Perceived social support improves health-related quality of life in cochlear implant patients.

PURPOSE: Perceived social support has been shown to positively correlate with health-related quality of life (HR-QoL) in a variety of conditions. This study investigated whether perceived social support is affecting HR-QoL of patients who receive a cochlear implant (CI) for deafness. METHODS: Eighty eight adults (56 males, 32 females; mean age: 60 years) with a uni- or bilateral CI for bilateral high-grade hearing loss were administered two questionnaires: a questionnaire for perceived social support (FSU-14) and the Nijmegen Cochlear Implant Questionnaire (NCIQ) for hearing-specific HR-QoL. Administration of the questionnaires occurred at four points in time: before implantation and three, 12 and 24 months after implant activation. RESULTS: The CI patients had quite high levels of perceived social support (mean percentile rank: 71), which remained stable at all four measurement points. Multivariate Analysis showed a significant interaction between perceived social support and HR-QoL indicating that higher perceived social support lead to higher improvement of HR-QoL after cochlear implantation. CONCLUSION: The CI patients in this study had higher than average levels of perceived social support, which did not change before and after cochlear implantation. Perceived social support and HR-QoL were related such that patients with high levels of perceived social support experienced greater improvement of their HR-QoL after cochlear implantation than patients with low levels of perceived social support. Based on this finding, perceived social support must be considered as an important factor for HR-QoL after cochlear implantation.

[Development of a German short version of the Nijmegen Cochlear Implant Questionnaire]. / Konstruktion einer Kurzversion des Nijmegen Cochlear Implant Questionnaire in deutscher Sprache.

BACKGROUND: The Nijmegen Cochlear Implant Questionnaire (NCIQ) is a questionnaire for assessing hearing-specific quality of life in the context of cochlear implantation. Its length (60 items) makes it difficult to use in clinical practice, so a short version is desirable. The question arises as to which items should be selected for the short version. METHODS: The items were selected statistically using uncorrected item-total score correlation. Item selection was made based on datasets from three measurement points: before implantation and 3 and 12 months after processor activation. The items were selected according to the criterion that they were among the 40 items with the highest item-total score correlation at each of the three measurement points. RESULTS: Of the 60 items in the NCIQ, 25 met the criterion and were hence included in the short version. The short version yields similar scores as the long version at the postoperative timepoints; however, at the preoperative timepoint, the agreement of the scores is suboptimal. Split-half reliability and internal homogeneity of the short version are very good. CONCLUSION: The present study constitutes an initial positive evaluation of a short form of the NCIQ in terms of standard psychometric criteria. Application of the short form is associated with significantly reduced resources in terms of processing and evaluating.

Multistate Redox-Switchable Ion Transport Using Chalcogen-Bonding Anionophores.

Synthetic supramolecular transmembrane anionophores have emerged as promising anticancer chemotherapeutics. However, key to their targeted application is achieving spatiotemporally controlled activity. Herein, we report a series of chalcogen-bonding diaryl tellurium-based transporters in which their anion binding potency and anionophoric activity are controlled through reversible redox cycling between Te oxidation states. This unprecedented in situ reversible multistate switching allows for switching between ON and OFF anion transport and is crucially achieved with biomimetic chemical redox couples.

Fullerene-Functionalized Halogen-Bonding Heteroditopic Hosts for Ion-Pair Recognition.

Despite their hydrophobic surfaces with localized π-holes and rigid well-defined architectures providing a scaffold for preorganizing binding motifs, fullerenes remain unexplored as potential supramolecular host platforms for the recognition of anions. Herein, we present the first example of the rational design, synthesis, and unique recognition properties of novel fullerene-functionalized halogen-bonding (XB) heteroditopic ion-pair receptors containing cation and anion binding domains spatially separated by C60. Fullerene spatial separation of the XB donors and the crown ether complexed potassium cation resulted in a rare example of an artificial receptor containing two anion binding sites with opposing preferences for hard and soft halides. Importantly, the incorporation of the C60 motif into the heteroditopic receptor structure has a significant effect on the halide binding selectivity, which is further amplified upon K+ cation binding. The potassium cation complexed fullerene-based receptors exhibit enhanced selectivity for the soft polarizable iodide ion which is assisted by the C60 scaffold preorganizing the potent XB-based binding domains, anion-π interactions, and the exceptional polarizability of the fullerene moiety, as evidenced from DFT calculations. These observations serve to highlight the unique properties of fullerene surfaces for proximal charged guest binding with potential applications in construction of selective molecular sensors and modulating the properties of solar cell devices.

Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2.

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.

Longitudinal Development of Verbal and Nonverbal Intelligence After Cochlear Implantation According to Wechsler Tests in German-speaking Children: A Preliminary Study.

OBJECTIVES: Intelligence as a construct of cognitive abilities is the basis of knowledge and skill acquisition and the main predictor of academic achievement. As a broad construct, it is usually divided into subdomains, such as nonverbal and verbal intelligence. Verbal intelligence is one domain of intelligence but is not synonymous with specific linguistic abilities like grammar proficiency. We aim to address the general expectation that early cochlear implantation enables children who are hard of hearing to develop comprehensively, including with respect to verbal intelligence. The primary purpose of this study is to trace the longitudinal development of verbal and nonverbal intelligence in children with cochlear implants (CIs). DESIGN: Sixteen children with congenital hearing loss who received unilateral or bilateral implants and completed at least two intelligence assessments around the age of school entrance were included in the study. The first assessment was performed around 3 years after CI fitting (chronological age range: 3.93 to 7.03 years). The second assessment was performed approximately 2 years after the first assessment. To analyze verbal and nonverbal IQ in conjunction and across children at different ages, we used corresponding standardized and normalized tests from the same test family (Wechsler Preschool and Primary Scale of Intelligence and/or Wechsler Intelligence Scale for Children). RESULTS: Regarding longitudinal development, both verbal and nonverbal IQ increased, but verbal IQ increased more substantially over time. At the time of the second measurement, verbal and nonverbal IQ were on a comparable level. Nevertheless, we also observed strong inter-individual differences. The duration between both assessments was significantly associated with verbal IQ at the second measurement time point and thus with verbal IQ gain over time. Education mode (regular vs. special kindergarten/school) was significantly correlated with nonverbal IQ at the second assessment time point. CONCLUSIONS: The results, despite the small sample size, clearly suggest that children with CIs can achieve intellectual abilities comparable to those of their normal-hearing peers by around the third year after initial CI fitting, and they continue to improve over the following 2 years. We recommend further research focusing on verbal IQ assessed around the age of school entrance to be used as a predictor for further development and for the establishment of an individual educational program.

Halogen-Bonding Heteroditopic [2]Catenanes for Recognition of Alkali Metal/Halide Ion Pairs.

The first examples of halogen bonding (XB) heteroditopic homo[2]catenanes were prepared by discrete Na+ template-directed assembly of oligo(ethylene glycol) units derived from XB donor-containing macrocycles and acyclic bis-azide precursors, followed by a CuI -mediated azide-alkyne cycloaddition macrocyclisation reaction. Extensive 1 H NMR spectroscopic studies show the [2]catenane hosts exhibit positive cooperative ion-pair recognition behaviour, wherein XB-mediated halide recognition is enhanced by alkali metal cation pre-complexation. Notably, subtle changes in the catenanes' oligo(ethylene glycol) chain length dramatically alters their ion-binding affinity, stoichiometry, complexation mode, and conformational dynamics. Solution-phase and single-crystal X-ray diffraction studies provide evidence for competing host-separated and direct-contact ion-pair binding modes. We further demonstrate the [2]catenanes are capable of extracting solid alkali-metal halide salts into organic media.

Selective Potassium Chloride Recognition, Sensing, Extraction, and Transport Using a Chalcogen-Bonding Heteroditopic Receptor.

