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Click here for the corresponding questions to this CME article. [ABSTRACT FROM AUTHOR]

Autosomal recessive congenital ichthyosis ( ARCI) caused by mutations in CYP4F22 is very rare. CyP4F22, a protein of the cytochrome-P450 family 4, encodes an epidermal ω-hydroxylase decisive in the formation of acylceramides, which is hypothesized to be crucial for skin-barrier function. We report a girl with consanguineous parents presenting as collodion baby with contractures of the great joints and palmoplantar hyperlinearity. In the course of the disease she developed fine scaling of the skin with erythroderma, the latter disappearing until the age of 6 months. Her sister showed a generalized fine-scaling phenotype, and, interestingly, was born without a collodion membrane. The analysis of all known candidate genes for ARCI in parallel with a next-generation sequencing approach using a newly designed dermatogenetics gene panel revealed a previously unknown homozygous splice-site mutation c.549+5G>C in CYP4F22 in both girls, confirming the diagnosis of ARCI. Ultrastructural analysis by transmission electron microscopy in both patients showed epidermal hyperplasia, orthohyperkeratosis with persistence of corneodesmosomes into the outer stratum corneum layers, fragmented and disorganized lamellar lipid bilayers, which could be ascribed to inhomogeneous lamellar body secretion, as well as lamellar body and lipid entombment in the corneocytes. These findings correlated with increased transepidermal water loss on the functional level. For the first time, we report a collodion baby phenotype and epidermal barrier impairment in CyP4F22-deficient epidermis at both the ultrastructural and functional level, and corroborate the importance of CyP4F22 for epidermal maturation and barrier function. [ABSTRACT FROM AUTHOR]

Objective: We sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep. Methods: This was an 8-week, double-blind, placebo-controlled, randomized, two period, crossover study of youth with attention-deficit hyperactivity disorder (ADHD) as confirmed by the Kiddie Schedule for Affective Disorders for School-Age Children-Present and Lifetime version (K-SADS-PL). Children aged 10-17 years were recruited from clinical practice, colleague referrals, and flyers. Participants were randomized to initially receive either d-MPH or MAS. During each 4-week drug period, children received three dose levels (10, 20, and 25/30 mg) in ascending order, with placebo substituted for active medication in a randomized fashion during 1 week of the study. After 4 weeks, participants were switched to the alternative medication for another 4 weeks of treatment. The main outcome measure was sleep duration as measured by actigraphy. Children, parents, and researchers were blinded to drug, dose, and placebo status. Results: Sixty-five participants met the inclusion criteria and were enrolled in the study. Of these, 37 participants with sufficient sleep data for analysis were included. Sleep schedule measures showed a significant effect for dose on sleep start time ( F(1,36) = 6.284; p < 0.05), with a significantly later sleep start time when children were receiving 20- or 30-mg doses, compared with placebo ( p < 0.05). A significant dose effect was found on actual sleep duration ( F(1,36) = 8.112; p < 0.05), with significantly shorter actual sleep duration for subjects receiving 30 mg compared with those receiving placebo ( p < 0.05). There were no significant differences on sleep duration or sleep schedule between the two stimulant medications. The trial is complete and closed to follow-up. Conclusions: Higher stimulant doses were associated with reduced sleep duration and later sleep start times, regardless of medication class. Trial registration: ClinicalTrials.gov: NCT00393042. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Catecholamines released from β-adrenergic neurons upon stress can interfere with periodontal regeneration. The cellular mechanisms, however, are unclear. Here, we assessed the effect of catecholamines on proliferation of periodontal fibroblasts. Methods: Fibroblasts from the gingiva and the periodontal ligament were exposed to agonists of the β-adrenergic receptors; isoproterenol (ISO, non-selective β-adrenergic agonist), salbutamol (SAL, selective β2-adrenergic receptor agonist) and BRL 37344 (BRL selective β3-receptor agonist). Proliferation was stimulated with platelet-derived growth factor-BB (PDGF-BB). Pharmacological inhibitors and gene expression analysis further revealed β-adrenergic signalling. Results: Gingiva and periodontal ligament fibroblast express the β2-adrenergic receptor. ISO and SAL but not BRL decreased proliferation of fibroblasts in the presence of PDGF-BB. The inhibitory effect of β-adrenergic signalling on proliferation but not protein synthesis in response to PDGF-BB was reduced by propranolol, a non-selective β-adrenergic antagonist. Conclusions: These results suggest that β2-receptor agonists can reduce the mitogenic response of periodontal fibroblasts. These data add to the compelling concept that blocking of β2-receptor signalling can support tissue maintenance and regeneration. [Copyright &y& Elsevier]

