Costello syndrome: Clinical phenotype, genotype, and management guidelines.

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

Water quality targets and maintenance of valued landscape character - experience in the Axe catchment, UK.

The Water Framework Directive (WFD) (Directive 2000/60/EC) requires new ecological standards for rivers, lakes and coastal waters by 2015. In the United Kingdom the English Catchment Sensitive Farming Initiative has identified 40 catchments which are at risk of failing the European Commission WFD targets for good ecological status of water bodies because of a range of issues. The river Axe catchment situated in south-west England, with a mixture of diffuse and point sources of pollution, is one of these priority sites, as intensive dairy farming and cultivation of high risk crops (maize) cause problems with enhanced suspended sediment, nitrate and phosphorus levels in the river. Much of the Axe is under national and county landscape designations, making land use or management measures taken to achieve river status sensitive to these designations. For the purpose of this research the Soil and Water Assessment Tool (SWAT-2005) was used. The baseline scenario was based on field observation and interviews with the Environment Agency and farmers; it was run with and without point sources. Three different mitigation scenarios, designed to maintain the landscape of the catchment, were then tested. Field buffer strips (FBS), extensive land use management (EXT) and sheep land use management (SHP), were used to assess the effectiveness of the measures in reducing nutrient loads in the river Axe, UK. Management scenarios reduced the average annual loads at the main catchment outlet by 21.2% (FBS), 37.3% (EXT) and 45.0% (SHP), for total nitrogen and 47.7% (FBS), 60.6% (EXT) and 62.4% (SHP) for total phosphorus. The results of this study suggest that there may be a fundamental incompatibility between the delivery of WFD targets and the maintenance of viable agricultural systems necessary to maintain landscapes which are highly valued for their aesthetic, recreational and economic value.

Using artificial fluorescent particles as tracers of livestock wastes within an agricultural catchment.

Evidence for the movement of agricultural slurry and associated pollutants into surface waters is often anecdotal, particularly with relation to its 'particulate' components which receive less attention than 'bio-available' soluble phases. To assess the extent of movement of slurry particles artificial fluorescent particles were mixed with slurry and applied to a field sub-catchment within a headwater catchment. Particles were 2-60 µm in diameter and two different densities, 2.7 and 1.2 g cm(-3) representing 'inorganic' and 'organic' material. Water samples from the field and catchment outlet were collected during two storm events following slurry application and analysed for particle and suspended sediment concentrations (SSC). SSC from the field and catchment outlet always formed clockwise hysteresis loops indicating sediment exhaustion and particles of the two densities were always found to be positively correlated. Particles from the field formed clockwise hysteresis loops during the first discharge event after slurry application, but anti-clockwise hysteresis loops during the second monitored event which indicated a depletion of readily mobilisable particles. Particles from the catchment outlet always formed anticlockwise hysteresis loops. Particle size became finer spatially, between field and catchment outlet, and temporally, between successive storm events. The results indicate that slurry particles may be readily transported within catchments but that different areas may contribute to pollutant loads long after the main peak in SSC has passed. The density of the particles did not appear to have any effect on particle transport however the size of the particles may play a more important role in the 2-60 µm range.

The hydrological response of heavy clay grassland soils to rainfall in south-west England using delta2H.

Stable isotopes of water have been previously used in catchment studies to separate rain-event water from pre-event groundwater. However, there are a lack of studies at the smaller scale looking at the separation of event water from pre-event water. This is particularly relevant for heavy clay soil systems through which the movement of water is uncertain but is thought to be rainwater-dominated. The data presented here were collected at a rural site in the south-west of England. The historic rainfall at the site was isotopically varied but similar to the global meteoric water line, with annual weighted means of -37 per thousand for delta(2)H and -5.7 per thousand for delta(18)O and with no seasonal variation. Drainage was sampled from the inter-flow (surface runoff + lateral through-flow) and drain-flow (55 cm deep mole drains) pathways of two 1 ha lysimeters during two rainfall events, which had delta(2)H values of -68 per thousand and -92 per thousand, respectively. The delta(2)H values of the lysimeter drainage water suggest that there was no contribution of event water during the first, small discharge (Q) event; however, the second larger event did show isotopic variation in delta(2)H values negatively related to Q indicating that rainwater was contributing to Q. A hydrograph separation indicated that only 49-58% of the inter-flow and 18-25% of the drain-flow consisted of event water. This was surprising given that these soil types are considered retentive of soil water. More work is needed on heavy clay soils to understand better the nature of water movement from these systems.

