Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development.

STUDY QUESTION: What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)? SUMMARY ANSWER: An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases. WHAT IS KNOWN ALREADY: Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear. STUDY, DESIGN, SIZE, DURATION: This study was a retrospective review of investigations performed on 122 boys. PARTICIPANTS/MATERIALS, SETTING, METHODS: All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1-11). Details of phenotype, endocrine and genetic investigations were obtained from case records. MAIN RESULTS AND THE ROLE OF CHANCE: An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1-10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5-11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5-11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1-9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations. LIMITATIONS, REASONS FOR CAUTION: A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel. WIDER IMPLICATIONS OF THE FINDINGS: The lack of a clear association between the extent of under-masculinization and presence of endocrine and genetic abnormalities suggests a role for parallel endocrine and genetic investigations in cases of suspected XY DSD. STUDY FUNDING/COMPETING INTEREST(S): RN was supported by the James Paterson Bursary and the Glasgow Children's Hospital Charity Summer Scholarship. SFA, RM and EST are supported by a Scottish Executive Health Department grant 74250/1 for the Scottish Genomes Partnership. EST is also supported by MRC/EPSRC Molecular Pathology Node and Wellcome Trust ISSF funding. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: None.

Detecting shifts in diversity limits from molecular phylogenies: what can we know?

Large complete species-level molecular phylogenies can provide the most direct information about the macroevolutionary history of clades having poor fossil records. However, extinction will ultimately erode evidence of pulses of rapid speciation in the deep past. Assessment of how well, and for how long, phylogenies retain the signature of such pulses has hitherto been based on a--probably untenable--model of ongoing diversity-independent diversification. Here, we develop two new tests for changes in diversification 'rules' and evaluate their power to detect sudden increases in equilibrium diversity in clades simulated with diversity-dependent speciation and extinction rates. Pulses of diversification are only detected easily if they occurred recently and if the rate of species turnover at equilibrium is low; rates reported for fossil mammals suggest that the power to detect a doubling of species diversity falls to 50 per cent after less than 50 Myr even with a perfect phylogeny of extant species. Extinction does eventually draw a veil over past dynamics, suggesting that some questions are beyond the limits of inference, but sudden clade-wide pulses of speciation can be detected after many millions of years, even when overall diversity is constrained. Applying our methods to existing phylogenies of mammals and angiosperms identifies intervals of elevated diversification in each.

What factors shape rates of phenotypic evolution? A comparative study of cranial morphology of four mammalian clades.

Understanding why rates of morphological evolution vary is a major goal in evolutionary biology. Classical work suggests that body size, interspecific competition, geographic range size and specialization may all be important, and each may increase or decrease rates of evolution. Here, we investigate correlates of proportional evolutionary rates in phalangeriform possums, phyllostomid bats, platyrrhine monkeys and marmotine squirrels, using phylogenetic comparative methods. We find that the most important correlate is body size. Large species evolve the fastest in all four clades, and there is a nonlinear relationship in platyrrhines and phalangeriformes, with the slowest evolution in species of intermediate size. We also find significant increases in rate with high environmental temperature in phyllostomids, and low mass-specific metabolic rate in marmotine squirrels. The mechanisms underlying these correlations are uncertain and appear to be size specific. We conclude that there is significant variation in rates of evolution, but that its meaning is not yet clear.

Nonrandom extinction and the loss of evolutionary history.

The hierarchical nature of phylogenies means that random extinction of species affects a smaller fraction of higher taxa, and so the total amount of evolutionary history lost may be comparatively slight. However, current extinction risk is not phylogenetically random. We show the potentially severe implications of the clumped nature of threat for the loss of biodiversity. An additional 120 avian and mammalian genera are at risk compared with the number predicted under random extinction. We estimate that the prospective extra loss of mammalian evolutionary history alone would be equivalent to losing a monotypic phylum.

The fast-slow continuum in mammalian life history: an empirical reevaluation.

Many life-history traits co-vary across species, even when body size differences are controlled for. This phenomenon has led to the concept of a "fast-slow continuum," which has been influential in both empirical and theoretical studies of life-history evolution. We present a comparative analysis of mammalian life histories showing that, for mammals at least, there is not a single fast-slow continuum. Rather, both across and within mammalian clades, the speed of life varies along at least two largely independent axes when body size effects are removed. One axis reflects how species balance offspring size against offspring number, while the other describes the timing of reproductive bouts.