Abstract: Purpose: To determine the accuracy of a probably benign assessment of non-palpable breast lesions (BI-RADS category 3) at mammography and/or ultrasound with immediate histological work-up. Materials and methods: Stereotactic or ultrasound guided core needle breast biopsy (NBB) was performed to evaluate 288 lesions, which were prospectively assessed as BI-RADS category 3. Imaging findings included 195 masses, 73 calcification cases, 16 focal asymmetries, and four architectural distortion cases. After NBB, patients underwent either open surgical biopsy (OSB) (n =204) or mammographic follow-up (n =84) for at least 24 months. Histological results of NBB were compared with those of OSB. Results: Three of the 288 lesions (1.0%) proved to be malignant at histological work-up, two of them were ductal carcinoma in situ (DCIS) and one of them was an invasive carcinoma. NBB revealed invasive carcinoma in 1/288 (0.35%) and atypical ductal hyperplasia (ADH) in 13/288 (4.5%) lesions. OSB revealed DCIS in 2/204 (1%) and invasive carcinoma in 1/204 (0.5%) lesions. The two DCIS were underestimated as ADH by NBB. The remaining 285 (99%) lesions proved to be benign at OSB or remained stable during follow-up. Conclusion: Confirmed by tissue diagnosis, the low likelihood of malignancy of prospectively assessed probably benign lesions is below the 2% threshold established for BI-RADS category 3. Imaging follow-up is a safe and effective alternative to immediate histological work-up for such lesions. [Copyright &y& Elsevier]

Abstract: Purpose: To determine the frequency with which stereotactic 11-g vacuum-assisted breast biopsy (11-g SVAB) obviates an open surgical biopsy (OSB), to compare the costs of these two biopsy methods, and to estimate the potential cost savings attributable to 11-g SVAB in the diagnosis of suspicious breast lesions in patients in Austria. Materials and methods: We retrospectively reviewed 318 consecutive breast lesions of BI-RADS categories IV and V (microcalcifications n =166; masses n =152) on which 11-g SVAB and OSB were performed. Cost savings were calculated using nationally allowed flat rates and patient charges. Costs were measured from a hospital and a socioeconomic perspective. Common clinical scenarios and sensitivity analyses assessed the extent of achievable cost savings. Results: 11-g SVAB obviated the need for an OSB in 93 (29%) of 318 women. Overall cost savings per 11-g SVAB over OSB were € 242 per case from a hospital perspective, and € 422 per case from a socioeconomic perspective. The use of 11-g SVAB decreased the cost of diagnosis by 7% from a hospital perspective, and by 10% from a socioeconomic perspective. Conclusion: In Austria, annual national savings of over 5 million Euro could be realized with the use of 11-g SVAB for the diagnosis of suspicious breast lesions. Although savings per case are modest, the national health care system realizes significant cost reduction as women benefit from a faster and less invasive approach to diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To examine the budget impact of ultrasound-guided 14-g large core breast biopsy (US-guided LCBB) by comparing the costs of US-guided LCBB and open surgical biopsy (OSB); to calculate the cost savings attributable to US-guided LCBB; and to assess the frequency with which US-guided LCBB obviates the need for an OSB. Materials and methods: In a retrospective study, we reviewed 399 suspicious breast lesions on which US-guided LCBB and OSB or, in cases of benign histology, clinical follow-up, were performed. Cost savings were calculated using nationally allowed flat rates (A-drg) and patient charges. Costs were measured from both, a hospital and a socioeconomic perspective. Deterministic sensitivity analyses were simulated to assess the extent of achievable cost savings. Results: Overall cost savings for US-guided LCBB over OSB were €977 (€2,337/€3,314) per case from a hospital perspective, resulting in a total cost decrease of 30% for the diagnosis of suspicious breast lesions. From a socioeconomic perspective, cost savings were €1,542 (€2,600/€4,142) per case, resulting in a 37% reduction in biopsy cost. US-guided LCBB obviated the need for a surgical procedure in 240 (60%) of 399 women. In all four sensitivity analyses, costs of US-guided LCBB remained lower than that of OSB. Conclusion: From an economic perspective, US-guided LCBB is highly recommended for the diagnosis of suspicious breast lesions, as this procedure reduces the cost of diagnosis substantially. In Austria, annual cost savings would be €18.5 million. [Copyright &y& Elsevier]

Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16 or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Loss-of-function mutations in the filaggrin ( FLG) gene underlie the most prevalent skin disorder of cornification, ichthyosis vulgaris (IV), which presents with generalized scaling and is also associated with atopic dermatitis. Recently, FLG mutations have been reported to increase phenotype severity of X-linked ichthyosis and alopecia areata. We report a parent–child trio in which the mother and the son have PC and the father has IV. Both the mother and the son are carriers for the KRT16 mutation p.Leu132Pro. The son, who is much more severely affected than his mother, in addition carries the heterozygous FLG mutation p.R2447X, which was inherited from the father. This observation suggests that coinheritance of mutations in KRT16 and FLG may aggravate the PC phenotype and that FLG could serve as a genetic modifier in PC. [ABSTRACT FROM AUTHOR]

