistent, with differing recommendations on what and how to measure. Findings from this study support efforts to promote indicator alignment and harmonization across adolescent health measurement stakeholders at the global, regional, and country levels.

Indicators to Measure Adolescent Health at the Country, Regional, and Global Levels: Results of a Five-Year Selection Process by the Global Action for the Measurement of Adolescent Health.

PURPOSE: To improve adolescent health measurement, the Global Action for the Measurement of Adolescent health (GAMA) Advisory Group was formed in 2018 and published a draft list of 52 indicators across six adolescent health domains in 2022. We describe the process and results of selecting the adolescent health indicators recommended by GAMA (hereafter, "GAMA-recommended indicators"). METHODS: Each indicator in the draft list was assessed using the following inputs: (1) availability of data and stakeholders' perceptions on their relevance, acceptability, and feasibility across selected countries; (2) alignment with current measurement recommendations and practices; and (3) data in global databases. Topic-specific working groups comprised of GAMA experts and representatives of United Nations partner agencies reviewed results and provided preliminary recommendations, which were appraised by all GAMA members and finalized. RESULTS: There are 47 GAMA-recommended indicators (36 core and 11 additional) for adolescent health measurement across six domains: policies, programs, and laws (4 indicators); systems performance and interventions (4); health determinants (7); health behaviors and risks (20); subjective well-being (2); and health outcomes and conditions (10). DISCUSSION: These indicators are the result of a robust and structured five-year process to identify a priority set of indicators with relevance to adolescent health globally. This inclusive and participatory approach incorporated inputs from a broad range of stakeholders, including adolescents and young people themselves. The GAMA-recommended indicators are now ready to be used to measure adolescent health at the country, regional, and global levels.

Exploring a Preliminary Set of Indicators to Measure Adolescent Health: Results From a 12-Country Feasibility Study.

PURPOSE: To explore data availability, perceived relevance, acceptability and feasibility of implementing 52 draft indicators for adolescent health measurement in different countries globally. METHODS: A mixed-methods, sequential explanatory study was conducted in 12 countries. An online spreadsheet was used to assess data availability and a stakeholder survey to assess perceived relevance, acceptability, and feasibility of implementing each draft indicator proposed by the Global Action for Measurement of Adolescent health (GAMA). The assessments were discussed in virtual meetings with all countries and in deep dives with three countries. Findings were synthesized using descriptive statistics and qualitative thematic analysis. RESULTS: Data availability varied across the 52 draft GAMA indicators and across countries. Nine countries reported measuring over half of the indicators. Most indicators were rated relevant by stakeholders, while some were considered less acceptable and feasible. The ten lowest-ranking indicators were related to mental health, sexual health and substance use; the highest-ranking indicators centered on broader adolescent health issues, like use of health services. Indicators with higher data availability and alignment with national priorities were generally considered most relevant, acceptable and feasible. Barriers to measurement included legal, ethical and sensitivity issues, challenges with multi-sectoral coordination and data systems flexibility. DISCUSSION: Most of the draft GAMA indicators were deemed relevant and feasible, but contextual priorities and perceived acceptability influenced their implementation in countries. To increase their use for a more comprehensive understanding of adolescent health, better multi-sectoral coordination and tailored capacity building to accommodate the diverse data systems in countries will be required.

Time-resolved X-ray diffraction diagnostic development for the National Ignition Facility.

We present the development of an experimental platform that can collect four frames of x-ray diffraction data along a single line of sight during laser-driven, dynamic-compression experiments at the National Ignition Facility. The platform is comprised of a diagnostic imager built around ultrafast sensors with a 2-ns integration time, a custom target assembly that serves also to shield the imager, and a 10-ns duration, quasi-monochromatic x-ray source produced by laser-generated plasma. We demonstrate the performance with diffraction data for Pb ramp compressed to 150 GPa and illuminated by a Ge x-ray source that produces ∼7 × 1011, 10.25-keV photons/ns at the 400 µm diameter sample.

Setting research priorities for adolescent sexual and reproductive health in low- and middle-income countries.

OBJECTIVE: To conduct an expert-led process for identifying research priorities in adolescent sexual and reproductive health in low- and middle-income countries. METHODS: The authors modified the priority-setting method of the Child Health and Nutrition Research Initiative (CHNRI) to obtain input from nearly 300 researchers, health programme managers and donors with wide-ranging backgrounds and experiences and from all geographic regions. In a three-Phase process, they asked these experts to: (i) rank outcome areas in order of importance; (ii) formulate research questions within each area, and (iii) rank the formulated questions. FINDINGS: seven areas of adolescent sexual and reproductive health were identified as important: (i) maternal health; (ii) contraception; (iii) gender-based violence; (iv) treatment and care of patients with human immunodeficiency virus (HIV) infection; (v) abortion; (vi) integration of family planning and HIV-related services and (vii) sexually transmitted infections. Experts generated from 30 to 40 research questions in each area, and to prioritize these questions, they applied five criteria focused on: clarity, answerability, impact, implementation and relevance for equity. Rankings were based on overall mean scores derived by averaging the scores for individual criteria. Experts agreed strongly on the relative importance of the questions in each area. CONCLUSION: Research questions on the prevalence of conditions affecting adolescents are giving way to research questions on the scale-up of existing interventions and the development of new ones. CHNRI methods can be used by donors and health programme managers to prioritize research on adolescent sexual and reproductive health.