Molecular chaperone properties of serum amyloid P component.

The selective binding of serum amyloid P component (SAP) to proteins in the pathological amyloid cross-beta fold suggests a possible chaperone role. Here we show that human SAP enhances the refolding yield of denatured lactate dehydrogenase and protects against enzyme inactivation during agitation of dilute solutions. These effects are independent of calcium ions and are not inhibited by compounds that block the amyloid recognition site on the B face of SAP, implicating the A face and/or the edges of the SAP pentamer. We discuss the possibility that the chaperone property of SAP, or its failure, may contribute to the pathogenesis of amyloidosis.

Body size and species-richness in carnivores and primates.

We use complete species-level phylogenies of extant Carnivora and Primates to perform the first thorough phylogenetic tests, in mammals, of the hypothesis that small body size is associated with species-richness. Our overall results, based on comparisons between sister clades, indicate a weak tendency for lineages with smaller bodies to contain more species. The tendency is much stronger within caniform carnivores (canids, procyonids, pinnipeds, ursids and mustelids), perhaps relating to the dietary flexibility and hence lower extinction rates in small, meat-eating species. We find significant heterogeneity in the size-diversity relationship within and among carnivore families. There is no significant association between body mass and species-richness in primates or feliform carnivores. Although body size is implicated as a correlate of species-richness in mammals, much of the variation in diversity cannot be attributed to size differences.

Macroevolutionary inferences from primate phylogeny.

We apply new statistical methods to a recent estimate of the phylogeny of all living primate species to test a range of models of cladogenesis. Null models in which probabilities of speciation and extinction do not differ among contemporaneous lineages are not consistent with the phylogeny. We present evidence that the net rate of cladogenesis (speciation rate minus extinction rate) increased in the lineage leading to the Cercopithecidae (Old World monkeys), and that there have been further increases in some lineages within that family. Such increases suggest the occurrence of clade selection, although we have not identified the selected trait or traits. There is no evidence that the net rate of cladogenesis is a function either of how many primate lineages are already present or of time. Intriguingly, three other clades--Strepsirhini, Platyrrhini and Hominoidea--appear to have had very similar rates of clade growth, in spite of their great biological differences.

Predicting extinction risk in declining species.

What biological attributes predispose species to the risk of extinction? There are many hypotheses but so far there has been no systematic analysis for discriminating between them. Using complete phylogenies of contemporary carnivores and primates, we present, to our knowledge, the first comparative test showing that high trophic level, low population density slow life history and, in particular, small geographical range size are all significantly and independently associated with a high extinction risk in declining species. These traits together explain nearly 50% of the total between-species variation in extinction risk. Much of the remaining variation can be accounted for by external anthropogenic factors that affect species irrespective of their biology.

Relations between song repertoire size and the volume of brain nuclei related to song: comparative evolutionary analyses amongst oscine birds.

Song and brain structure are compared amongst 41 species of oscine birds by using the method of independent evolutionary contrasts. We find a significant correlation between the relative volume of the song control centre, the high vocal centre (HVC), and the number of song types typically found in the repertoire. Relative HVC volume is not correlated with the number of different syllable types per song bout. The relative volume of a second song nucleus, area X, is not significantly correlated with either measure. Relative HVC volume is uncorrelated with relative volume of the hippocampus, a brain area involved in other forms of memory. This is the first evidence for repeated independent evolution of an association between complexity of learned song and the relative volume of one of the song control nuclei though to be involved in song learning.

Seed size and establishment conditions in tropical trees : On the use of taxonomic relatedness in determining ecological patterns.

Within a multi-species study, species do not necessarily represent independent data points. The data set used by Foster and Janson (1985) to look at the relationship between seed size and establishment conditions for naturally occurring tropical trees was re-analyzed, to take into account the effect of relatedness among species. The re-analysis showed that 1) this data set does not support the hypothesis that large-seeded species are more likely to establish in small gaps or shade than are small-seeded species, and 2) more than 1/3 (16 of 39) of the data points were extraneous to the test of the hypothesis. It is recommended that all ecologists, and not just those interested in evolutionary questions, consider species relatedness prior to inception of any multi-species study.