Objectives: The present study was conducted to test the hypothesis that preshaped polylactic acid (PLA) implants loaded with recombinant human bone morphogenic protein 2 (rhBMP-2) can induce bone formation in a rat ectopic model. Materials and methods: Two groups of porous cylindrical poly-dl-lactic acid implants of 8-mm diameter were produced by gas foaming with CO2, incorporating 48 and 96 μg rhBMP-2, respectively, into each implant. Blank PLA implants were used as controls. The release of BMPs and the induction of alkaline phosphatase were assessed in vitro. Osteoinduction in vivo was tested by insertion of 15 implants from each group into the gluteal muscles of Wistar rats. Five implants from each group were retrieved after 6, 13 and 26 weeks and assessed using flat panel volume detector computed tomography and light microscopy. Results: Both groups of implants showed increased release of rhBMP-2 during the first 24–48 h, with a slightly higher amount being released from the implants with 48 μg. Release during subsequent intervals was <100 ng/72 h in the low-concentration group and >100 ng in the group with 96 μg rhBMP-2. Implants with 95 μg rhBMP-2 exhibited bone formation in vivo on the outside of the implants across the observation period of 26 weeks with invasion of bone into the pores, whereas implants with 48 μg rhBMP-2 failed to induce the formation of bone tissue. No bone formation was found in the control implants. Conclusions: The results suggest that release rates of rhBMP-2 for ectopic bone induction have to be >100 ng/72 h to maintain the osteoinductive activity of the tested porous PLA implants. This slow release system may have impact on alveolar bone augmentation procedures when used as individually preformed osteoinductive implants. [ABSTRACT FROM AUTHOR]

Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud’s disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia. [ABSTRACT FROM AUTHOR]

Background Different systems for preparation of platelet-rich plasma are commercially available, but data for comparison of these systems have not been published so far. Materials and Methods We investigated the performance of Vivostat PRF Preparation Kit®, PCCS Platelet Concentrate Collection System®, Harvest® SmartPReP 2 APC 60 Process, and Fibrinet® Autologous Fibrin & Platelet System. The preparations provided by these systems are platelet concentrates with high numbers of platelets in a small volume of plasma and PDGF-AB is released continuously during the 5 days after preparation. Results Vivostat PRF Preparation Kit, PCCS Platelet Concentrate Collection System, Harvest SmartPReP 2 APC 60 Process are comparable in platelet yield and total amount of released PDGF-AB after 120 h while with Fibrinet the lowest platelet yield and PDGF-AB content of supernatant was achieved. The ability of growth factor release was equal in all four systems. Conclusion In conclusion, all four systems for preparation of platelet-rich plasma investigated result in considerable growth factor release. In what extent the total content of PDGF-AB as a consequence of platelet yield has an impact on wound healing has to be further investigated [ABSTRACT FROM AUTHOR]

Gruber R, Jindra C, Kandler B, Watzak G, Fischer MB, Watzek G. Proliferation of dental pulp fibroblasts in response to thrombin involves mitogen-activated protein kinase signalling. International Endodontic Journal, 37, 145–150, 2004. To examine the involvement of mitogen-activated protein kinases (MAPK) signalling on thrombin-stimulated human dental pulp fibroblasts (DPF). Dental pulp fibroblasts were isolated from dental pulp connective tissue of third molars and expanded in vitro. Expression of thrombin receptors was analysed by RT-PCR, and cell proliferation was measured by 3[H]-thymidine incorporation assay. Phosphorylation levels of MAPK were determined by Western blot analysis, and alkaline phosphatase activity was measured to serve as a marker for odontogenic differentiation. Statistical analysis was performed by Student's t-test. Dental pulp fibroblasts express the thrombin receptors protease-activated receptor-1 (PAR-1), PAR-3 and PAR-4. Measurement of 3[H]-thymidine incorporation revealed a dose-dependent increase of DNA synthesis in response to thrombin treatment. The thrombin-induced mitogenic activity was decreased by the extracellular signal-regulated protein kinase (ERK) signalling inhibitor PD98059 ( P < 0.05), and by SB203580 ( P < 0.05), a p38 MAPK inhibitor. Western blot analysis demonstrated increased phosphorylation of ERK in DPF following stimulation with thrombin, while p38 MAPK and c-Jun NH2-terminal kinase (JNK) were not activated. Alkaline phosphatase activity of DPF remained unchanged upon incubation with thrombin. These results suggest that signalling via MAPK mediates the mitogenic activity of thrombin on DPF and may thus play a role during the early stages of pulp repair. [ABSTRACT FROM AUTHOR]

Time-of-flight (TOF) experiments in the low energy ion scattering (LEIS) regime are reported for He projectiles and a copper target for a scattering angle of 129°, aiming at a more profound physical understanding of the neutralization process. In our experiment, the ions are separated from the neutrals by post-acceleration along the flight path between the target and the detector. The spectrum of the neutrals yields information about deeper layers, as in Rutherford backscattering (RBS). Ions originate from scattering by surface atoms, the ion yield being characterized by the ion fraction P+. Our P+ results indicate that at energies >2 keV a second neutralisation mechanism sets in that is similarly effective as the one that is important at low energies. Above the threshold energy for reionization, a non-monotonous behavior of P+ as function of the reciprocal velocity is found. Our data are compared to available data from the literature, yielding mutual agreement within the combined error bars. [Copyright &y& Elsevier]

