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The mating system and microevolution.

Studies of natural and experimental plant populations have revealed that genotypic frequency distributions are highly structured in predominantly selfing species. This high degree of genetic organization is manifested in intense correlations in allelic state over loci and also in striking micro-geographical heterogeneity. Both aspects of this structure are facilitated by self-fertilization. Development of non-random associations of alleles within populations is facilitated because inbreeding reduces heterozygosity and thus also the randomizing effect of recombination. Spatial differentiation is facilitated because self-fertilization retards gene flow from population to population. The effect of organizing the entire populational genotype into a sort of giant supergene is to increase the frequency in the population of genotypes which confers high fitness and hence to increase adaptation to the local environment. However the recombinational potential remains substantial. As a result considerable free genetic variability remains in the population and it is available for long-term response to natural selection. Thus the organization of genetic variability within populations provides for high immediate fitness and also for flexibility to meet longer term evolutionary needs. At the same time selfing is a barrier to migration and it promotes the development and maintenance of different multilocus organizations in adjacent populations occupying unlike habitats. In total, therfore, a pattern of genetic differentiation develops in space which is an almost exact overlay of the environmental heterogeneity. The plant genetic and plant breeding literature contains extensive evidence that the mating system in plants can be modified simply and drastically by selection and that different populations within the same species often practice very different amounts of inbreeding. Considering the ease with which the mating system can be altered, and the benefits of adjusting genetic variability through regulation of the mating system, it is not surprising that a high proportion of flowering plants self-fertilize to some extent and that at least one-third of species have adopted predominant selfing as a strategy in ecogenetic adaptation.

Adaptation, Biological↗

Lifetime fitness of short- and long-distance dispersing great reed warblers.

Dispersal is of prime importance for many evolutionary processes and has been studied for decades. The reproductive consequences of dispersal have proven difficult to study, simply because it is difficult to keep track of dispersing individuals. In most previous studies evaluating the fitness effects of dispersal, immigrants at a study locality have been lumped into one category and compared to philopatric individuals. This is unfortunate, because there are reasons to believe that immigrants with long and short dispersal distances may differ substantially in reproductive success. In the present study, we used a combination of capture-recapturing and multilocus microsatellite genotyping to categorize great reed warblers at our Swedish study site as philopatric individuals or short- or long-distance dispersing immigrants. We then performed novel comparisons of lifetime reproductive success (LRS) and survival rates of these three dispersal categories. The birds belonged to cohorts 1987-1996, and data for their LRS were gathered between 1988 and 2003. The analyses showed that philopatric males attracted more females, produced more fledglings and recruits throughout their lives, and survived better than immigrants. Among the immigrant males, those categorized as long-distance dispersers had lowest LRS and survival probability. Models that included covariates of potential importance showed that the difference in LRS between dispersal categories was partly caused by corresponding variation in number of breeding years at our study site. These results indicate that short- and, in particular, long-distance dispersers were of poor phenotypic quality, but it may also be proposed that immigrants attracted few females because they were poorly adapted to the local social environment. In females, the number of local recruits corrected for the number of breeding years (as well as for number of fledglings) differed between dispersal categories in a pattern that suggests an intermediate optimal dispersal distance. Short-distance dispersers recruited more offspring per year (and per fledgling) than both philopatric individuals and long-distance dispersers. Data suggest that the low LRS of philopatric females was related to costs of inbreeding. The low LRS of long-distance dispersing females may have resulted from their offspring being especially prone to disperse outside the study area, but also other potential explanations exist, such as local maladaptation. Our study highlights the importance of separating immigrant birds on the basis of their genetic similarity to the local study population when analyzing variation in LRS and inferring realized gene flow.

Animals↗

Genomic diversity and selection signatures in Asian Zebu Cattle: insights into adaptation and genetic erosion.