Assessing multiple novel tracers to improve the understanding of the contribution of agricultural farm waste to diffuse water pollution.

A study was undertaken on drained and undrained 1 ha grassland lysimeters to assess the effectiveness of multiple novel tracing techniques in understanding how agricultural slurry waste moves from land to water. Artificial fluorescent particles designed to mimic the size and density of organic slurry particles were found to move off the grassland via inter-flow (surface + lateral through-flow) and drain-flow. Where both pathways were present the drains carried the greater number of particles. The results of the natural fluorescence and δ13C of water samples were inconclusive. Natural fluorescence was higher from slurry-amended lysimeters than from zero-slurry lysimeters, however, a fluorescence decay experiment suggested that no slurry signal should be present given the time between slurry application and the onset of drainage. The δ13C values of >0.7 microm and <0.7 microm material in drainage were varied and unrelated to discharge. The mean value of >0.7 microm δ13C in water from the drain-flow pathways was higher from the lysimeter which had received naturally enriched maize slurry compared to the lysimeter which received grass slurry indicating a contribution of slurry-derived material. Values of <0.7 microm δ13C from the same pathway, however, produced counter intuitive trends and may indicate that different fractions of the slurry have different δ13C values.

Pesticide modelling for a small catchment using SWAT-2000.

Pesticides in stream flow from the 142 ha Colworth catchment in Bedfordshire, UK were monitored from October 1999 to December 2000. About 47% of the catchment is tile-drained and different pesticides and cropping patterns have recently been evaluated in terms of their effect on nutrient and pesticide losses to the stream. The data from Colworth were used to test soil and water assessment tool (SWAT) 2000 predictions of pesticide concentrations at the catchment outlet. A sound model set-up to carry out pesticide modelling was created by means of hydrological modelling with proper simulation of crop growth and evapotranspiration. The pesticides terbuthylazine, terbutryn, cyanazine and bentazone were modelled. There was close agreement between SWAT-predicted pesticide concentration values and observations. Scenario trials were conducted to explore management options for reducing pesticide loads arriving at the catchment outlet. The results obtained indicate that SWAT can be used as a tool to understand pesticide behavior at the catchment scale.

Unstable Robertsonian translocations der(13;15)(q10;q10): heritable chromosome fission without phenotypic effect in two kindreds.

Robertsonian translocations (RTs) are amongst the most common chromosome abnormalities, but being essentially balanced are not usually associated with phenotypic abnormality. Despite being dicentric, RTs are almost always transmitted stably through cell division without chromosome breakage. We have investigated spontaneous fission of der(13;15)(q10;q10) chromosomes in eight individuals from two unrelated kindreds with a view to assessing clinical significance and to seek an explanation for the peculiar heritable instability displayed by these chromosomes. In Family 1, fission products were observed in five members in three generations. The instability was observed in cells derived from chorionic villus and lymphocytes. In Family 2, the same phenomenon was observed in amniocytes from two separate pregnancies and maternal blood lymphocytes. Detailed FISH analysis of these RTs showed them to be dicentric with an unremarkable pericentromeric structure. Notably, combined immunofluoresence and FISH analysis showed the presence of the centromere-specific proteins CENP-A and CENP-E, consistent with functional dicentricity in >75% of cells analyzed. The fission products are, therefore, presumed to be the result of sporadic, bipolar kinetochore attachment, anaphase bridging with resultant inter-centromeric breakage in a small proportion of mitoses. None of the eight carriers shows phenotypic abnormality and therefore, for prenatal counseling purposes, there appears to be no increased specific risk associated with this phenomenon.