Chalcogen bonding (ChB) is rapidly rising to prominence in supramolecular chemistry as a powerful sigma (σ)-hole-based noncovalent interaction, especially for applications in the field of molecular recognition. Recent studies have demonstrated ChB donor strength and potency to be remarkably sensitive to local electronic environments, including redox-switchable on/off anion binding and sensing capability. Influencing the unique electronic and geometric environment sensitivity of ChB interactions through simultaneous cobound metal cation recognition, herein, we present the first potassium chloride-selective heteroditopic ion-pair receptor. The direct conjugation of benzo-15-crown-5 ether (B15C5) appendages to Te centers in a bis-tellurotriazole framework facilitates alkali metal halide (MX) ion-pair binding through the formation of a cofacial intramolecular bis-B15C5 M+ (M+ = K+, Rb+, Cs+) sandwich complex and bidentate ChB···X- formation. Extensive quantitative 1H NMR ion-pair affinity titration experiments, solid-liquid and liquid-liquid extraction, and U-tube transport studies all demonstrate unprecedented KCl selectivity over all other group 1 metal chlorides. It is demonstrated that the origin of the receptor's ion-pair binding cooperativity and KCl selectivity arises from an electronic polarization of the ChB donors induced by the cobound alkali metal cation. Importantly, the magnitude of this switch on Te-centered electrophilicity, and therefore anion-binding affinity, is shown to correlate with the inherent Lewis acidity of the alkali metal cation. Extensive computational DFT investigations corroborated the experimental alkali metal cation-anion ion-pair binding observations for halides and oxoanions.

Anion Recognition with Antimony(III) and Bismuth(III) Triaryl-Based Pnictogen Bonding Receptors.

The synthesis and characterisation of a library of acyclic antimony(III) and bismuth(III) triaryl pnictogen bonding (PnB) receptor systems are reported. In the first-generation receptor series, quantitative 1 H NMR chloride titration experiments in THF solvent media reveal halide anion binding potency is intimately correlated with both the electronic-withdrawing nature of the aryl- substituent and the polarisability of the PnB donor. Further extensive anion binding investigations with the most potent Sb- and Bi-based PnB receptors: 1⋅Sb2CF3 and 1⋅Bi2CF3 , reveal novel selectivity profiles, both displaying Cl- selectivity relative to the heavier halides and, impressively, to a range of highly basic oxoanions. The synthesis and preliminary chloride anion binding studies of a series of novel tripodal tris-proto-triazole triaryl Sb(III) and Bi(III) mixed PnB-HB receptor systems are also described. Whereas parent triphenyl Sb(III) and Bi(III) compounds are incapable of binding Cl- in THF solvent media, the PnB-triazole HB host systems exhibit notable halide affinity.

Highly Active Halogen Bonding and Chalcogen Bonding Chloride Transporters with Non-Protonophoric Activity.

Synthetic anion transporters show much promise as potential anti-cancer agents and therapeutics for diseases associated with mis-regulation of protein anion channels. In such applications high activity and anion selectivity are crucial to overcome competing proton or hydroxide transport which dissipates cellular pH gradients. Here, highly active bidentate halogen bonding and chalcogen bonding anion carriers based on electron deficient iodo- and telluromethyl-triazole derivatives are reported. Anion transport experiments in lipid bilayer vesicles reveal record nanomolar chloride transport activity for the bidentate halogen bonding anion carrier, and remarkably high chloride over proton/hydroxide selectivity for the chalcogen bonding anionophore. Computational studies provide further insight into the role of sigma-hole mediated anion recognition and desolvation at the membrane interface. Comparison with hydrogen bonding analogues demonstrates the importance of employing sigma-hole donor motifs in synthetic anionophores for achieving both high transport activity and selectivity.

Modulating Chalcogen Bonding and Halogen Bonding Sigma-Hole Donor Atom Potency and Selectivity for Halide Anion Recognition.

A series of acyclic anion receptors containing chalcogen bond (ChB) and halogen bond (XB) donors integrated into a neutral 3,5-bis-triazole pyridine scaffold are described, in which systematic variation of the electronic-withdrawing nature of the aryl substituents reveal a dramatic modulation in sigma-hole donor atom potency for anion recognition. Incorporation of strongly electron-withdrawing perfluorophenyl units appended to the triazole heterocycle telluro- or iodo- donor atoms, or directly linked to the tellurium donor atom dramatically enhances the anion binding potency of the sigma-hole receptors, most notably for the ChB and XB receptors displaying over thirty-fold and eight-fold increase in chloride anion affinity, respectively, relative to unfluorinated analogues. Linear free energy relationships for a series of ChB based receptors reveal the halide anion recognition behaviour of the tellurium donor is highly sensitive to local electronic environments. This is especially the case for those directly appended to the Te centre (3⋅ChB), where a remarkable enhancement of strength of binding and selectivity for the lighter halides is observed as the electron-withdrawing ability of the Te-bonded aryl group increases, highlighting the exciting opportunity to fine-tune anion affinity and selectivity in ChB-based receptor systems.