Platelets are activated at fracture sites or upon the insertion of implants as a consequence of vascular disruption and secrete the contents of their granules into the developing hematoma. The regeneration of injured tissue requires bone remodeling and the resorbing activity of osteoclasts. To test our hypothesis that platelets can stimulate osteoclastogenesis, we examined the effects of supernatants released from thrombin-activated platelets on osteoclast-like cell formation in murine bone marrow cultures. Histochemical analysis indicated the presence of bone-resorbing, tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. Transcripts that are characteristically expressed in native osteoclasts were increased in these cultures, as determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. The inhibition of both cyclooxygenases with indomethacin, as well as the addition of the cyclooxygenase-2 (COX-2)-selective antagonist, NS398, completely blocked osteoclast-like cell formation and decreased endogenous prostaglandin E2 production. Platelet-released supernatants stimulated the expression of receptor activator of NF-κB ligand (RANKL), whereas mRNA levels of osteoprotegerin (OPG) were decreased. The formation of osteoclast-like cells was prevented by recombinant OPG. Our results suggest that COX-2 activity is necessary for osteoclast-like cell formation in response to platelet-released supernatants, and that endogenously produced prostaglandin E2 can, in turn, increase the RANKL:OPG ratio, indicating that platelets can contribute to bone remodeling by stimulation of osteoclastogenesis. [Copyright &y& Elsevier]

A letter to the editor is presented which discusses a case study that focuses on the occurrence of refractory takayasu arteritis in a 65-year-old patient.

Bilateral renal agenesis causes uniformly fatal outcome due to associated pulmonary hypoplasia caused by the absence of amniotic fluid. Amniocentesis for karyotyping and amnio-infusion to improve ultrasound quality are suggested and termination of pregnancy is discussed. Postnatal MRI confirms bilateral renal agenesis, but also shows duodenal atresia, intestine stenosis and caudal regression syndrome including anal atresia. [Extracted from the article]

Patient (F5-1) had a cirrhosis at the age of 34 years (after 12 years of OR), but liver blood parameters remained stable during the 31 years of follow-up. Before introducing OR, all also had liver anomalies, that consisted in either increased liver enzymes, hyper echogenic liver, hepatosplenomaly or cirrhosis for one patient (F6-1). In conclusion, awaiting future targeted therapy for DCS or prospective monitoring studies, there is no safety signal to contraindicate OR in CDS patients with disabling skin anomalies, on condition that a close monitoring is performed. [Extracted from the article]

The article discusses research on the risk of psoriasis in subjects with childhood asthma. It references a study by A. Egeberg et al published within the issue. Topics covered include the underlying pathophysiology in psoriasis, the major advantages of the study, and the bidirectional relationship between psoriasis and asthma.

In this study a close to reality one component (1K) structural epoxy adhesive is introduced. The physical properties have been investigated by means of gravimetric water uptake, bulk tensile tests, and lap shear tests. The influence of two different types of hollow glass microspheres (HGM) on the ageing behaviour has been observed via accelerated ageing tests followed by lap shear tests of galvanized steel. Results show that the formulation described outperforms very brittle and basic systems consisting of bisphenol A diglycidyl ether (DGEBA) and dicyandiamide (DICY) in terms of ductility. The addition of HGM resulted in higher water absorption suggesting that water gathers as a liquid in the HGM. Further, the addition of HGM led to an increase of the cohesion failure percentage on unaged lap shear specimens without significantly influencing the tensile shear strength and the addition of the bigger HGM observed led to a change in fracture mechanism from substrate-near cohesion failure to cohesion failure. The results of this study on the long-term durability of bonded steel joints indicate that the addition of HGM into the adhesive system has no significant effect on the ageing behaviour in two of three corrosion tests. It can be concluded that the incorporation of HGM is a possible solution not only reducing the amount of chemicals required for automotive adhesive production, but also promoting lightweight construction because of the decreased density of the adhesive system. • A novel, near to realism structural epoxy adhesive for scientific purposes. • Gravimetric water uptake in structural epoxy adhesive. • Ageing resistance of adhesively bonded steel sheets. • Addition of hollow glass microspheres changes fracture mechanism. [ABSTRACT FROM AUTHOR]

Linked Article: Valentin et al. Br J Dermatol 2021; 184:1123–1131. [ABSTRACT FROM AUTHOR]

In the current paper, we first introduce the research themes of the attention, behaviour and sleep (ABS) laboratory, namely, sleep and ADHD, sleep and obesity, and sleep and academic performance. We then focus in on the topic to be reviewed in the current paper – the association between sleep restriction and neurobehavioral functioning (NBF) in typically developing children. We review the research thus far conducted by the ABS lab specific to this topic and posit the unique methodological contributions of the ABS lab (e.g. home-based assessment of sleep architecture and patterns, extensive phenotyping, etc.) in terms of advancing this research area. In the second section of the paper, we review 13 studies investigating the causal association between experimental sleep restriction and NBF in normally developing pediatric populations. Eight of the 13 studies found that sleep restriction causes impairments in neurobehavioural functioning. However, given the inconsistency in outcome measures, experimental protocols and statistical power, the studies reviewed herein are difficult to interpret. Strategies used by the ABS including implementing home assessments of sleep, restricting sleep relative to the participants’ typical sleep schedules, blinding raters who assess NBF, and using valid and reliable NBF assessments are an attempt to address the gaps in this research area and clarify the causal relationship between sleep restriction and NBF in typically developing children and adolescents. [ABSTRACT FROM AUTHOR]

Abstract: This paper describes a new hp method for the numerical solution of the two-dimensional eigenvalue problem in primal variational formulation. In standard methods with triangular or quadrangular finite elements, or with spectral elements, the spectrum contains spurious modes if the mesh is non-Cartesian. With the new hp method described in this paper we show that, although it delivers a approximation on the same grid for both velocity components, the spectrum is represented without any spurious mode whether a Cartesian or a non-Cartesian quadrangular grid is chosen. Spectra computed with standard high-order methods and with the new element are presented and compared with the analytic solutions. [Copyright &y& Elsevier]

