Author Correction: Crowther et al. reply.

In this Brief Communications Arising Reply, the affiliation for author P. H. Templer was incorrectly listed as 'Department of Ecology & Evolutionary Biology, University of California Irvine, Irvine, California 92697, USA' instead of 'Department of Biology, Boston University, Boston, Massachusetts 02215, USA'. This has been corrected online.

Anthropocene survival of southern New England's salt marshes.

In southern New England, salt marshes are exceptionally vulnerable to the impacts of accelerated sea level rise. Regional rates of sea level rise have been as much as 50% greater than the global average over past decades: a more than four-fold increase over late-Holocene background values. In addition, coastal development blocks many potential marsh migration routes, and compensatory mechanisms relying on positive feedbacks between inundation and sediment deposition are insufficient to counter inundation increases in extreme low turbidity tidal waters. Accordingly, multiple lines of evidence suggest marsh submergence is occurring in southern New England. A combination of monitoring data, field re-surveys, radiometric dating, and analysis of peat composition have established that, beginning in the early and mid-twentieth century, the dominant low marsh plant, Spartina alterniflora, has encroached upwards in tidal marshes, and typical high marsh plants, including Juncus gerardii and Spartina patens have declined, providing strong evidence that vegetation changes are being driven, at least in part, by higher water levels. Additionally, aerial and satellite imagery show shoreline retreat, widening and headward extension of channels, and new and expanded interior depressions. Papers in this special section highlight changes in marsh-building processes, patterns of vegetation loss, and shifts in species composition. The final papers turn to strategies for minimizing and coping with marsh loss by managing adaptively and planning for landward marsh migration. It is hoped that this collection offers lessons that will be of use to researchers and managers on coasts where relative sea level is not yet rising as fast as in southern New England.

Contrasting decadal-scale changes in elevation and vegetation in two Long Island Sound salt marshes.

Northeastern US salt marshes face multiple co-stressors, including accelerating rates of relative sea level rise (RSLR), elevated nutrient inputs, and low sediment supplies. In order to evaluate how marsh surface elevations respond to such factors, we used surface elevation tables (SETs) and surface elevation pins to measure changes in marsh surface elevation in two eastern Long Island Sound salt marshes, Barn Island and Mamacoke Marsh. We compare marsh elevation change at these two systems with recent rates of RSLR and find evidence of differences between the two sites; Barn Island is maintaining its historic rate of elevation gain (2.3± 0.24 mm yr-1 from 2003 to 2013) and is no longer keeping pace with RSLR, while Mamacoke shows evidence of a recent increase in rates (4.2 ± 0.52 mm yr-1 from 1994 to 2014) to maintain its elevation relative to sea level. In addition to data on short-term elevation responses at these marshes, both sites have unusually long and detailed data on historic vegetation species composition extending back more than half a century. Over this study period, vegetation patterns track elevation change relative to sea levels, with the Barn Island plant community shifting towards those plants that are found at lower elevations and the Mamacoke vegetation patterns showing little change in plant composition. We hypothesize that the apparent contrasting trend in marsh elevation at the sites is due to differences in sediment availability, salinity, and elevation capital. Together these two systems provide critical insight into the relationships between marsh elevation, high marsh plant community, and changing hydroperiods. Our results highlight that not all marshes in southern New England may be responding to accelerated rates of RSLR in the same manner.

Quantifying global soil carbon losses in response to warming.

The majority of the Earth's terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12-17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon-climate feedback that could accelerate climate change.

Bone resorption in syndromes of the Ras/MAPK pathway.

Disorders of the Ras/mitogen-activated protein kinase (MAPK) pathway have an overlapping skeletal phenotype (e.g. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and neurofibromatosis type 1 (NF1) individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine-derived crosslinks of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Participants were individuals with Noonan syndrome (n = 14), Costello syndrome (n = 21), and cardiofaciocutaneous (CFC) syndrome (n = 14). Pyridinium crosslinks from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by high performance liquid chromatography. Three separate analyses of covariance were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. The Dpd and the Dpd/Pyd ratio were elevated (p < 0.0001) in all three conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function.

BACKGROUND: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE: To characterise genetic and clinical findings in patients with SIX3 mutations. METHODS: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. RESULTS: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. CONCLUSIONS: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.

Subtelomeric analysis detects a familial 10p;12p rearrangement in two relatives with a distinct syndrome.