Halogen Bonding Tetraphenylethene Anion Receptors: Anion-Induced Emissive Aggregates and Photoswitchable Recognition.

A series of tetraphenylethene (TPE) derivatives functionalized with highly potent electron-deficient perfluoroaryl iodo-triazole halogen bond (XB) donors for anion recognition are reported. 1 H NMR titration experiments, fluorescence spectroscopy, dynamic light scattering measurements, TEM imaging and X-ray crystal structure analysis reveal that the tetra-substituted halogen bonding receptor forms luminescent nanoscale aggregates, the formation of which is driven by XB-mediated anion coordination. This anion-coordination-induced aggregation effect serves as a powerful sensory mechanism, capable of luminescence chloride sensing at parts per billion concentration. Furthermore, the doubly substituted geometric isomers act as unprecedented photoswitchable XB donor anion receptors, where the composition of the photostationary state can be modulated by the presence of a coordinating halide anion.

Pharmacotherapy in Rare Skeletal Diseases.

New therapeutic approaches have been established in the field of rare skeletal diseases (e.g., for osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia, and fibrodysplasia ossificans progressiva). After elucidation of the underlying genotypes and pathophysiologic alterations of these diseases, new treatment options have been designed. Most drugs are based on an interaction with the disease-specific cascade of enzymes and proteins involved in the disease. Thereby an approved treatment is available for children with severe forms of hypophosphatasia and hypophosphatemic rickets (asfotase alfa, burosumab). Additionally, there are different phase 3 trials ongoing assessing the efficacy and safety of drugs for osteogenesis imperfecta, achondroplasia, and fibrodysplasia ossificans progressiva (denosumab, vosoritide, palovarotene).Because all these diseases are rare, the number of investigated patients in the trials is small, and the knowledge about rare side effects and long-term outcome is limited. Therefore it is recommended to treat the patients in specialized centers where the effects of the drugs can be evaluated and data about safety, side effects, and efficacy can be collected.Based on the fact that most drugs for rare diseases are highly expensive clear indications for start of a treatment, evaluation of the therapy and recommendations how long a treatment has to be administrated are urgently needed.

Cochlear implantation in adults with single-sided deafness: generic and disease-specific long-term quality of life.

PURPOSE: To determine the 2-year outcome of health-related quality of life (HRQoL) in adults who received a cochlear implant (CI) for single-sided deafness (SSD). METHODS: Twenty adults (mean age at implantation: 47 ± 11 years) with SSD (PTA worse ear: 113 dB HL, PTA better ear: 14 dB HL) were administered the Nijmegen Cochlear Implant Questionnaire (NCIQ), and the Health Utility Index 3 (HUI 3). Questionnaire administration occurred before cochlear implantation and 3, 6, 12, and 24 months after implant activation. RESULTS: Of the 20 patients, 2 discontinued CI use within the observation period due to poor benefit. The NCIQ total score of the sample increased significantly over time (p = 0.003). The largest increase occurred within the first 3 months of CI use. Also, the HUI 3 multi-attribute utility score increased significantly (p = 0.03). The post-treatment increase of this score (+ 0.11 points) indicated that the gain in HRQoL was clinically relevant. Patients with a duration of deafness > 10 years had in all measures an equal HRQoL improvement than had patients with a duration of deafness < 10 years. CONCLUSION: Cochlear implantation led to significant improvement of hearing-specific and generic HRQoL in our patients. The improvement was seen after 3 or 6 months but did not increase further at later intervals. Patients with long-lasting SSD may be at higher risk of discontinuing CI use. However, if they adapt to the CI, they can experience an equal increase of HRQoL as patients with a short duration of SSD.

Do Personality Factors Assessed Before Cochlear Implantation Predict Hearing-Related Quality Of Life After Cochlear Implantation in Postlingually Deafened Adults?