Aims: An association between inflammatory bowel disease (IBD) and spondyloarthropathies (SpA) has repeatedly been reported. The aim of the present study was to investigate whether serologic markers of IBD, e.g. antibodies against Saccharomyces cerevisiae (ASCA), antibodies against exocrine pancreas (PAB) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) are present in HLA-B27-associated SpA. Methods: 87 patients with HLA-B27-positive SpA and 145 controls were tested for ASCA, PAB and pANCA employing ELISA or indirect immunofluorescence, respectively. Antibody-positive patients were interviewed regarding IBD-related symptoms using a standardized questionnaire. Results/Conclusion: When compared to the controls, ASCA IgA but not ASCA IgG levels were significantly increased in patients with SpA, in particular in ankylosing spondylitis (AS) and undifferentiated SpA (uSpA). pANCA were found in increased frequency in patients with SpA whereas PAB were not detected. The existence of autoantibodies was not associated with gastrointestinal symptoms but sustains the presence of a pathophysiological link between bowel inflammation and SpA. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The antibiotic Beauvericin (BEA) was previously shown to express ionophoric properties under simple experimental systems. Its channel-forming activity was examined in inside–out patches of ventricular myocytes and synthetic membranes with the patch clamp and fluorescence imaging techniques. Current transitions to several open state levels were evident after wash-in. The BEA channel is cation-selective. Conductance and kinetics are presented for K+ and Na+ substates and main states. The pore was blocked by La3+. In myocytes, the [K+]i was reduced, while [Na+]i and [Ca2+]i increased, leading to cytolysis. These results indicate that BEA forms cation-selective channels in lipid membranes, which can affect the ionic homeostasis. [Copyright &y& Elsevier]

The preparation of active carbons containing nitrogen surface functions is considered by ammoxidation of various raw materials like pinewood, peat and lignite. To have an accurate knowledge of the nitrogen functions introduced, diffuse reflectance IR/FT and X-ray photoelectron spectroscopies were used. Taking into account the complexity of the raw materials, the structural characterisation of the cellulose ammoxidation products was undertaken in the first step of our study, since cellulose is one of the major compounds of woods. The thermal treatment of cellulose, at around 250 °C and at different durations (1, 2, 4 h), was realised for comparison under several conditions: air, argon, ammonia and air–ammonia mixtures (ammoxidation). Several nitrogenated structures were characterised. The mechanism of their formation from the C4 fragment formed from the heterolytic cleavage of cellulose by thermal treatment was proposed pointing out the fundamental role of intermediate imine function. [Copyright &y& Elsevier]

Abstract Immunological abnormalities in schizophrenic patients have been reported for many years. However, the question of whether these parameters are involved in the pathophysiology of the disorder or represent treatment effects is still not answered. We investigated a combination of humoral and soluble immune parameters in 30 unmedicated schizophrenic patients before and during antipsychotic treatment and in 31 healthy controls. The aim of our study was to unravel an underlying immune process, to elucidate the influence of neuroleptic treatment and to identify a subgroup of schizophrenics. Antibodies against human 60-kDa heat-shock protein (HSP60), serum levels of soluble ICAM-1 and IL-2R were determined and correlated with parameters of blood-brain barrier and of psychopathology. In 10% of the drug-free but in 20% of the medicated schizophrenics, especially in females, we observed immunoreactivity against HSP60, high levels of IgG in CSF and a blood-brain barrier impairment. The high HSP antibody titres correlated with high levels of sIL-2R and sICAM-1. Only one of the controls showed antibodies against HSP60. Our results suggest that the observed immunological alterations are more pronounced during neuroleptic treatment than in the drug-free state. Whether or not this differential response to treatment with altered antibody production represents a subgroup of patients has yet to be determined. [ABSTRACT FROM AUTHOR]

The microstructural origins of premature fatigue failures were investigated on a variety of forged components manufactured from AZ80 and ZK60 magnesium, both at the test specimen level and the full-scale component level. Both stress and strain-controlled approaches were used to characterize the macroscopically defect-free forged material behaviour as well as with varying levels of defect intensities. The effect of thermomechanical processing defects due to forging of an industrially relevant full-scale component were characterized and quantified using a variety of techniques. The fracture initiation and early crack growth behaviour was deterministically traced back to a combination of various effects having both geometric and microstructural origins, including poor fusion during forging, entrainment of contaminants sub-surface, as well as other inhomogeneities in the thermomechanical processing history. At the test specimen level, the fracture behaviour under both stress and strain-controlled uniaxial loading was characterized for forged AZ80 Mg and a structure-property relationship was developed. The fracture surface morphology was quantitatively assessed revealing key features which characterize the presence and severity of intrinsic forging defects. A significant degradation in fatigue performance was observed as a result of forging defects accelerating fracture initiation and early crack growth, up to 6 times reduction in life (relative to the defect free material) under constant amplitude fully reversed fatigue loading. At the full-scale component level, the fatigue and fracture behaviour under combined structural loading was also characterized for a number of ZK60 forged components with varying levels of intrinsic thermomechanical processing defects. A novel in-situ non-contact approach (utilizing Digital-Image Correlation) was used as a screening test to establish the presence of these intrinsic defects and reliably predict their effect on the final fracture behaviour in an accelerated manner compared to conventional methods. [ABSTRACT FROM AUTHOR]