In recent years, subtelomeric rearrangements have been identified as a major cause of multiple congenital anomalies (MCA)/mental retardation (MR) syndromes. Currently, more than 2,500 individuals with MR have been tested and subtelomeric rearrangements were detected in about 6%. Therefore, subtelomeric FISH analysis is indicated as a second tier test after high-resolution G-banding analysis, in subjects with otherwise unexplained developmental delay/MR and/or MCA. We describe a female patient and her maternal aunt, both showing a distinct phenotype, associated with the same complex subtelomeric rearrangement. Subtelomeric FISH testing performed between 1 year 9 months and 20 years after the initial karyotype showed, in both patients, distal trisomy 12p and distal monosomy 10p as follows: 46,XX.ish der(10)t(10;12)(p15.3;p13.31). Parental subtelomeric FISH analysis showed the proposita's mother (sister of Patient 2) and grandmother (mother to Patient 2), to have a balanced 10p:12p translocation. Both girls showed a similar phenotype with pre/postnatal growth retardation, moderate-to-severe developmental delay/MR, very poor/absent speech, hypotonia, lax ligaments, and a distinct pattern of malformation. On examination there were blepharophimosis; bilateral ptosis/epicanthus; broad, depressed nasal bridge with a beaked nose; short philtrum; low-set, posteriorly rotated, overfolded ears; micrognathia; mild webbing of the neck; mild broadening of thumbs; puffy hands/feet; long hallux; and sacral/coccygeal dimples. A slow overall improvement was seen in both patients over time. To our knowledge, a complex subtle rearrangement as the one seen in our patients has not been reported thus far. Our patients show features of partial 10p deletion syndrome rather than those of partial duplication 12p, confirming the general rule that deletions are more phenotypically penetrant than duplications.

The FG syndrome: report of a large Italian series.

Initially described as a rare MCA/MR syndrome occurring only in boys, due to a recessive mutation on the X chromosome [Opitz and Kaveggia, 1974], the FG syndrome (FGS) now emerges as a more common disorder also occurring in girls. Based on over 50 reported cases, FGS is associated with developmental delay (especially speech), hypotonia, postnatal onset relative macrocephaly, prominent forehead, frontal hair upsweep, telecanthus, or ocular hypertelorism, thin vermilion border of the upper lip, relatively short fingers with broad thumbs and halluces, persistent fetal fingertip pads, anal anomalies, and/or constipation. Major malformations are rare, and include pyloric stenosis, anal agenesis, cryptorchidism, hypospadias, and congenital heart defects. Abnormal EEGs and seizures have been reported in almost 70% of patients. Brain MRI shows corpus callosum abnormalities associated with dilatation of lateral ventricles and, less frequently, periventricular nodular heterotopias, mild cerebellar defects, and reduced periventricular white matter. Chiari 1 malformation seems to be frequent. The behavior phenotype appears to be characterized by ADHD, and relatively less developed language, fine motor and executive function skills; whereas visual-spatial abilities seem to be a relative strength. Five candidate loci are already known but no gene identified. We describe 25 patients referred to the Stella Maris Institute for evaluation of DD/MR, and diagnosed as FGS. They were between 2 and 15 1/2 years at the first observation. High resolution banding, FRAXA/FRAXE DNA analysis, and subtelomere FISH analysis were performed in all of them, and all had normal results. Thirteen patients were followed-up from 6 months to 9 years. Our report focuses on physical, neurological, developmental findings, and natural history of FGS. Experience with our series of patients suggests that the syndrome may be common, and should be routinely considered in the evaluation of children and adolescents with DD/MR.

Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype.

Neurofibromatosis-Noonan syndrome (NFNS) has been described as a unique phenotype, combining manifestations of neurofibromatosis type 1 (NF1) and Noonan syndrome, which are separate syndromes. Potential etiologies of NFNS include a discrete syndrome of distinct etiology, co-segregation of two mutated common genes, variable clinical expressivity of NF1, and/or allelic heterogeneity. We present an informative family with an unusual NF1 mutation with variable features of NF1 and Noonan syndrome. We hypothesize that an NF1 mutant allele can lead to diagnostic manifestations of Noonan syndrome, supporting the hypothesis that NF1 allelic heterogeneity causes NFNS.

Familial complex 3q;10q rearrangement unraveled by subtelomeric FISH analysis.