Indigenous cattle breeds in Asia are highly adapted to their local environments providing essential commodities such as meat, milk and draught power while also playing a key role in traditional ceremonies, and sports. Despite ongoing efforts to characterize and conserve these breeds, the increasing trend of indiscriminate crossbreeding of Zebu cattle with high-yielding taurine breeds, threatens their genetic diversity. This study investigates the population structure, inbreeding levels, effective population size, gene flow and identification of selection footprints of Asian Zebu (Bos indicus) cattle. Using an Axiom 60 K SNP chip, we analyzed genotypes from 1303 cattle across 36 populations in nine countries, including seven taurine outgroups and 29 Zebu populations from Bangladesh, Cambodia, India, Myanmar, Pakistan, and Sri Lanka. Zebu populations demonstrated moderate genetic diversity, with heterozygosity levels averaging 0.356, inbreeding coefficients ranging from 0.026 to 0.074 and genetic differentiation (FST) varied between 0.01 and 0.11. Breed clusters aligned closely with their geographic locations except for Achai (Pakistan) and Baru Harak (Sri Lanka) breeds that appeared in both Zebu and taurine clusters indicating evidence of taurine admixture. Genomic analyses identified regions under selection using extended haplotype homozygosity (EHH) and fixation index (FST) methods. Candidate genes associated with key biological functions related to environmental responsiveness, including heat tolerance (HSP90AA1), immunity (RIPK3), metabolism and fertility (REC8, CLIC4, TSSK4), were identified, reflecting adaptive traits critical for Zebu survival and utility across diverse environments. These findings provide valuable insights for conservation and management strategies aimed at preserving the unique genetic diversity of Asian Bos indicus breeds.

Animals↗

Dose-dependent competitive block by topical acetylsalicylic and salicylic acid of low pH-induced cutaneous pain.

In a human acid pain model, which uses continuous intradermal pressure infusion of a phosphate-buffered solution (pH 5.2) to induce localized non-adapting pain, the flow was adjusted to result in constant pain ratings of about 20% or 50% on a visual analog scale (VAS). Six volunteers in each group participated in 4 different placebo-controlled double-blind cross-over studies to measure rapidly evolving cutaneous analgesia from topically applied new ointment formulations of acetylsalicylic acid (ASA) and salicylic acid (SA) as well as of commercial ibuprofen and benzocain creams. Similar, log-linear dose-response curves were found for both ASA and SA, significant in effect at 3 g/kg and higher drug contents and reaching saturation level at 15 or 30 g/kg, respectively, which, 20 min after application, caused a mean pain suppression of 95% using ASA and 80% using SA. Half-maximal effects were achieved using 3 g/kg ASA or 15 g/kg SA. The SA action was also clearly slower to develop. With an increased flow of the acidic buffer, producing lower effective tissue pH and more intense pain, the effect of ASA and SA decreased to 73% pain suppression. A competitive mechanism of both drug effects was suggested by the fact that, with 15 g/kg ASA and SA, pain reduction could be reversed by increasing the buffer flow by a factor of 1.75, on average. Commercial ibuprofen (50 g/kg) and benzocain creams (100 g/kg) were comparably as effective as ASA and SA, but the local anesthetic caused a loss of all cutaneous sensations while the touch threshold (von Frey) under the specific analgesics was the same as under the placebo ointment. Thus, topical applications of non-steroidal anti-inflammatory drugs (NSAIDS) dissolved in different ointment formulations have proven dose-dependently effective and specific in suppressing experimental acidotic pain by a local and competitive mechanism.

Administration, Topical↗

Specific properties of the extracellular chondroitin sulphate proteoglycans in the mandibular condylar growth centre in pigs.

