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The number of genes controlling mimetic traits has been a topic of much research and discussion. In this paper, we examine a mimetic, dendrobatid frog Ranitomeya imitator, which harbours extensive phenotypic variation with multiple mimetic morphs, not unlike the celebrated Heliconius system. However, the genetic basis for this polymorphism is unknown, and not easy to determine using standard experimental approaches, for this hard-to-breed species. To circumvent this problem, we first develop a new protocol for automatic quantification of complex colour pattern phenotypes from images. Using this method, which has the potential to be applied in many other systems, we define a phenotype associated with differences in colour pattern between different mimetic morphs. We then proceed to develop a maximum-likelihood method for estimating the number of genes affecting a quantitative trait segregating in a hybrid zone. This method takes advantage of estimates of admixture proportions obtained using genetic data, such as microsatellite markers, and is applicable to any other system where a phenotype has been quantified in an admixture/introgression zone. We evaluate the method using extensive simulations and apply it to the R. imitator system. We show that probably one or two, or at most three genes, control the mimetic phenotype segregating in a R. imitator hybrid zone identified using image analyses., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

Species distributed across vast continental areas and across major biomes provide unique model systems for studies of biotic diversification, yet also constitute daunting financial, logistic and political challenges for data collection across such regions. The tree frog Dendropsophus minutus (Anura: Hylidae) is a nominal species, continentally distributed in South America, that may represent a complex of multiple species, each with a more limited distribution. To understand the spatial pattern of molecular diversity throughout the range of this species complex, we obtained DNA sequence data from two mitochondrial genes, cytochrome oxidase I (COI) and the 16S rhibosomal gene (16S) for 407 samples of D. minutus and closely related species distributed across eleven countries, effectively comprising the entire range of the group. We performed phylogenetic and spatially explicit phylogeographic analyses to assess the genetic structure of lineages and infer ancestral areas. We found 43 statistically supported, deep mitochondrial lineages, several of which may represent currently unrecognized distinct species. One major clade, containing 25 divergent lineages, includes samples from the type locality of D. minutus. We defined that clade as the D. minutus complex. The remaining lineages together with the D. minutus complex constitute the D. minutus species group. Historical analyses support an Amazonian origin for the D. minutus species group with a subsequent dispersal to eastern Brazil where the D. minutus complex originated. According to our dataset, a total of eight mtDNA lineages have ranges >100,000 km2. One of them occupies an area of almost one million km2 encompassing multiple biomes. Our results, at a spatial scale and resolution unprecedented for a Neotropical vertebrate, confirm that widespread amphibian species occur in lowland South America, yet at the same time a large proportion of cryptic diversity still remains to be discovered.

In a mimetic radiation--when a single species evolves to resemble different model species--mimicry can drive within-species morphological diversification, and, potentially, speciation. While mimetic radiations have occurred in a variety of taxa, their role in speciation remains poorly understood. We study the Peruvian poison frog Ranitomeya imitator, a species that has undergone a mimetic radiation into four distinct morphs. Using a combination of colour-pattern analysis, landscape genetics and mate-choice experiments, we show that a mimetic shift in R. imitator is associated with a narrow phenotypic transition zone, neutral genetic divergence and assortative mating, suggesting that divergent selection to resemble different model species has led to a breakdown in gene flow between these two populations. These results extend the effects of mimicry on speciation into a vertebrate system and characterize an early stage of speciation where reproductive isolation between mimetic morphs is incomplete but evident.

Peru is well known for amphibian diversity and endemism, yet there have been relatively few field studies of glassfrog (Centrolenidae) diversity in this country. Research in Colombia and Ecuador indicates that centrolenid diversity is higher in the northern Andes. However, part of this trend appears to be due to sampling effort. We conducted fieldwork throughout northern Peru, and based on phylogenetic analysis of DNA sequences, combined with bioacoustic and morphological analyses of new and available material we now recognize 33 species from the country (versus 30 species prior to this work). Field surveys led to the discovery of four remarkable species: Centrolene charapita new species is a large, ornamented glassfrog that appears to be sister to Ce. geckoideum; Chimerella corleone new species represents the second-known member of the genus Chimerella; Cochranella guayasamini new species is the second-known member of the genus with humeral spines; and Hyalinobatrachium anachoretus new species occurs in the cloud forest of the east-Andean versant in Peru. In addition to the new species described here, we provide new country records, new localities including range extensions of up to 875 km, information on diagnostic characters and phylogenetic relationships, call and larval descriptions, and observations on natural history for several Peruvian centrolenids. Our results also revealed several taxonomic problems concerning species of the genus Rulyrana, and we conclude that R. croceopodes and R. tangarana are junior synonyms of R. saxiscandens. By implication of our phylogenetic analyses, we recognize the following new combinations: Espadarana audax new combination, Espadarana durrelorum new combination, and Espadarana fernandoi new combination.

