Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure

Aims Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). Methods and results A proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95% confidence interval: 0.79-0.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. Conclusion The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1.     

Neuropathological features in a female fetus with OPHN1 deletion and cerebellar hypoplasia

We report the case of a 33-year-old pregnant woman. The third-trimester ultrasound scan during pregnancy revealed fetal bilateral ventricular dilatation, macrosomia and a transverse diameter of the cerebellum at the 30th centile. A brain MRI scan at 31 weeks of gestation led to a diagnosis of hypoplasia of the cerebellar vermis without hemisphere abnormalities and a non compressive expansion of the cisterna magna. The fetal karyotype was 46,XX. The pregnancy was terminated and array-CGH analysis of the fetus identified a 238 kb de novo deletion on chromosome Xp12, encompassing part of OPHN1 gene. Further studies revealed a completely skewed pattern of X inactivation. OPHN1 is involved in X-linked mental retardation (XLMR) with cerebellar hypoplasia and encodes a Rho-GTPase-activating protein called oligophrenin-1, which is produced throughout the developing mouse brain and in the hippocampus and Purkinje cells of the cerebellum in adult mice. Neuropathological examination of the female fetus revealed cerebellar hypoplasia and the heterotopia of Purkinje cells at multiple sites in the white matter of the cerebellum. This condition mostly affects male fetuses in humans. We report here the first case of a de novo partial deletion of OPHN1, with radiological and neuropathological examination, in a female fetus.     

Autosomal insertional translocation mimicking an X-linked mode of inheritance

Unbalanced insertional translocations are a rare cause of intellectual disability. An unbalanced insertional translocation is a rare chromosomal imbalance, which may result from a balanced insertional translocation present in a phenotypically normal parent. We report here three brothers with intellectual disability, short stature, microcephaly, craniofacial anomalies and small testes. Since their parents and their sister were all phenotypically normal, the pattern of the family suggested an X-linked mode of inheritance. Surprisingly, we identified by array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) in the three brothers an 8q22.3q23.2 deletion resulting from a balanced insertional translocation present in their healthy father. The deletion encompassed the ZFPM2 gene known to be involved in gonadal development, which is consistent with the small testes and abnormal endocrine dosages in the affected brothers. The present report also illustrates that parental analyses by aCGH or qPCR methods are not sufficient when a de novo deletion or duplication is identified in an affected child and that FISH analysis should be performed on metaphase spreads in both parents to deliver an accurate genetic counseling.     

The psychological impact of cryptic chromosomal abnormalities diagnosis announcement

This qualitative study aims to describe the psychological impact of the diagnosis announcement of pathogenic Copy Number Variations (pCNVs). We performed semi-structured interviews of 60 parents of 41 affected children and 5 geneticists who announced the diagnoses. The diagnosis of the best characterized microdeletion syndromes, often defined by patronymic names (e.g. Williams syndrome), is generally made on a clinical basis by geneticists and confirmed by fluorescence in situ hybridization analysis. Chromosomal microarray, on the contrary, can allow the disclosure of rare pCNVs named after cytogenetic formulas, with poorly known clinical consequences: this makes doctors feel less confident with these diagnosis announcements. The disclosure of pCNVs named after cytogenetic formulas does not facilitate the parental mental representation of the disease, leading some parents to call into question the genotype-phenotype correlation or the very notion of a diagnosis. The announcement of inherited pCNVs can increase the feeling of parental guilt; the disclosure of de novo pCNVs can induce a feeling of “breakage” in the mental representation of the parent-child vertical transmission. In conclusion, our study shows that the disclosure of pCNVs has a significant psychological impact: a multidisciplinary approach to the diagnosis announcement, including a psychological support, should be systematically warranted.     

Characterisation of bone following ultrasonic cutting

Objectives

Ultrasonic surgery is an increasingly popular technique for cutting bone, but little research has investigated how the ultrasonic tip oscillations may affect the cuts they produce in bone. The aim of this investigation was to evaluate the oscillation and cutting characteristics of an ultrasonic surgical device.

Materials and methods

A Piezosurgery 3 (Mectron, Carasco, Italy) ultrasonic cutting system was utilised with an OP3 style tip. The system was operated with the tip in contact with porcine bone samples (loads of 50 to 200 g) mounted at 45° to the vertical insert tip and with a water flow of 57 ml/min. Tip oscillation amplitude was determined using scanning laser vibrometry. Bone surfaces defects were characterised using laser profilometry and scanning electron microscopy.

Results

A positive relationship was observed between the magnitude of tip oscillations and the dimensions of defects cut into the bone surface. Overloading the tip led to a reduction in oscillation and hence in the defect produced. A contact load of 150 g provided the greatest depth of cut. Defects produced in the bone came from two clear phases of cutting.

Conclusions

The structure of the bone was found to be an important factor in the cut characteristics following piezosurgery.

Clinical relevance

Cutting of bone with ultrasonics is influenced by the load applied and the setting used. Care must be used to prevent the tip from sliding over the bone at low loadings.