The developing condylar cartilage of the temporomandibular joint responds to changes in load by adaptive growth. Because local regulatory events taking place during growth processes are not well understood, investigation of extracellular matrix composition could provide new information about which matrix molecules are involved in the regulation of growth processes in this avascular tissue. The large chondroitin sulphate-rich proteoglycans in the mandibular condyle were compared to the proteoglycans in the weight-bearing femoral condyle of juvenile domestic pigs with respect to their buoyant density, chemical composition and immunological identity after isolation by dissociative extraction and CsCl density-gradient centrifugation. The distribution of these proteoglycans was studied in cryosections of mandibular condyle by immunohistochemistry using polyclonal antibodies produced against pig large proteoglycans. In the mandibular condyle, predominantly in the articular zone, the relative amount of proteoglycans with a low glycosaminoglycan content was greater than in femoral cartilage. The large proteoglycan immunologically related to aggrecan gave a protein core of 450 kDa after enzymatic deglycosylation and clearly possessed less keratan sulphate than in femoral aggrecan. Furthermore, the mandibular tissue contained another large proteoglycan with a protein core of 550 kDa after enzymatic deglycosylation, which was immunologically related to the fibroblast-like versican. Immunohistochemistry showed aggrecan increasing in amount inferiorly. In contrast, "versican' was exclusively found in the fibrous and differentiation layers. Aggrecan is mainly responsible for shock absorption and versican and its homologues may be involved in the control of cell proliferation and differentiation. Thus the matrix components of the mandibular condyle seem to be adapted to its special functional needs including parallel articulation and growth.

Aggrecans↗

Implementing global knowledge in local practice: a WHO lung health initiative in Nepal.

Clinical practice guidelines are used widely to improve the quality of primary health care in different health systems, including those of low-income countries. Often developed at international level and adapted to national contexts to increase the feasibility of effective uptake, guideline initiatives aim to transfer global scientific knowledge into local practice. The WHO's Practical Approach to Lung Health (PAL) is an example of such an initiative and is currently being developed to improve the quality of care for youths and adults with respiratory diseases. We assessed ex-ante the feasibility of successful implementation of PAL in a pilot programme in rural Nepal, studying three components: the quality of the innovation (i.e. the guidelines), the effectiveness of the implementation strategy (i.e. training) and the receptiveness of the social system of health staff at all levels (i.e. social and organizational characteristics). We assessed the guideline innovation with the AGREE instrument for guidelines, the intended implementation strategy by critical comparison with literature on effective strategies, and the social system with both a stakeholder analysis and a descriptive analysis of the health care system at district level. This ex-ante assessment of an adaptive local implementation of international WHO guidelines showed that in July 2002 the 'implementability' of the package was challenged on the three components studied. To increase the chances of successful implementation, the national guideline development process should be improved and the implementation strategy needs to be upgraded. In order to successfully transfer global knowledge into local practice, we need to develop additional multifactorial sustained interventions that tackle other culture-specific and health system-specific barriers as well. The primary health workers are key informants for these barriers.

Community Health Services↗

Improving the use of research evidence in guideline development: 10. Integrating values and consumer involvement.

BACKGROUND: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 10th of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. OBJECTIVES: We reviewed the literature on integrating values and consumers in guideline development. METHODS: We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We reviewed the titles of all citations and retrieved abstracts and full text articles if the citations appeared relevant to the topic. We checked the reference lists of articles relevant to the questions and used snowballing as a technique to obtain additional information. We did not conduct a full systematic review ourselves. Our conclusions based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. KEY QUESTIONS AND ANSWERS: We did not find a systematic review of methods for integrating values in guidelines, but we found several systematic reviews that dealt with related topics. Whose values should WHO use when making recommendations? Values, the relative importance or worth of a state or consequences of a decision (outcomes relating to benefits, harms, burden and costs), play a role in every recommendation. Ethical considerations, concepts that determine what is right, also play a role. The values used in making recommendations should reflect those of the people affected. Judgements should be explicit and should be informed by input from those affected (including citizens, patients, clinicians and policy makers). When differences in values may lead to different decisions or there is uncertainty about values, this should also be explicit. If differences in values are likely to affect a decision, such that people in different setting would likely make different choices about interventions or actions based on differences in their values, global recommendations should be explicit in terms of which values were applied and allow for adaptation after incorporating local values. How should WHO ensure that appropriate values are integrated in recommendations? All WHO guideline groups should uniformly apply explicit, transparent and clearly described methods for integrating values. WHO should consider involving relevant stakeholders if this is feasible and efficient. WHO should develop a checklist for guidelines panels to help them to ensure that ethical considerations relevant to recommendations are addressed explicitly and transparently. How should users and consumers be involved in generating recommendations? Including consumers in groups that are making global recommendations presents major challenges with respect to the impossibility of including a representative spectrum of consumers from a variety of cultures and settings. Nonetheless, consideration should be given to including consumers in groups who are able to challenge assumptions that are made about the values used for making recommendations, rather than represent the values of consumers around the world. WHO should establish a network to facilitate involvement of users. Draft recommendations should be reviewed by consumers, who should be asked explicitly to consider the values that were used. How should values be presented in recommendations? Recommendations should include a description of how decisions were made about the relative importance of the consequences (benefits, harms and costs) of a decision. Values that influence recommendations should be reported along with the research evidence underlying recommendations. When differences in values would lead to different decisions or there is important uncertainty about values that are critical to a decision, this should be flagged and reflected in the strength of the recommendation. Adaptable guideline templates that allow for integration of different values should be developed and used when differences in values are likely to be critical to a decision.