Résumé OBJECTIF: Établir un processus, sous la direction d'experts, visant à identifier les priorités de la recherche en matière de santé sexuelle et reproductive chez l'adolescent dans les pays à revenu faible et moyen. MÉTHODES: Les auteurs ont modifié la méthode d'établissement des priorités de l'Initiative pour la recherche en santé et nutrition infantiles (CHNRI) afin d'obtenir la contribution de près de 300 chercheurs, gestionnaires de programmes de santé et donateurs, de formation et d'expérience très diverses, et provenant de toutes les régions géographiques. Dans le cadre d'un processus en trois phases, ils ont demandé à ces experts de: (i) classer les domaines de résultats par ordre d'importance, (ii) formuler des questions de recherche au sein de chaque domaine, et (iii) classer les questions formulées. RÉSULTATS: Sept domaines de la santé sexuelle et reproductive des adolescents ont été identifiés comme importants: (i) la santé maternelle; (ii) la contraception; (iii) la violence sexiste; (iv) le traitement et les soins des patients infectés par le virus de l'immunodéficience humaine (VIH); (v) l'avortement; (vi) l'intégration de la planification familiale et des services liés au VIH et (vii) les infections sexuellement transmissibles. Les experts ont généré de 30 à 40 questions de recherche dans chaque domaine. Pour déterminer le caractère prioritaire de ces questions, ils ont appliqué cinq critères: clarté, capacité de réponse, impact, mise en œuvre et pertinence en termes d'équité. Les classements se basaient sur les scores moyens généraux, dérivés de la moyenne des scores pour les critères individuels. Les experts étaient entièrement d'accord sur l'importance relative des questions dans chaque domaine. CONCLUSION: Les questions de recherche sur la prévalence des maladies qui affectent les adolescents cèdent la place à des questions de recherche sur l'intensification des interventions existantes et le développement de nouvelles interventions. Les méthodes de la CHNRI peuvent être utilisées par les donateurs et les gestionnaires de programmes de santé pour fixer les priorités de la recherche sur la santé sexuelle et reproductive chez les adolescents.

Resumen OBJETIVO: Llevar a cabo un proceso dirigido por expertos a fin de identificar las prioridades en la investigación sobre la salud sexual y reproductiva de los adolescentes en países con ingresos bajos y medios. MÉTODOS: Los autores modificaron el método de establecimiento de prioridades de la Iniciativa de Salud del Niño e Investigación Nutricional para conseguir la contribución de casi 300 investigadores, gestores de programas sanitarios y donantes con diversas trayectorias y experiencias y procedentes de todas las regiones geográficas. En un proceso que constó de tres fases, se solicitó a dichos expertos que: (i) clasificaran las áreas de resultados según su importancia; (ii) formularan temas de investigación en cada área y (iii) clasificaran los temas formulados. RESULTADOS: Se identificaron como importantes siete áreas de la salud sexual y reproductiva de los adolescentes: (i) la salud materna; (ii) la anticoncepción; (iii) la violencia de género; (iv) el tratamiento y cuidado de los pacientes con el virus de la inmunodeficiencia humana (VIH); (v) el aborto; (vi) la unificación de la planificación familiar y los servicios relacionados con el VIH y (vii) las infecciones de transmisión sexual. Los expertos crearon entre 30 y 40 temas de investigación en cada área y, con objeto de priorizar dichos temas, aplicaron cinco criterios: claridad, responsabilidad, impacto, aplicación y pertinencia para la equidad. Las clasificaciones se basaron en las puntuaciones medias globales obtenidas al calcular el promedio de las puntuaciones de los criterios individuales. Los expertos coincidieron en la importancia relativa de los temas en cada área. CONCLUSIÓN: Los temas de investigación sobre el predominio de las situaciones que afectan a los adolescentes dan paso a temas que tratan tanto la ampliación de las intervenciones existentes como el desarrollo de nuevas intervenciones. Tanto donantes como gestores de programas sanitarios pueden emplear los métodos de la Iniciativa de Salud del Niño e Investigación Nutricional para establecer las prioridades en la investigación sobre la salud sexual y reproductiva de los adolescentes.

Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia.

X-linked hypohidrotic ectodermal dysplasia results in abnormal morphogenesis of teeth, hair and eccrine sweat glands. The gene (ED1) responsible for the disorder has been identified, as well as the analogous X-linked gene (Ta) in the mouse. Autosomal recessive disorders, phenotypically indistinguishable from the X-linked forms, exist in humans and at two separate loci (crinkled, cr, and downless, dl) in mice. Dominant disorders, possibly allelic to the recessive loci, are seen in both species (ED3, Dlslk). A candidate gene has recently been identified at the dl locus that is mutated in both dl and Dlslk mutant alleles. We isolated and characterized its human DL homologue, and identified mutations in three families displaying recessive inheritance and two with dominant inheritance. The disorder does not map to the candidate gene locus in all autosomal recessive families, implying the existence of at least one additional human locus. The putative protein is predicted to have a single transmembrane domain, and shows similarity to two separate domains of the tumour necrosis factor receptor (TNFR) family.

X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein.

Ectodermal dysplasias comprise over 150 syndromes of unknown pathogenesis. X-linked anhidrotic ectodermal dysplasia (EDA) is characterized by abnormal hair, teeth and sweat glands. We now describe the positional cloning of the gene mutated in EDA. Two exons, separated by a 200-kilobase intron, encode a predicted 135-residue transmembrane protein. The gene is disrupted in six patients with X;autosome translocations or submicroscopic deletions; nine patients had point mutations. The gene is expressed in keratinocytes, hair follicles, and sweat glands, and in other adult and fetal tissues. The predicted EDA protein may belong to a novel class with a role in epithelial-mesenchymal signalling.