The terpsichore three-dimensional linear ideal magnetohydrodynamic (MHD) stability code [Theory of Fusion Plasmas, Proceedings of the Joint Varenna–Lausanne International Workshop, Chexbres, Switzerland, 1988 (Editrice Compositori, Bologna, Italy, 1989), p. 93; Controlled Fusion and Plasma Heating, Proceedings of the 17th European Conference, Amsterdam, The Netherlands (European Physical Society, Petit-Lancy, Switzerland, 1990), Vol. 14B, Part II, p. 931; Theory of Fusion Plasmas, Proceedings of the Joint Varenna–Lausanne International Workshop, Valla Monastero, Varenna, Italy, 1990 (Editrice Compositori, Bologna, Italy, 1990), p. 655] has been extended to the full MHD equations. The new code is used to calculate the physical growth rates of nonlocal low-n modes for l=2 torsatron configurations. A comprehensive investigation of the relation between the Mercier modes and the low-n modes has been performed. The unstable localized low-n modes are found to be correlated with the Mercier criterion. Finite growth rates of the low-n modes correspond to finite values of the Mercier criterion parameter. Near the Mercier marginal stability boundary, the low-n modes tend to be weakly unstable with very small growth rates. However, the stability of global-type low-n modes is found to be decorrelated from that of Mercier modes. The low-n modes with global radial structures can be more stable or more unstable than Mercier modes. [ABSTRACT FROM AUTHOR]

The ability to plan for future events is one of the defining features of human intelligence. Whether non-human animals can plan for specific future situations remains contentious: despite a sustained research effort over the last two decades, there is still no consensus on this question. Here, we show that New Caledonian crows can use tools to plan for specific future events. Crows learned a temporal sequence where they were (a) shown a baited apparatus, (b) 5 min later given a choice of five objects and (c) 10 min later given access to the apparatus. At test, these crows were presented with one of two tool-apparatus combinations. For each combination, the crows chose the right tool for the right future task, while ignoring previously useful tools and a low-value food item. This study establishes that planning for specific future tool use can evolve via convergent evolution, given that corvids and humans shared a common ancestor over 300 million years ago, and offers a route to mapping the planning capacities of animals. [ABSTRACT FROM AUTHOR]

The ability to plan for future events is one of the defining features of human intelligence. Whether non-human animals can plan for specific future situations remains contentious: despite a sustained research effort over the last two decades, there is still no consensus on this question. Here, we show that New Caledonian crows can use tools to plan for specific future events. Crows learned a temporal sequence where they were (a) shown a baited apparatus, (b) 5 min later given a choice of five objects and (c) 10 min later given access to the apparatus. At test, these crows were presented with one of two tool--apparatus combinations. For each combination, the crows chose the right tool for the right future task, while ignoring previously useful tools and a low-value food item. This study establishes that planning for specific future tool use can evolve via convergent evolution, given that corvids and humans shared a common ancestor over 300 million years ago, and offers a route to mapping the planning capacities of animals. [ABSTRACT FROM AUTHOR]

Molar incisor hypomineralization (MIH) is an endemic pediatric disease with an unclear pathogenesis. Considering that saliva controls enamel remineralization and that MIH is associated with higher saliva flow rate, we hypothesized that the protein composition of saliva is linked to disease. To test this, we enrolled 5 children aged 6–14 years with MIH showing at least one hypersensitive molar and 5 caries-free children without hypomineralization. Saliva samples were subjected to proteomic analysis followed by protein classification in to biological pathways. Among 618 salivary proteins identified with high confidence, 88 proteins were identified exclusively in MIH patients and 16 proteins in healthy controls only. Biological pathway analysis classified these 88 patient-only proteins to neutrophil-mediated adaptive immunity, the activation of the classical pathway of complement activation, extracellular matrix degradation, heme scavenging as well as glutathione -and drug metabolism. The 16 controls-only proteins were associated with adaptive immunity related to platelet degranulation and the lysosome. This report suggests that the proteaneous composition of saliva is affected in MIH patients, reflecting a catabolic environment which is linked to inflammation. [ABSTRACT FROM AUTHOR]

Background: This study was prompted by a desire to measure human age by a means other than chronological or biological age. The purpose of the study was to use the total lifetime caloric intake in men as an index of aging.Method: The study was carried out by developing an algorithm to approximate the lifetime caloric intake. The total caloric intake is expressed such that one calorie-age year is defined as the total calories expended by an individual during his/her 20th year.Results: The results indicated that (1) the caloric intake of men progressively decreases with advancing age, that (2) the caloric-age is usually less than chronological age, and that (3) the caloric-age algorithm is a simple although crude method to assess lifetime caloric intake.Conclusion: The most important conclusion is that a person can get a better appreciation of the importance of avoiding excess caloric intake if human age is measured in terms of lifetime caloric intake. [ABSTRACT FROM AUTHOR]

