On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model

During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer

Criteria for evaluation of disease extent by 123I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force

BackgroundNeuroblastoma is an embryonic tumour of the sympathetic nervous system, metastatic in half of the patients at diagnosis, with a high preponderance of osteomedullary disease, making accurate evaluation of metastatic sites and response to therapy challenging. Metaiodobenzylguanidine (mIBG), taken into cells via the norepinephrine transporter, provides a sensitive and specific method of assessing tumour in both soft tissue and bone sites. The goal of this report was to develop consensus guidelines for the use of mIBG scans in staging, response assessment and surveillance in neuroblastoma.MethodsThe International Neuroblastoma Risk Group (INRG) Task Force, including a multidisciplinary group in paediatric oncology of North and South America, Europe, Oceania and Asia, formed a subcommittee on metastatic disease evaluation, including expert nuclear medicine physicians and oncologists, who developed these guidelines based on their experience and the medical literature, with approval by the larger INRG Task Force.ResultsGuidelines for patient preparation, radiotracer administration, techniques of scanning including timing, energy, specific views, and use of single photon emission computed tomography are included. Optimal timing of scans in relation to therapy and for surveillance is reviewed. Validated semi-quantitative scoring methods in current use are reviewed, with recommendations for use in prognosis and response evaluation.ConclusionsMetaiodobenzylguanidine scans are the most sensitive and specific method of staging and response evaluation in neuroblastoma, particularly when used with a semi-quantitative scoring method. Use of the optimal techniques for mIBG in staging and response, including a semi-quantitative score, is essential for evaluation of the efficacy of new therapy

Combining a targeted radiotherapy and gene therapy approach for adenocarcinoma of prostate

A targeted radiotherapy/gene therapy approach for prostate cancer, using the radiopharmaceutical [<sup>131</sup>1]meta- iodobenzylguanidine ([<sup>131</sup>1]MIBG), would restrict the effects of radiotherapy to malignant cells, thereby increasing efficacy and decreasing morbidity of radiotherapy. Prostate cancer cells were transfected with a transgene encoding the noradrenaline transporter (NAT) under the control of tumour-specific telomerase promoters, enabling them to actively take up [<sup>131</sup>1]MIBG. This led to tumour-specific cell kill. This strategy has the advantage of generating a radiological bystander effect, leading to the destruction of neighbouring tumour cells that have escaped transfection. This targeted approach could be a promising tumour-specific treatment option for prostate cancer

Support for a rare pattern of temperature-dependent sex determination in archaic reptiles: evidence from two species of tuatara (Sphenodon)

<p>Abstract</p> <p>Background</p> <p>The sex of many reptiles is determined by the temperature an embryo experiences during its development. Three patterns of temperature-dependent sex determination (TSD) have been defined, but one pattern where only males are produced above an upper temperature threshold (Type IB) is controversial. Here we report new data on the relationship between constant temperature incubation and sexual phenotype in two species of tuatara (<it>Sphenodon</it>), archaic reptiles of enormous zoological significance as the sole representatives of a once widespread reptilian order.</p> <p>Results</p> <p>In both species, the pattern observed with constant incubation temperatures from 18 to 23°C (or 24°C) supported a female→male (FM or Type IB) pattern of TSD: in <it>Sphenodon guntheri </it>males were produced above a pivotal temperature of 21.6°C, and in <it>S. punctatus </it>(unnamed subspecies on Stephens Island, Cook Strait), males were produced above a pivotal temperature of 22.0°C. The pivotal temperatures and scaling parameters differed between species (p < 0.001). The thermosensitive period (TSP), where temperature influences gonad morphogenesis, occurs between 0.25 and 0.55 of embryonic development. While it is possible that the more common female→male→female (FMF or Type II) pattern exists, with a second pivotal temperature above 23–24°C, we review several lines of evidence to the contrary. Most notably, we show that in <it>S. punctatus</it>, the warmest natural nests during the TSP produce predominantly males.</p> <p>Conclusion</p> <p>An FM pattern of TSD could be currently adaptive in promoting sexual size dimorphism in tuatara. However, an FM pattern has particularly serious consequences for <it>S. guntheri </it>because current patterns of global warming could exacerbate the male bias already present in the relic population.</p