In recent years, subtelomeric rearrangements have been identified as a major cause of multiple congenital anomalies/mental retardation syndromes. Currently, more than 2,500 individuals with mental retardation have been tested and reported in whom subtelomeric rearrangements were detected ranging from 2% to 29%. Therefore, subtelomeric FISH analysis is indicated as a second tier test after high-resolution G-banding analysis in patients with otherwise unexplained developmental delay/mental retardation and/or multiple congenital anomalies. We describe a patient and her three maternal female cousins, all showing an undiagnosed MCA/MR syndrome, associated with the same complex subtelomeric rearrangement. Subtelomeric FISH testing performed between 3(1/2) and 18 years after the initial karyotype showed, in all four patients, distal trisomy 3q and distal monosomy 10q as follows: 46,XX,ish der(10)t(3;10)(q29;q26.3)mat(D10S2488+,D10S2490-, D3S1272+,D10Z1+). Parental subtelomeric FISH analysis showed that the proposita's mother and three of four brothers and one of two sisters had a cryptic balanced 3:10 telomere translocation. The three brothers with the balanced translocation were father to one each of the three proband's cousins. All four affected girls showed a similar phenotype with pre/postnatal growth retardation, microcephaly, severe developmental delay/mental retardation, poor/absent speech, and a distinct pattern of malformation. On examination there were coarsening of facial features with low fronto-temporal hairline; thick eyebrows; bilateral epicanthal folds; hypertelorism; prominent nose with squared nasal root and narrow alar base; low-set posteriorly rotated large ears with a prominent anthelix; high arched palate; prominent chin; hands/feet brachydactyly; bilateral squint; hypotonia; and muscle hypotrophy. A slow overall improvement was seen in all patients over time. To our knowledge, this complex subtelomeric rearrangement in our patients has never been reported so far. Monosomy 10q has recently been described either isolated or as part of a complex rearrangement involving telomeres other than the 3q. Trisomy 3q29 has not yet been reported, but our patients resembled cases with 3q26 trisomy suggesting that the critical region of duplication for this phenotype is in 3q29.

Case-control study of the muscular compartments and osseous strength in neurofibromatosis type 1 using peripheral quantitative computed tomography.

Skeletal anomalies are observed in neurofibromatosis type 1 (NF1), but the pathogenesis is unknown. Given that muscle mass is important in the development of the strength of bone, peripheral quantitative computed tomography (pQCT) was utilized to compare measurements of muscle compartments between NF1 individuals and controls. Forty individuals with NF1 (age 5-18 years) were evaluated. Cross-sectional measurements, at the 66% tibial site, were obtained using pQCT (XCT-2000, Stratec) and variables were compared to controls without NF1 ((age 5-18 years, N=380) using analysis-of-covariance controlling for age, height, Tanner stage, and gender. The NF1 cohort showed decreased total cross-sectional area [p<0.001], decreased muscle plus bone cross-sectional area [p<0.001], decreased muscle cross-sectional area [p<0.001], and decreased Stress Strain Index [p=0.010]. These data indicate that NF1 individuals have decreased muscle cross-sectional area and decreased bone strength than individuals without NF1.

Recombinant 4 syndrome due to an unbalanced pericentric inversion of chromosome 4.

An informative patient with a MCA/MR syndrome consisting of developmental delay, prenatal onset growth delay, microcephaly, distinctive face, iris coloboma, and a congenital heart defect was found, on chromosome analysis, to have the following complement: 46,XY,rec(4) dup(4p) inv(4)(p14q35.1) mat. He has a partial 4p trisomy/distal 4q deletion due to an unbalanced pericentric inversion inherited from his mother. Dup (4p) trisomy was originally described by Wilson et al. [1970: Am J Hum Genet 22:679-690] in a similar case with the same chromosome 4 inversion. To date, at least 85 cases of dup (4p) syndrome have been published, mostly due to unbalanced translocations. Recent articles suggest that the phenotype is hard to recognize clinically due to the lack of specificity of findings. In contrast, 4p trisomy due to an unbalanced pericentric inversion of chromosome 4(p14q35), i.e., the recombinant 4 syndrome observed in our patient, appears to be a discrete entity with relatively consistent features. In total there are four other kindreds described in the literature with this inversion, and the phenotype seems recognizable. Thus, we suggest that recombinant 4 syndrome is a discrete entity among 4p trisomy patients.

Pure trisomy 10p resulting from an extra ring chromosome: characterization by methods of advanced molecular cytogenetics.

With the use of advanced molecular cytogenetic techniques, we have identified an extra ring chromosome consisting of the entire short arm of chromosome 10 (10p) in a 9-month-old girl with multiple congenital anomalies. This case represents another cytogenetic mechanism leading to the formation of pure complete trisomy 10p, which has not been reported previously. Pure trisomy 10p is rare. This case will further delineate those features associated with trisomy 10p.

Metronidazole treatment of women with a positive fetal fibronectin test result.

Eighty-nine women with either bacterial vaginosis, Trichomonas vaginalis, or both, who also had a positive fetal fibronectin test result were randomized to two courses of metronidazole treatment as part of a Maternal-Fetal Medicine Network Units study of the National Institute of Child Health and Human Development. In this subgroup analysis, compared with the placebo group, women who were treated with metronidazole had a nonsignificant reduction in spontaneous preterm birth from 14.6% to 8.3%.

