Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion

We report on newborn monozygotic twins with a Noonan-like phenotype, and multiple congenital anomalies due to a monocentric recombinant chromosome 18. The mother carried a paracentric inversion of the long arm of chromosome 18, inv(18)(q21.1q22.3). Cytogenetic, fluorescent in situ hybridization, comparative genomic hybridization and DNA marker analyses allowed the delineation of the deleted (18q22.3–qter) and duplicated (18q12.1–q21.1) chromosomal regions in the recombinant chromosome 18, and suggest that this duplication-deletion chromosome 18 resulted from breakage of a dicentric recombinant chromosome 18 with subsequent reconstitution of telomeric sequences on the long arm. Marked variability is observed in the phenotypic expression of the same chromosomal anomaly in these monozygotic twins. The clinical findings of these patients are compared with those reported in proximal 18q-duplication and distal 18q-deletion patients. The clinical features of both infants are compatible with Noonan syndrome, suggesting that a locus for this syndrome may be located on the long arm of chromosome 18. Received: 16 April 1998 / Accepted: 17 June 1998     

A “Love” Dart Allohormone Identified in the Mucous Glands of Hermaphroditic Land Snails

Animals have evolved many ways to enhance their own reproductive success. One bizarre sexual ritual is the “love” dart shooting of helicid snails, which has courted many theories regarding its precise function. Acting as a hypodermic needle, the dart transfers an allohormone that increases paternity success. Its precise physiological mechanism of action within the recipient snail is to close off the entrance to the sperm digestion organ via a contraction of the copulatory canal, thereby delaying the digestion of most donated sperm. In this study, we used the common garden snail Cornu aspersum to identify the allohormone that is responsible for this physiological change in the female system of this simultaneous hermaphrodite. The love dart allohormone (LDA) was isolated from extracts derived from mucous glands that coat the dart before it is stabbed through the partner''s body wall. We isolated LDA from extracts using bioassay-guided contractility measurement of the copulatory canal. LDA is encoded within a 235-amino acid precursor protein containing multiple cleavage sites that, when cleaved, releases multiple bioactive peptides. Synthetic LDA also stimulated copulatory canal contractility. Combined with our finding that the protein amino acid sequence resembles previously described molluscan buccalin precursors, this indicates that LDA is partially conserved in helicid snails and less in other molluscan species. In summary, our study provides the full identification of an allohormone that is hypodermically injected via a love dart. More importantly, our findings have important consequences for understanding reproductive biology and the evolution of alternative reproductive strategies.     

Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis

Background

Alterations in waveforms in the uterine artery are associated with the development of pre-eclampsia and intrauterine growth restriction. We investigated the predictive accuracy of all uterine artery Doppler indices for both conditions in the first and second trimesters.

Methods

We identified relevant studies through searches of MEDLINE, EMBASE, the Cochrane Library and Medion databases (all records to April 2006) and by checking bibliographies of identified studies and consulting with experts. Four of us independently selected studies, extracted data and assessed study validity. We performed a bivariable meta-analysis of sensitivity and specificity and calculated likelihood ratios.

Results

We identified 74 studies of pre-eclampsia (total 79 547 patients) and 61 studies of intrauterine growth restriction (total 41 131 patients). Uterine artery Doppler ultrasonography provided a more accurate prediction when performed in the second trimester than in the first-trimester. Most Doppler indices had poor predictive characteristics, but this varied with patient risk and outcome severity. An increased pulsatility index with notching was the best predictor of pre-eclampsia (positive likelihood ratio 21.0 among high-risk patients and 7.5 among low-risk patients). It was also the best predictor of overall (positive likelihood ratio 9.1) and severe (positive likelihood ratio 14.6) intrauterine growth restriction among low-risk patients.

Interpretation

Abnormal uterine artery waveforms are a better predictor of pre-eclampsia than of intrauterine growth restriction. A pulsatility index, alone or combined with notching, is the most predictive Doppler index. These indices should be used in clinical practice. Future research should also concentrate on combining uterine artery Doppler ultrasonography with other tests.Pre-eclampsia and intrauterine growth restriction remain important causes of maternal and perinatal morbidity and mortality.^1–3 Maternal complications of pre-eclampsia include coagulopathy, renal and liver failure, and stroke.¹ Adults who were affected by intrauterine growth restriction in utero are at increased risk for cardiovascular disease, hypertension and type 2 diabetes.^4,5Pre-eclampsia and intrauterine growth restriction are characterized by abnormal placenta formation,⁶ which results in inadequate uteroplacental blood flow. This has led to the idea of using Doppler ultrasonography to assess the velocity of uterine artery blood flow as part of routine ultrasound screening.⁷ Low end-diastolic velocities and an early diastolic notch characterize the waveforms of uterine artery blood flow in women who are not pregnant or are in their first trimester. Persistence of a diastolic notch (beyond 24 weeks'' gestation) or abnormal flow velocity ratios have been associated with inadequate trophoblast invasion.⁸Accurate prediction of pre-eclampsia and intrauterine growth restriction is crucial to allow judicious allocation of resources for monitoring and preventive treatment to improve maternal and perinatal outcomes.^9,10 However, studies investigating the predictive accuracy of uterine artery Doppler indices (Box 1) have revealed considerably varied results. Thus, it is questionable whether uterine artery Doppler ultrasonography should be used as a predictive test. We undertook this review to investigate the accuracy of all uterine artery Doppler indices in predicting pre-eclampsia and intrauterine growth restriction.Open in a separate windowBox 1     

Preventive action of organosilicon treatments against disfigurement of wood under laboratory and outdoor conditions