BACKGROUND: Studies have shown that cochlear implants improve deaf patients' hearing-related quality of life (hrQoL), but the degree of improvement varies considerably between patients. This study investigated whether personality factors contribute to hrQoL outcome after cochlear implantation. METHOD: Fifty adult patients with postlingual hearing loss who received a unilateral cochlear implant were administered the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI; a personality inventory) and the Nijmegen Cochlear Implant Questionnaire (NCIQ; a hrQoL questionnaire). The NEO-FFI was administered only before implantation; the NCIQ was administered before implantation and 12 months after implant activation. A linear regression analysis was computed to detect whether NCIQ scores at 12 months were predicted by the NEO-FFI personality factors (i.e., Extraversion, Neuroticism, Openness to Experience, Agreeableness, and Conscientiousness) assessed before implantation. RESULTS: HrQoL scores had significantly improved 12 months after cochlear implantation in all subdomains of the NCIQ. Of the five personality factors, solely Neuroticism was negatively associated to the NCIQ subdomain self-esteem (ß = -0.34; p = 0.013) at 12 months after cochlear implantation. CONCLUSIONS: While significant improvement of hrQoL was seen 12 months after implant activation, this improvement was barely predicted by the Big-Five personality traits measured before implantation. Only Neuroticism was found to moderately influence postimplantation hrQoL in our patients, in the way that higher degrees of Neuroticism tend to go along with lower degrees of self-esteem (as conceptualized by the NCIQ). The failure to detect personality effects on hrQoL could partly be due to the low levels of Extraversion and Openness to Experience observed in our sample of patients with hearing loss.

TBS as a Tool to Differentiate the Impact of Antiresorptives onCortical and Trabecular Bone in Children With OsteogenesisImperfecta.

INTRODUCTION/BACKGROUND: Osteogenesis imperfecta is a hereditary connective tissue disorder, resulting in low bone mass and high bone fragility. Dual-energy X-ray absorptiometry (DXA) and in adulthood also the trabecular bone score (TBS) are well established to assess bone health and fracture risk. The purpose of this investigation was to assess the usefulness of TBS in respect to different treatment regimes in children with osteogenesis imperfecta. Changes of areal bone mineral density (aBMD) and TBS using DXA scans of children treated with antiresorptive therapies were evaluated. METHODOLOGY: DXA scans (aBMD, TBS) of 8 children with OI were evaluated. The scans were taken during a 1 yr period of treatment with bisphosphonates and during 1 yr pilot trial using denosumab. Changes of aBMD and TBS during both treatment regimens were compared. RESULTS: During bisphosphonate treatment aBMD increased about 6.2%, while TBS increased about 2.1%. The difference between aBMD and TBS before and after bisphosphonate treatment was not significant (p = 0.25). During denosumab treatment aBMD increased around 25.1%, while TBS increased 6.7%. The change of aBMD was significant (p = 0.007), as was the difference between aBMD and TBS (p < 0.001). CONCLUSIONS: Denosumab had a significant effect on both aBMD and TBS but was significantly more pronounced in aBMD. These results suggest a stronger effect of denosumab on cortical bone and the growth plate in comparison to bisphosphonates. Beside the lack of paediatric reference data and the small sample size, the results suggest TBS to be a useful tool for monitoring skeletal changes during development, growth, and antiresorptive therapy in children with OI.

The impact of etiology and duration of deafness on speech perception outcomes in SSD patients.

OBJECTIVE: To investigate a cohort of adult single-sided deafness (SSD) patients who received a cochlear implant and to determine the impact of underlying causes of etiology and duration of deafness on outcome STUDY DESIGN: Retrospective data analysis SETTING: Tertiary referral centre with a large cochlear implant program SUBJECTS AND METHODS: A demographic description of 55 adult patients implanted between 2009 and 2016. The best available speech perception score in every patient using the Freiburg Numbers, Freiburg Monosyllables and the Hochmair-Schulz-Moser (HSM) sentence test measured at the 1-, 3-, 6- and 12-month intervals, and the yearly follow-up appointments were examined. A multivariate regression analysis was conducted on the variables speech test, duration of deafness and etiology. Patients were split into four groups according to their duration of deafness (shorter duration of 10 years or less versus longer duration of more than 10 years) and etiology (inflammatory disease versus other causes). RESULTS: The median word reception score for the Monosyllables at 65 dB SPL were 43.75% (IQR: 29.38) and 67.50% (IQR: 25.63) at 80 dB SPL at 1 year following cochlear implantation. The median percentage score correct for the HSM sentence test was 80% (IQR: 62.95). Etiology of the reviewed patient cohort revealed that most frequent causes for deafness were sudden hearing losses and inflammatory etiologies, e.g. otitis media, labyrinthitis, meningitis, cholesteatoma or mumps. The duration of deafness was not significantly associated with poor speech perception outcome. A significant correlation was found for inflammatory diseases and duration of deafness of longer than 10 years. CONCLUSION: The etiology and duration of deafness are important factors for the estimated outcome in speech perception in SSD patients. Presented data reveal that an inflammatory disease leading to deafness in combination with a long duration of deafness (10 + years) lead to poorer speech perception outcomes.

Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta.

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205(∗)) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).

Complex lipid globules in early-life nutrition improve long-term metabolic phenotype in intra-uterine growth-restricted rats.

Intra-uterine growth restriction (IUGR) is associated with adverse metabolic outcome later in life. Healthy mice challenged with a Western-style diet (WSD) accumulated less body fat when previously fed a diet containing large lipid globules (complex lipid matrix (CLM)). This study was designed to clarify whether an early-life CLM diet mitigates 'programmed' visceral adiposity and associated metabolic sequelae after IUGR. In rats, IUGR was induced either by bilateral uterine vessel ligation (LIG) or sham operation (i.e. intra-uterine stress) of the dam on gestational day 19. Offspring from non-operated (NOP) dams served as controls. Male offspring of all groups were either fed CLM or 'normal matrix' control diet (CTRL) from postnatal days (PND) 15 to 42. Thereafter, animals were challenged with a mild WSD until dissection (PND 98). Fat mass (micro computer-tomograph scan; weight of fat compartments), circulating metabolic markers and expression of 'metabolic' genes (quantitative real-time PCR) were assessed. CLM diet significantly reduced visceral fat mass in LIG at PND 40. At dissection, visceral fat mass, fasted blood glucose, TAG and leptin concentrations were significantly increased in LIG-CTRL v. NOP-CTRL, and significantly decreased in LIG-CLM v. LIG-CTRL. Gene expression levels of leptin (mesenteric fat) and insulin-like growth factor 1 (liver) were significantly reduced in LIG-CLM v. LIG-CTRL. In conclusion, early-life CLM diet mitigated the adverse metabolic phenotype after utero-placental insufficiency. The supramolecular structure of dietary lipids may be a novel aspect of nutrient quality that has to be considered in the context of primary prevention of obesity and metabolic disease in at-risk populations.

Correlation of Bone Mineral Density on Quality of Life in Patients with Osteogenesis Imperfecta during Treatment with Denosumab.

Osteogenesis imperfecta (OI) is a rare hereditary skeletal disease leading to recurrent fractures, short stature and impaired mobility. The phenotype varies from mildly affected patients to perinatal lethal forms. In most cases an impaired collagen production due to mutations in COL1A1 or COL1A2 cause this hereditary bone fragility syndrome with an autosomal dominant inheritance. Currently an interdisciplinary therapeutic approach with antiresorptive drugs, physiotherapy and surgical procedures is the state of the art therapy. The effect of such a therapy is evaluated by measuring different surrogate parameters like areal bone mineral density or by using different mobility tests or questionnaires. Up till now the impact of these parameters on quality of life of the patients is not evaluated. Currently pharmacological strategies are based on antiresorptive treatment with bisphosphonates. In this trial we investigated the effect of an antiresorptive therapy with the monoclonal antibody denosumab decreasing the activity of osteoclasts. Denosumab was administered subcutaneously in a dose of 1mg/kg body weight in 10 children with OI (5-10 years of age) every 12 weeks for 48 weeks. Areal bone mineral density, mobility, pain scores and quality of life were measured. The results showed a good effect of the treatment on bone mineral density but this improvement showed no correlation to pain and quality of life. In conclusion further trials have to define parameters to assess interventions which influence activities of daily life of the patients. An interdisciplinary approach including physicians, basic researchers and patient organisation is needed to focus research on topics improving quality of life of patients with severe skeletal diseases.