We discuss possible aetiological factors, MRI evolution of injury and neuro-developmental outcomes of neonatal encephalopathy (NE). Thirty-six consecutive infants diagnosed with NE were included. In this cohort, four infants (11%) were identified with injury predominantly in the deep white matter on MRI who were significantly of younger gestation, lower birthweight with higher Apgars at one and five minutes compared to controls. Placental high grade villitis of unknown aetiology (VUA) was identified in all four of these infants. Our hypothesis states VUA may induce white matter injury by causing a local inflammatory response and/or oxidative stress during the perinatal period. We underline the importance of continued close and systematic evaluation of all cases of NE, including examination of the placenta, in order to come to a better understanding of the clinical presentation, the patterns of brain injury and the underlying pathophysiological processes.

The evolution of Müllerian mimicry is, paradoxically, associated with high levels of diversity in color and pattern. In a mimetic radiation, different populations of a species evolve to resemble different models, which can lead to speciation. Yet there are circumstances under which initial selection for divergence under mimicry may be reversed. Here we provide evidence for the evolution of extensive phenotypic divergence in a mimetic radiation in Ranitomeya imitator, the mimic poison frog, in Peru. Analyses of color hue (spectral reflectance) and pattern reveal substantial divergence between morphs. However, we also report that there is a "transition-zone" with mixed phenotypes. Analyses of genetic structure using microsatellite variation reveals some differentiation between populations, but this does not strictly correspond to color pattern divergence. Analyses of gene flow between populations suggest that, while historical levels of gene flow were low, recent levels are high in some cases, including substantial gene flow between some color pattern morphs. We discuss possible explanations for these observations.

Posterior Reversible Encephalopathy Syndrome (PRES) is a clinicoradiologic syndrome characterised clinically by headaches, altered consciousness, visual disturbances and seizures and radiological changes which can resolve. However left untreated it can be fatal and not all cases are reversible. It can occur in many settings, the most common being hypertensive crisis. We discuss the clinical and radiological features of this increasingly diagnosed condition among children and current thinking on its pathogenesis. A brief case is used to highlight the variable presentation of PRES. PRES is often unsuspected by the clinician and radiologists may be first to suggest the diagnosis. Accurate assessment including blood pressure measurement, appropriate imaging and rapid treatment is required to avoid a devastating outcome., (Copyright © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Morbidity attributable to hypoxic-ischaemic injury (HIE) in the perinatal period remains problematic, and timely and accurate assessment of the degree of injury is required for clinical management and prognosis. Conventional MR sequences typically appear normal in the first 48 h post HIE. While diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps register the injury earlier, perhaps within the first 24 h, it has been suggested that there may be a propensity at that early stage to underestimate the lesion severity or extent., Objective: To assess whether MR imaging that included DWI, measured ADC values and T1- and T2-weighted sequences ultimately correlated with either neurodevelopmental outcome or with late MR imaging at 2 years of age. In addition, we wished to compare the performance of MR imaging with cranial US imaging., Materials and Methods: All infants presenting with HIE who had an MRI within 10 days of life were eligible for enrollment and subsequently underwent a full neurodevelopmental assessment at 2 years of age. All children underwent repeat MRI at this time. All neonates had at least one cranial US study. The US findings were categorized as normal, abnormalities confined to the cerebral cortex and subcortical white matter, isolated central grey matter hyperechogenicity, and central hyperechogenicity combined with cerebral cortical/subcortical changes. All MRI studies were retrospectively reviewed by three radiologists. The patterns of injury on the early DWI and ADC maps and early T1- and T2-W studies were recorded as diffuse, central, watershed or atypical. The patterns of signal abnormality were assessed using a scoring system that yielded four separate scores [basal ganglia (BG), watershed (W), BG/W and summation (S)] for the three sets of images, a total of 12 scores in all. The appearance of the posterior limb of the internal capsule (PLIC) on T1-W inversion recovery sequences and of the corpus callosum on all sequences was also documented. After detailed neurodevelopmental assessment at 2 years of age, infants were classified into two groups according to whether they had a favourable or unfavourable outcome., Results: Of the 26 infants, 6 infants died before formal assessment at the age of 2 years. A further 5 infants had moderate to severe cerebral palsy in addition to severe cognitive impairment. The remaining 15 infants were categorized in the favourable outcome group. The US appearance performed well in terms of predicting final outcome (P = 0.005). The pattern of ischaemia seen on early MRI was a significant predictor of outcome (P < 0.0001). The BG, BG/W and S scores of the diffusion imaging were significantly associated with outcome (P < 0.0001, P < 0.0001 and P = 0.0005 respectively). DWI was predictive of outcome group (P < 0.0001), as were the early T1- and T2-W sequences (P = 0.002) and cranial US (P = 0.005). Assessment of the PLIC in infants with watershed or atypical patterns of ischaemia was found to be less reliable in predicting outcome. The measured ADC value in the PLIC was significantly reduced in those children who had an unfavourable outcome (P = 0.03)., Conclusion: While early MRI performed better than cranial US, the sonography findings were useful. The pattern of ischaemia on early MRI was a good predictor of prognosis. All infants with watershed or atypical patterns had a favourable outcome. The majority of infants with central patterns of ischaemia had an unfavourable outcome and all infants with a diffuse pattern had an unfavourable outcome. DWI was predictive of outcome group, as were early T1- and T2-W sequences and cranial US.