Journal Article↗

Dose response of A/Alaska/6/77 (H3N2) cold-adapted reassortant vaccine virus in adult volunteers: role of local antibody in resistance to infection with vaccine virus.

An attenuated influenza A candidate vaccine virus, derived from the A/Ann Arbor/6/60 (H2N2) cold-adapted (ca) donor virus and the A/Alaska/6/77 (H3N2) wild-type virus, was evaluated in adult seronegative volunteers (serum hemagglutination-inhibiting antibody titer, less than or equal to 1:8) for level of attenuation, infectivity, antigenicity, and genetic stability. Four groups with similar preinoculation mean titers of serum and nasal wash antibodies were inoculated intranasally with 10(4.5), 10(5.5), 10(6.5), or 10(7.5) 50% tissue culture infectious doses (TCID50) of the ca reassortant virus, and eight other seronegative adult volunteers received the wild-type virus. Only 2 of 66 vaccinees developed fever or mild and brief systemic or upper respiratory tract illness or both. Both volunteers with vaccine-related reactions received the highest dose (10(7.5) TCID50) of ca virus, which indicates that the vaccine retains some mild reactogenicity at a high dosage. In contrast, four of eight volunteers infected with the wild-type virus became ill. Each of the 54 isolates tested retained the temperature-sensitive phenotype of the vaccine virus. Thus, the ca reassortant was genetically stable and attenuated at 10(4.5) to 10(7.5) TCID50 for seronegative adults. The 50% human infective dose of ca virus was approximately 10(5.3) TCID50. Ten and one hundred 50% human infectious doses infected 73 and 83% of vaccinees, respectively, and approximately 75% developed an immunological response at these doses. The failure of the vaccine virus to infect some volunteers was correlated with the presence of pre-inoculation nasal wash immunoglobulin A hemagglutinin antibody.

Adult↗

High intensity exercise decreases global brain glucose uptake in humans.

Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro-deoxy-glucose ([18F]FDG). Fourteen healthy, right-handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6+/-4.6 versus 26.1+/-5.0 micromol (100 g)-1 min-1, P<0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37% versus 20%, P<0.05 between 30% and 75% of VO2max) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.

Blood Glucose↗

Plasticity in human directional hearing.

Interaural time difference (ITD), the main cue for localization of low-frequency sound in azimuth, is widely thought to be evaluated according to Jeffress' model. This theory proposes that each of an array of neurons detects coinciding input from both ears, conducted along axonal delay lines, with the azimuth angle corresponding to the activation of selected neurons. Thus, sound source localization is assumed to depend on axon conduction velocities, a relatively fixed parameter. Clinical experience suggests that directional hearing is adaptable. We investigated if sound localization in azimuth could adapt plastically to altered ITDs. We equipped binaural insert hearing aids with adjustable electronic delay lines. Subjects with normal hearing were required to wear these devices during all waking hours for several days. Localization of an invisible sound source was measured in an anechoic room before and at various intervals after introduction of a constant delay in one ear between 171 and 684 mus. Test sounds were high-pass, low-pass and broad-band noises. Introduction of a delay in one ear lead to an immediate displacement of the perceived sound location towards the opposite side. Within hours of exposure, the displacement was reduced, and further normalization of the perceived localization occurred over several days. After removal of the delays sound localization normalized rapidly. We conclude that ITD alterations can lead to plastic adaptation of directional hearing, which cannot rely exclusively on fixed axon conduction velocities. Our results suggest additional mechanisms for directional hearing on the basis ITD.