Failure of metronidazole to prevent preterm delivery among pregnant women with asymptomatic Trichomonas vaginalis infection.

BACKGROUND: Infection with Trichomonas vaginalis during pregnancy has been associated with preterm delivery. It is uncertain whether treatment of asymptomatic trichomoniasis in pregnant women reduces the occurrence of preterm delivery. METHODS: We screened pregnant women for trichomoniasis by culture of vaginal secretions. We randomly assigned 617 women with asymptomatic trichomoniasis who were 16 to 23 weeks pregnant to receive two 2-g doses of metronidazole (320 women) or placebo (297 women) 48 hours apart. We treated women again with the same two-dose regimen at 24 to 29 weeks of gestation. The primary outcome was delivery before 37 weeks of gestation. RESULTS: Between randomization and follow-up, trichomoniasis resolved in 249 of 269 women for whom follow-up cultures were available in the metronidazole group (92.6 percent) and 92 of 260 women with follow-up cultures in the placebo group (35.4 percent). Data on the time and characteristics of delivery were available for 315 women in the metronidazole group and 289 women in the placebo group. Delivery occurred before 37 weeks of gestation in 60 women in the metronidazole group (19.0 percent) and 31 women in the placebo group (10.7 percent) (relative risk, 1.8; 95 percent confidence interval, 1.2 to 2.7; P=0.004). The difference was attributable primarily to an increase in preterm delivery resulting from spontaneous preterm labor (10.2 percent vs. 3.5 percent; relative risk, 3.0; 95 percent confidence interval, 1.5 to 5.9). CONCLUSIONS: Treatment of pregnant women with asymptomatic trichomoniasis does not prevent preterm delivery. Routine screening and treatment of asymptomatic pregnant women for this condition cannot be recommended.

Wolf-Hirschhorn (4p-) syndrome.

Wolf-Hirschhorn syndrome (WHS) is a well-known congenital malformation syndrome caused by deletion of the short arm of chromosome 4 (4p-). In spite of more than 100 reported cases, information on its natural history remained very limited until recently. It was generally thought that these children had severe developmental disabilities and tended to be mere survivors devoid of personality. However, it is now evident that individuals with WHS are capable of more acquisition of developmental milestones than previously suggested. It is therefore very important to have guidelines for health supervision and anticipatory guidance of such patients. Although thought to affect 1 per 50,000 births, we believe that the syndrome is more common because of the many syndromes with which it is still misdiagnosed, and because only 58% of cases can be recognized on regular G-banding. The following discussion outlines the historical evolution of our recognition of the several complex aspects of this syndrome, from the very early description to the latest knowledge on clinical and cytogenetic/molecular genetic aspects. Its purpose is to draw the attention of professionals (particularly pediatricians and family practitioners) to a clinical disorder that probably affects many more individuals than previously thought. Accurate identification of such patients can lead to the organization of the most appropriate laboratory testing, to the prediction of the prognosis with relative certainty, to the development of the most appropriate health maintenance and educational plans, and to referral of the patient and the family to support groups.

del (9p) syndrome: proposed behavior phenotype.

Over recent years interest in the study of behavior phenotypes has gained increasing momentum. We present three white female patients, age respectively 9 years 9 months, 14 years 6 months and 18 years at the time of the last observation, seen because of developmental delay/mental retardation, seizures and learning disabilities. Cytogenetic analysis showed a de novo deletion of the short arm of chromosome 9 in all three, with the breakpoint being located at band 9p22. Although several studies have described the somatic phenotype, analytical evaluation of verbal and non-verbal cognitive functions are lacking. Our patients received a detailed neuropsychological and linguistic evaluation that showed a particular behavior profile, in the context of mental retardation of variable degree. On selective tests there was a marked deficit in visuo-praxic and visuo-spatial skills associated with memory disturbance. Visuo-motor integration abilities [VMI; Beery, 1997] and visuo-perceptual and visuo-spatial abilities [Benton line orientation test, 1992] seemed particularly impaired, both in relation to verbal mental age (vocabulary and grammatical production/comprehension) and to some non-verbal competencies [Benton face recognition test, 1992]. The profile shows advanced performances in face recognition. In addition, there is also a dissociation between verbal and visuo-spatial short term memory. This behavior phenotype is similar to that of Williams syndrome (WS) individuals. Our patients also showed some unusual within-domain dissociations regarding linguistic abilities. To better demonstrate similarities and differences between the behavior phenotypes of the del (9p22) syndrome and WS, we studied three IQ-gender-matched WS subjects. The comparison between the cognitive phenotypes of the two syndromes shows similarities in neuropsychological pattern. We hypothesize that there is a gene within the 9p22 region responsible for the neuropsychological profile described here.