Summary: These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert‐based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis. What's already known about this topic? Various symptomatic treatment options exist for congenital ichthyoses, but there are no European guidelines. What does this study add? These European guidelines for the management of congenital ichthyosis may help to improve outcomes and quality of life for patients. Linked Comment:Akiyama. Br J Dermatol 2019; 180:449–450. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016 and a consensus on the discussions. They summarize evidence and expert‐based recommendations and are intended to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part one, covering topical therapies, systemic therapies, psychosocial management, communicating the diagnosis and genetic counselling. Linked Comment:  Levy. Br J Dermatol 2019; 180:253. [ABSTRACT FROM AUTHOR]

Soil management techniques, such as mulching, are used to enhance soil organic carbon sequestration. However, we demonstrate that the potential of crop residue mulching to increase soil organic carbon (SOC) sequestration varies by cropping system and soil type in Austrian agricultural soils. Effects of mulch (as harvested crop residues applied at 1.0 t C ha −1 ) on soil and microbial carbon (C) and nitrogen (N) and soil δ 13 C were measured in an Austrian Cambisol field experiment with sole maize or vetch or vetch-maize rotation cropping systems after five years with or without mulching to elucidate how SOC is affected. The direct role of mulch on SOC in different soil types was also investigated in a similar greenhouse mesocosm study with controlled moisture using the same Cambisols and an Austrian agricultural Chernozem. Only sole maize cropping in the field experiment resulted in higher SOC with mulching and when legumes were included in a legume-maize rotation SOC did not improve. Mulching in the field experiment only resulted in higher SOC in the top 0–5 cm of soils with sole maize cropping (by 22%) compared to soils without mulch. Although mulch did not increase SOC in vetch-maize rotation, the δ 13 C of SOC was less negative with mulch indicating larger C contribution from maize than vetch mulch. After four years of annual soybean-maize rotation in the mesocosm experiment, no significant differences in SOC were observed in Cambisols with or without mulch. Again, δ 13 C of both soil types was less negative with mulching indicating a larger C contribution from maize than soybean mulch. No relationships between microbial biomass C and N and SOC were observed in either experiment and only soil N concentration was positively correlated with SOC. Together these studies indicate that maize can increase SOC when crop residues are applied in Austrian Cambisols but that inclusion of legume production and legume mulch in rotation can mute these benefits. [ABSTRACT FROM AUTHOR]

Aim To investigate the inflammatory response of dental pulp fibroblasts and the respective explants to whole saliva. Methodology Explants from human and porcine dental pulp tissue and isolated dental pulp fibroblasts were used to investigate the inflammatory response to sterile saliva. Cytokine and chemokine expression was assessed by RT- PCR. Western blot analysis and pharmacologic inhibitors were used to determine the involvement of signalling pathways. Results Dental pulp explants of human and porcine origin exposed to human saliva exhibited no major changes of IL-6 and IL-8 mRNA expression ( P > 0.05). In contrast, isolated porcine and human dental pulp fibroblasts, when stimulated with human saliva, exhibited a vastly increased expression of IL-6 and IL-8 mRNA ( P < 0.05). In pulp fibroblasts, saliva also increased the expression of other cytokines and chemokines via activation of NFkappaB, ERK and p38 signalling. Notably, a significantly reduced inflammatory response was elicited when pulp fibroblasts were transiently exposed to saliva. Conclusions Saliva has a potential impact on inflammation of dental pulp fibroblasts in vitro but not when cells are embedded in the intrinsic extracellular matrix of the explant tissue. [ABSTRACT FROM AUTHOR]

The article demonstrate that New Caledonian crows are an excellent candidate for testing the conservative criteria for mental time travel with the details of the experiment and interpretation accurately. Topics include actual task complexity by ignoring key aspects of the cognitive process required in the experiment; and promising avenue for resolving the many antagonistic debates within comparative psychology.

Autosomal recessive exfoliative ichthyosis ( AREI) results from mutations in CSTA, encoding cysteine protease inhibitor A (cystatin A). We present a 25-year-old man from Iran with consanguineous parents, who presented with congenital erythroderma, hyperhidrosis and diffuse hyperkeratosis with coarse palmoplantar peeling of the skin, aggravated by exposure to water and by occlusion. Candidate gene analysis revealed a previously unknown homozygous loss-of-function mutation c.172C>T (p.Arg58Ter) in CSTA, and immunostaining showed absence of epidermal cystatin A, confirming the diagnosis of AREI. Ultrastructural analysis by transmission electron microscopy showed normal degradation of corneodesmosomes, mild intercellular oedema in the spinous layer but not in the basal layer, normal-appearing desmosomes, and prominent keratin filaments within basal keratinocytes. Thickness of cornified envelopes was reduced, lamellar lipid bilayers were disturbed, lamellar body secretion occurred prematurely and processing of secreted lamellar body contents was delayed. These barrier abnormalities were reminiscent of (albeit less severe than in) Netherton syndrome, which results from a deficiency of the serine protease inhibitor LEKTI. This work describes ultrastructural findings with evidence of epidermal barrier abnormalities in AREI. [ABSTRACT FROM AUTHOR]