This retrospective study calculated the cumulative radiation dose for children with cystic fibrosis (CF) attending a tertiary CF centre. Information on 77 children with a mean age of 9.5 years, a follow up time of 658 person years and 1757 studies including 1485 chest radiographs, 215 abdominal radiographs and 57 computed tomography (CT) scans, of which 51 were thoracic CT scans, were analysed. The average cumulative radiation dose was 6.2 (0.04-25) mSv per CF patient. Cumulative radiation dose increased with increasing age and number of CT scans and was greater in children who presented with meconium ileus. No correlation was identified between cumulative radiation dose and either lung function or patient microbiology cultures. Radiation carries a risk of malignancy and children are particularly susceptible. Every effort must be made to avoid unnecessary radiation exposure in these patients whose life expectancy is increasing.

Myosin phosphatase target subunit 1 (MYPT1), together with catalytic subunit of type1 delta isoform (PP1cdelta) and a small 20-kDa regulatory unit (M20), form a heterotrimeric holoenzyme, myosin phosphatase (MP), which is responsible for regulating the extent of myosin light chain phosphorylation. Here we report the identification and characterization of a molecular interaction between Seven in absentia homolog 2 (SIAH2) and MYPT1 that resulted in the proteasomal degradation of the latter in mammalian cells, including neurons and glia. The interaction involved the substrate binding domain of SIAH2 (aa 116-324) and a central region of MYPT1 (aa 445-632) containing a degenerate consensus Siah-binding motif RLAYVAP (aa 493-499) evolutionally conserved from fish to humans. These findings suggest a novel mechanism whereby the ability of MP to modulate myosin light chain might be regulated by the degradation of its targeting subunit MYPT1 through the SIAH2-ubiquitin-proteasomal pathway. In this manner, the turnover of MYPT1 would serve to limit the duration and/or magnitude of MP activity required to achieve a desired physiological effect.

Idiopathic orbital inflammation (IOI) is defined as a benign non-infective clinical syndrome characterized by features of non-specific inflammation of the orbit without identifiable local or systemic causes. This can be called orbital myositis if the inflammation is predominantly in the orbital muscles. It is a diagnosis of exclusion based on clinical, radiological, and if necessary, histological findings. The most commons symptoms are swelling, ptosis, proptosis and painful eye movements. To our knowledge, this patient is the first with IOI to demonstrate relapsing flitting bilateral involvement of several individual extra-ocular muscles.

Linoleic acid-phospholipids stimulate high-density lipoprotein (HDL) net secretion from liver cells by blocking the endocytic recycling of apoA-I. Experiments were undertaken to determine whether apoA-I accumulation in the cell media is associated with membrane ATPase expression. Treatment of HepG2 cells with dilinoeoylphosphatidylcholine (DLPC) increased apoA-I secretion fourfold. DLPC also significantly reduced cell surface F1-ATPase expression and reduced cellular ATP binding cassette (ABC)A1 and ABCG1 protein levels by approximately 50%. In addition, treatment of HepG2 cells with the ABC transporter inhibitor, glyburide, stimulated the apoA-I secretory effects of both DLPC and clofibrate. Pretreatment of HepG2 cells with compounds that increased ABC transport protein levels (TO901317, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal, and resveratrol) blocked the DLPC-induced stimulation in apoA-I net secretion. Furthermore, whereas HepG2 cells normally secrete nascent prebeta-HDL, DLPC treatment promoted secretion of alpha-migrating HDL particles. These data show that an linoleic acid-phospholipid induced stimulation in hepatic HDL secretion is related to the expression and function of membrane ATP metabolizing proteins.