Stress-induced changes in ubiquinone concentration and alternative oxidase in plant mitochondria.

We have investigated the influence of stress conditions such as incubation at 4 degrees C and incubation in hyperoxygen atmosphere, on plant tissues. The ubiquinone (Q) content and respiratory activity of purified mitochondria was studied. The rate of respiration of mitochondria isolated from cold-treated green bell peppers (Capsicum annuum L) exceeds that of controls, but this is not so for mitochondria isolated from cold-treated cauliflower (Brassica oleracea L). Treatment with high oxygen does not alter respiration rates of cauliflower mitochondria. Analysis of kinetic data relating oxygen uptake with Q reduction in mitochondria isolated from tissue incubated at 4 degrees C (bell peppers and cauliflowers) and at high oxygen levels (cauliflowers) reveals an increase in the total amount of Q and in the percentage of inoxidizable QH2. The effects are not invariably accompanied by an induction of the alternative oxidase (AOX). In those mitochondria where the AOX is induced (cold-treated bell pepper and cauliflower treated with high oxygen) superoxide production is lower than in the control. The role of reduced Q accumulation and AOX induction in the defense against oxidative damage is discussed.

Reach out and cure someone.

A new 900 number offers medical advice by phone, but can it replace a family physician's personal touch?

Sex and congenital diaphragmatic hernia.

BACKGROUND AND PURPOSE: Human studies note sex reversal syndromes and sex difference(s) in the incidence of congenital diaphragmatic hernia (CDH). Epidemiology surveys record a higher incidence of CDH in females, whilst other reports cite a higher frequency in males. Nitrofen, a teratogen, produces experimental CDH. This agent is speculated to interfere with retinoid acid-steroid signalling pathways and may also be linked with sexual differentiation. This study was designed therefore to test the hypothesis that nitrofen may influence sexual phenotype and frequency of CDH. METHODS: Time mated Sprague Dawley rats were dosed with nitrofen at day 9.5 to generate predominantly left sided CDH. Fetuses were delivered by caesarean section on days 20 or 21 of gestation (term=day 22). External genitalia were examined to define external genital phenotype. The abdominal cavity was opened and the genito-urinary system carefully examined. The internal genital organs were assigned a phenotype and findings correlated with external appearances. The diaphragm of each fetus was studied for the absence or presence of CDH and the laterality of defect recorded. Controls (non nitrofen fed) were used for all comparative analysis. RESULTS: Control (n=600) and nitrofen exposed offspring (n=504) had equal frequencies of males and females. CDH occurred with similar incidence in male and female nitrofen treated pups. In all nitrofen exposed fetuses and normal controls, internal and external genitalia concorded without evidence of significant genital tract malformations or intersex states. CONCLUSIONS: Prenatal nitrofen exposure is not associated with significant gender differences (or prenatal loss) in the risk of CDH. Genital tract malformations do not appear to accompany CDH in the nitrofen model.

Macroevolutionary trends in the Dinosauria: Cope's rule.

Cope's rule is the tendency for body size to increase over time along a lineage. A set of 65 phylogenetically independent comparisons, between earlier and later genera, show that Cope's rule applied in dinosaurs: later genera were on average about 25% longer than the related earlier genera to which they were compared. The tendency for size to increase was not restricted to a particular clade within the group, nor to a particular time within its history. Small lineages were more likely to increase in size, and large lineages more likely to decrease: this pattern may indicate an intermediate optimum body size, but can also be explained as an artefact of data error. The rate of size increase estimated from the phylogenetic comparisons is significantly higher than the rate seen across the fauna as a whole. This difference could indicate that within-lineage selection for larger size was opposed by clade selection favouring smaller size, but data limitations mean that alternative explanations (which we discuss) cannot be excluded. We discuss ways of unlocking the full potential usefulness of phylogenies for studying the dynamics of evolutionary trends.

Nonplanar photolithography with computer-generated holograms.

We outline a method for accomplishing photolithography on grossly nonplanar substrates. First we compute an approximation of the diffraction pattern that will produce the desired light-intensity distribution on the substrate to be patterned. This pattern is then digitized and converted into a format suitable for manufacture by a direct-write method. The resultant computer-generated hologram mask is then used in a custom alignment tool to expose the photoresist-coated substrate. The technique has many potential applications in the packaging of microelectronics and microelectromechanical systems.