Acoustic Stimulation↗

Use of clinical practice guidelines in managed care physician groups.

There is increasing interest in the use of clinical guidelines as a tool to improve the quality and cost-effectiveness of health care. Yet, relatively little data are available regarding the use of guidelines by health care provider organizations. We developed a written descriptive survey investigating the development, implementation, and evaluation of clinical guidelines that was administered to medical directors or their designees from physician medical groups and independent practice associations. Eighty-seven percent of physician organizations were reported to be developing or implementing clinical guidelines. The reasons most often cited for developing clinical guidelines were quality improvement and cost containment. Local expert opinion or judgment was rated as the most important influence in the development of clinical guidelines, followed by medical and scientific literature and externally developed guidelines. Feedback of information was the most popular method of increasing compliance with clinical guidelines, although 19% of physician organizations reported imposing sanctions on physicians who did not use guidelines. Most of the physician organizations surveyed have embraced clinical guidelines. Local development or adaptation of clinical guidelines may be common. There has been disproportionately little attention paid to guideline implementation and to evaluation of guideline effects relative to their development.

California↗

Functional-cranial approach to the influence of economic strategy on skull morphology.

Environmental factors are assumed to play an important role in the shaping of craniofacial morphology. Here we propose a statistical approach which can be of utility in estimating the magnitude and localization of a particular nongenetic factor upon the specific functional components of the skull. Our analysis is a combination of previous attempts of apportionment of variance and the application of craniofunctional theory. The effect of subsistence strategy on craniofacial functional components was studied on 18 populations of hunter-gatherers and farmers from South America. Results demonstrate that the environmental factors studied likely influenced the masticatory component's size and shape. Even when this effect is not large enough to clearly differentiate among subsistence strategies (since whole craniofacial variation among populations remains greater), the method used here provides interesting clues to localize plastic or adaptive responses to external stimuli.

Biological Evolution↗

Prediction of volumetric productivity of an outdoor photobioreactor.

Volumetric productivity of Monodus subterraneus cultivated in an outdoor pilot-plant bubble column was predicted with a mathematical model. Two border cases to model the photobioreactor were chosen. Firstly, a model with no light integration in which it is assumed that microalgae can adapt immediately to local light conditions. Secondly, full light integration implicating that microalga can convert all absorbed light with a photosynthetic yield based on average light intensity. Because temperature and light conditions in our photobioreactor changed during the day, photosynthetic yields at any combination of temperature and light intensity were needed. These were determined in repeated-batch lab-scale experiments with an experimental design. The model was evaluated in an outdoor bubble column at different natural light conditions and different temperatures. Volumetric productivities in the bubble column were predicted and compared with experimental volumetric productivities. The light integration model over-estimated productivity, while the model in which we assumed no light integration under-estimated productivity. Light integration occurred partly (47%) during the period investigated. The average observed biomass yield on light was 0.60 g.mol(-1). The model of partly light integration predicted an average biomass yield on light of 0.57 g.mol(-1) and predicted that productivity could have been increased by 19% if culture temperature would have been maintained at 24 degrees C.

Bioreactors↗

Health sector reform and STD/AIDS control in resource poor settings--the case of Tanzania.