Organosilicons and biocides with known effectiveness against fungal disfigurement were used for dipping or impregnating Scots pine sapwood specimens. All specimens were artificially or naturally weathered and the colour of all specimens was determined with a spectrophotometer at fixed times. After artificial weathering the specimens were used in blue stain tests according to EN 152 or according to the EN 152 reverse method. The naturally exposed specimens were inspected for fungal disfigurement on their back side. Although the results learn that the coating approach is far better than the wood preservatives approach for evaluating blue stain attack of organosilicon-treated wood, organosilicons fail to protect wood under laboratory conditions. Outdoor exposure, however, revealed that organosilicon impregnated specimens were better protected against fungal disfigurement. The addition of a biocide improves the performance. Artificially aged specimens did not show significant colour differences compared to untreated Scots pine sapwood, while naturally aged specimens did, depending on the treatment conditions and presence of biocides. Organosilicons are able to reduce leaching of (degraded) wood constituents, leading to fewer colour changes compared to untreated scots pine and to decreased availability of nutrients for superficial fungal growth.     

Coupling of Domain Swapping to Kinetic Stability in a Thioredoxin Mutant

The thioredoxin (Trx) fold is a small monomeric domain that is ubiquitous in redox-active enzymes. Trxs are characterized by a typical WCGPC active-site sequence motif. A single active-site mutation of the tryptophan to an alanine in Staphylococcus aureus Trx converts the oxidized protein into a biologically inactive domain-swapped dimer. While the monomeric protein unfolds reversibly in a two-state manner, the oxidized dimeric form is kinetically stable and converts to the monomeric form upon refolding. After reduction, the half-life of the dimer decreases many orders of magnitude to ∼ 4.3 h, indicating that the active-site disulfide between Cys29 and Cys32 is an important determinant for the kinetics of unfolding. We propose kinetic stability as a possible evolutionary strategy in the evolution of multimeric proteins from their monomeric ancestors by domain swapping, which, for this biologically inactive Trx mutant, turned out to be an evolutionary dead end.     

Mitochondrial dysfunction leads to reduced chronological lifespan and increased apoptosis in yeast

We previously isolated a Saccharomyces cerevisiae mutant (HsTnII), which displays 40% reduced chronological lifespan as compared to the wild type (WT). In this study, we found HsTnII cultures to be characterized by fragmented and dysfunctional mitochondria, and by increased initiation of apoptosis during chronological aging as compared to WT. Expression of genes encoding subunits of mitochondrial electron transport chain and ATP synthase is significantly downregulated in HsTnII, and as a consequence, HsTnII is not able to respire ethanol. All these data confirm the importance of functional mitochondria and respiration in determining yeast chronological lifespan and apoptosis.     

An experimental loop design for the detection of constitutional chromosomal aberrations by array CGH

Background  

Comparative genomic hybridization microarrays for the detection of constitutional chromosomal aberrations is the application of microarray technology coming fastest into routine clinical application. Through genotype-phenotype association, it is also an important technique towards the discovery of disease causing genes and genomewide functional annotation in human. When using a two-channel microarray of genomic DNA probes for array CGH, the basic setup consists in hybridizing a patient against a normal reference sample. Two major disadvantages of this setup are (1) the use of half of the resources to measure a (little informative) reference sample and (2) the possibility that deviating signals are caused by benign copy number variation in the "normal" reference instead of a patient aberration. Instead, we apply an experimental loop design that compares three patients in three hybridizations.     

Forging Links between Human Mental Retardation–Associated CNVs and Mouse Gene Knockout Models

Rare copy number variants (CNVs) are frequently associated with common neurological disorders such as mental retardation (MR; learning disability), autism, and schizophrenia. CNV screening in clinical practice is limited because pathological CNVs cannot be distinguished routinely from benign CNVs, and because genes underlying patients'' phenotypes remain largely unknown. Here, we present a novel, statistically robust approach that forges links between 148 MR–associated CNVs and phenotypes from ∼5,000 mouse gene knockout experiments. These CNVs were found to be significantly enriched in two classes of genes, those whose mouse orthologues, when disrupted, result in either abnormal axon or dopaminergic neuron morphologies. Additional enrichments highlighted correspondences between relevant mouse phenotypes and secondary presentations such as brain abnormality, cleft palate, and seizures. The strength of these phenotype enrichments (>100% increases) greatly exceeded molecular annotations (<30% increases) and allowed the identification of 78 genes that may contribute to MR and associated phenotypes. This study is the first to demonstrate how the power of mouse knockout data can be systematically exploited to better understand genetically heterogeneous neurological disorders.     

Assessment of blue-stain resistance according to the EN 152 and a reverse test method using visual and computer-aided techniques

A computer technique for assessing blue-stained coated wood has been implemented for evaluating the discoloration of coatings and analysing the interior wood staining of samples subjected to testing according to European Standard EN 152. The comparison of visual assessment and computer-evaluated percentages of blue staining is based on a combination of correlation measures, principal components and cluster analysis. It appears difficult to imitate human evaluation with image processing, since computer ratings represent exact percentages, while subjective evaluations do not. Additionally, more specific techniques for exploring fungal growth in coated wood have been described. As EN 152 was specifically developed for testing efficacy of wood preservatives, a modified test methodology was elaborated for testing the efficacy of wood coatings, called here as the EN 152-reverse method. Furthermore three-dimensional (3D) reconstruction is validated as a tool for in-depth analysis of blue-stain disfigurement. This 3D visualisation indicates important differences in fungal infestation and proves its suitability for blue-stain resistance testing.