Objectives: To determine the long-term outcome of dietary intervention in siblings from 14 Irish families with classical galactosemia (McKusick 230400), an autosomal recessive disorder of carbohydrate metabolism and galactose-1-phosphate uridyltransferase (GALT) deficiency., Study Design: Outcomes in siblings on dietary galactose restriction were studied to evaluate whether birth order (ie, time of commencement of diet) and compliance with lactose-restricted diet (galactose intake > or < 20 mg /day), assessed by dietary recall and biochemical monitoring of galactose-1-phosphate [Gal-1-P] and galactitol values, affected outcomes. The outcome variables assessed were IQ, speech, and language assessment scores, neurologic examination results, and magnetic resonance imaging (MRI) of the brain., Results: There was a high incidence of complications in the overall group, particularly speech and language delay (77%) and low IQ (71%). There was no significant difference in outcome between earlier-treated and later-treated siblings or any correlation with mean Gal-1-P or galactitol values. In most cases, cerebral white matter disease was evident on MRI scanning, with evidence of progressive cerebellar degeneration seen in 2 highly compliant families., Conclusion: The subjects with a higher galactose intake did not exhibit an increased incidence of complications; conversely, those who were very compliant with dietary restrictions did not have more favorable outcomes.

Phosphatidylinositol (PI) has been shown to stimulate reverse cholesterol transport in animal models and to increase plasma apolipoprotein (apo) A-I levels and high-density lipoprotein cholesterol in human subjects. The objective of this study was to determine the molecular mechanism through which PI stimulates apo A-I secretion in hepatic cells. PI (12 mumol/L) significantly stimulates apo A-I secretion from HepG2 cells over 24 hours. The stimulation in apo A-I secretion is completely blocked by phospholipase C inhibitors (D609 and U73122) and the Ras inhibitor sulindac sulfide. Apolipoprotein A-I secretion is augmented with a protein kinase C agonist (dioctanoyl glycerol) and inhibited by a protein kinase C inhibitor (dioleoyl ethylene glycol). The PI-induced apo A-I secretion is unaffected by PI-3-kinase inhibitors but is sensitive to mitogen-activated protein kinase (MAPK) inhibitors. Whereas the p38MAPK inhibitor SB203580 has no effect on PI-induced apo A-I secretion, the MAPK kinase 1/2 inhibitor U0126 and the c-Jun-N-terminal kinase/stress-activated protein kinase inhibitor SP600125 block PI-induced apo A-I secretion. PI also increased extracellular-regulated protein kinase 1 and 2 phosphorylation in HepG2 cells in a time-dependent manner. PI does not appear to stimulate apo A-I gene transcription, as cellular apo A-I messenger RNA levels remained unchanged over the 24-hour incubation. However, PI significantly decreases apo A-I binding and degradation in HepG2 cells. Collectively, the data suggest that PI acts through MAPK pathways to increase plasma apo A-I levels by protecting it from reuptake and degradation.

Objectives: To provide information on twin deliveries among Igbos in a rural/semi-urban community of South-Eastern Nigeria, and compare the twinning rate with data from the other two major tribes., Methods: An analysis of the records of deliveries conducted over a 20-year period in a rural/semi-urban community of South-Eastern Nigeria., Results: The twinning rate of the community was 1:24, and increased with increasing maternal age, and generally with birth rank. Twin births were associated with a MMR of 895/100,000, and PMR of 213/1000 maternities, figures 3.4 and 1.7 times those of the total maternal and perinatal mortalities respectively. Ninty percent of the twin mothers delivered vaginally, 2% with the aid of symphysiotomy. Caesarean section rate was 10.6%., Conclusion: The twinning rate within Nigeria may probably be dictated by location rather than ethnicity. The maternal and perinatal mortalities associated with twin pregnancies in this study appear higher than for singleton births.

A prototype respirometric biochip dedicated to monitoring oxygen consumption of preimplantation embryos has been developed. The biochip comprises a linear array of eight flow-through microchambers profiled on silicon substrate, and functions together with a phosphorescent oxygen sensitive probe and fluorescence plate reader detection. A high level of sensitivity to changes in dissolved oxygen was achieved through miniaturisation and optimization of biochip geometry, and incorporation of appropriate sealing and humidification systems. The biochips have allowed characterisation of oxygen consumption, by 2 cell and blastocyst stage preimplantation mouse embryos, through monitoring as few as ten preimplantation embryos over a one-hour time period. They provide a non-invasive, simple and convenient means for assessing preimplantation embryo metabolism.

Purpose: To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma., Patients and Methods: Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR)., Results: The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively., Conclusion: 131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

The risk of an aneurysm leaking is related to its size. The operative mortality of elective surgery should be less than 5% but is frequently more than 50% following rupture. Many patients previously undiagnosed present with rupture, yet are on long-term treatment for hypertension. Two-hundred hypertensive male patients over the age of 50 have been clinically examined, and subsequently undergone ultrasound examination of the abdominal aorta. Fourteen asymptomatic aneurysms were detected, 9 on clinical examination, confirmed by ultrasound and C.T., and a further 5 detected by ultrasound, and also confirmed by C.T. Twenty-four patients were found to have carotid bruits, in 12 of whom the bruits were bilateral. Sixty-seven patients were found to have peripheral vascular disease. Routine abdominal ultrasound examination should be included in the regular assessment of hypertensive patients.