Integration in health sector reform tends to mean horizontal interaction between vertical programmes. This can result in a larger more complex system than a set of individual vertical programmes. This article looks at the HIV/AIDS programme in Tanzania and the possible impact of system-wide health sector reform involving 'decentralization' and horizontal integration. It implies that the build-up to reform is likely to be costly, at least initially (although eventually the system may become more cost-effective). Integration can thus save resources, but it will also demand additional inputs, and may lead to reduced service output if operations depend on horizontal functions that fail to deliver. The objective of reform must be to create a reasonably sized, well-balanced, system which aims to maximize the output of quality services, both preventive and curative, and to facilitate community efforts to improve health. It is doubtful whether present reform efforts in Tanzania will contribute to more effective services, if not based on a more thorough analysis adapted to the local situation and given considerably more resources, both human and financial. There is also a risk that key preventive programmes, such as those aimed at the control of STD/AIDS, will be further weakened because of both integration with subsequent dependence on poorly functioning horizontal units and reduction in allocated resources.

Acquired Immunodeficiency Syndrome↗

Toward dynamic isotopomer analysis in the rat brain in vivo: automatic quantitation of 13C NMR spectra using LCModel.

The LCModel method was adapted to analyze localized in vivo (13)C NMR spectra obtained from the rat brain in vivo at 9.4 T. Prior knowledge of chemical-shifts, J-coupling constants and J-evolution was included in the analysis. Up to 50 different isotopomer signals corresponding to 10 metabolites were quantified simultaneously in 400 microl volumes in the rat brain in vivo during infusion of [1,6-(13)C(2)]glucose. The analysis remained accurate even at low signal-to-noise ratio of the order of 3:1. The relative distribution of isotopomers in glutamate, glutamine and aspartate determined in vivo in 22 min was in excellent agreement with that measured in brain extracts. Quantitation of time series of (13)C spectra yielded time courses of total (13)C label incorporation into up to 16 carbon positions, as well as time courses of individual isotopomer signals, with a temporal resolution as low as 5 min (dynamic isotopomer analysis). The possibility of measuring in vivo a wealth of information that was hitherto accessible only in extracts is likely to expand the scope of metabolic studies in the intact brain.

Algorithms↗

Starting an adolescent cancer unit: why does it take so long?

A pragmatic approach is discussed based on the authors' differing experiences while designing new units specifically for adolescents with cancer in Leeds and Newcastle upon Tyne. Planning and implementation are complex and very time consuming. Areas to be considered include: formally identifying needs and adapting to existing local circumstances, convening a working group and involving potential stakeholders at an early stage, designing a suitable physical space, recruiting and integrating staff to create a supportive environment, obtaining financial support, and developing operational policies. For successful running of an adolescent unit, old prejudices must be disavowed and new models of medical care considered.

Adolescent↗

Detection of neural activity in fMRI using maximum correlation modeling.

A technique for detecting neural activity in functional MRI data is introduced. It is based on a novel framework termed maximum correlation modeling. The method employs a spatial filtering approach that adapts to the local activity patterns, which results in an improved detection sensitivity combined with good specificity. A spatially varying hemodynamic response is simultaneously modelled by a sum of two gamma functions. Comparisons to traditional analysis methods are made using both synthetic and real data. The results indicate that the maximum correlation modeling approach is a strong alternative for analyzing fMRI data.

Brain↗

Intraoperative detection of pheochromocytoma with iodine-125 labelled meta-iodobenzylguanidine: a feasibility study.

We evaluated the feasibility of intraoperative detection of pheochromocytoma sites after injection of meta-iodobenzylguanidine labelled with iodine-125. Six patients with multiple or recurrent pheochromocytoma were injected for intraoperative detection. During surgery, all count rates were recorded using a CdTe detector diode. Tumour foci were found in all cases. Tumour count rates ranged from 50 to 1000 counts per second (mean approximately 400). Blood activity, used as a reference level, ranged from 10 to 50 counts per second (mean approximately 35). In all patients, the intraoperative probe was helpful to the surgeon and facilitated the discovery of the pathological foci even when they were small (< or = 1 cm). Complete resection under probe control was correlated with postoperative normalization of urinary normetanephrine excretion. The use of a probe designed to detect low-energy gamma-ray radionuclides bound to a highly specific molecule provides an accurate detection tool which is well adapted for ectopic localizations and for small foci.

3-Iodobenzylguanidine↗