Aim To assess the pro-angiogenic and pro-inflammatory capacity of the dentine-pulp complex in response to the prolyl hydroxylase inhibitor L-mimosine in a tooth slice organ culture model. Methodology Human teeth were sectioned transversely into 600-μm-thick slices and cultured in medium supplemented with serum and antibiotics. Then, pulps were stimulated for 48 h with L-mimosine. Pulps were subjected to viability measurements based on formazan formation in MTT assays. In addition, histological evaluation of pulps was performed based on haematoxylin and eosin staining. Culture supernatants were subjected to immunoassays for vascular endothelial growth factor ( VEGF) to determine the pro-angiogenic capacity and to immunoassays for interleukin ( IL)-6 and IL-8 to assess the pro-inflammatory response. Interleukin-1 served as pro-inflammatory control. Echinomycin was used to inhibit hypoxia-inducible factor-1 ( HIF-1) alpha activity. Data were analysed using Student's t-test and Mann-Whitney U test. Results Pulps within tooth slices remained vital upon L-mimosine stimulation as indicated by formazan formation and histological evaluation. L-mimosine increased VEGF production when normalized to formazan formation in the pulp tissue of the tooth slices ( P < 0.05). This effect on VEGF was reduced by echinomycin ( P < 0.01). Changes in normalized IL-6 and IL-8 levels upon treatment with L-mimosine did not reach the level of significance ( P > 0.05), whilst treatment with IL-1, which served as positive control, increased IL-6 ( P < 0.05) and IL-8 levels ( P < 0.05). Conclusions The prolyl hydroxylase inhibitor L-mimosine increased VEGF production via HIF-1 alpha in the tooth slice organ culture model whilst inducing no prominent increase in IL-6 and IL-8. Pre-clinical studies will reveal if these in vitro effects translate into dental pulp regeneration. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study is to evaluate the effects of a paste-like bone substitute material with easy handling properties and improved mechanical stability on periodontal regeneration of intrabony defects in dogs. Materials and methods: Mandibular and maxillary first and third premolars were extracted, and three-wall intrabony defects were created on second and fourth premolars. After a healing period of 3 months, acute type defects were filled with a paste-like formulation of deproteinized bovine bone mineral (DBBM) (particle size, 0.125-0.25 mm) in a collagenous carrier matrix (T1), pulverized DBBM (particle size, 0.125-0.25 mm) without the carrier (T2), or Bio-Oss® granules (particle size, 0.25-1.00 mm) as control (C). All defects were covered with a Bio-Gide® membrane. The dogs were sacrificed after 12 weeks, and the specimens were analyzed histologically and histometrically. Results: Postoperative healing of all defects was uneventful, and no histological signs of inflammation were observed in the augmented and gingival regions. New cementum, new periodontal ligament, and new bone were observed in all three groups. The mean vertical bone gain was 3.26 mm (T1), 3.60 mm (T2), and 3.81 mm (C). That of new cementum was 2.25 mm (T1), 3.88 mm (T2), and 3.53 mm (C). The differences did not reach statistical significance. The DBBM particles were both incorporated in new bone and embedded in immature bone marrow. Conclusions: The results of this preclinical study showed that the 0.125-0.25-mm DBBM particles in a powder or paste formulation resulted in periodontal regeneration comparable to the commercially available DBBM. Osteoconductivity, in particular, was not affected by DBBM size or paste formulation. Clinical relevance: The improved handling properties of the paste-like bone substitute consisting of small DBBM particles embedded in a collagen-based carrier hold promise for clinical applications. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: 22q11.2 deletion syndrome (22q11.2DS) and Williams syndrome (WS) are common neurogenetic microdeletion syndromes. The aim of the present study was to compare the neuropsychiatric and neurocognitive phenotypes of 22q11.2DS and WS. Methods: Forty-five individuals with 22q11.2DS, 24 with WS, 22 with idiopathic developmental disability (DD) and 22 typically developing (TD) controls were compared for the rates of psychiatric disorders as well as cognitive executive and visuospatial functions. Results: We found that while anxiety, mood and disruptive disorders had an equally high prevalence among individuals with 22q11.2DS, WS and DDs, the 22q11.2DS group had the highest rates of psychotic disorders and the WS group had the highest rates of specific phobia. We also found that the WS group demonstrated more severe impairments in both executive and visuospatial functions than the other groups. WS and 22q11.2DS subjects had worse Performance-IQ than Verbal-IQ, a feature typical of non-verbal learning disorders. Conclusion: These findings offer a wide perspective on unique versus common phenotypes in 22q11.2DS and WS. [Copyright &y& Elsevier]

Abstract: Destruxins (Dtx) are secondary metabolites of the entomopathogenic fungus Metarhizium anisopliae. Recently, Dtx came into focus of interest as anticancer therapeutics. However, data on human and especially on cancer cells are fragmentary. In order to successfully establish novel anticancer therapeutics, a broad knowledge on the cellular and molecular mechanisms underlying their activity is essential. Consequently, this study aimed to investigate the impact of the most common Dtx derivatives A, B and E on human cancer cell growth and survival with a focus on colon cancer cell models. Summarizing, the experimental data showed that (i) Dtx A and B exert potent antiproliferative activity in the micromolar and Dtx E in the nanomolar range in KB-3-1, A549, CaCo-2, and especially in HCT116 colon cancer cells, (ii) all three Dtx derivatives cause imbalance of cell cycle distribution, (iii) their cytostatic/cytotoxic effects are widely p53-independent but reduced by p21- and bax-deletion, respectively, (iv) cytotoxicity is based on intrinsic apoptosis induction and associated with phosphoinositide-3-kinase (PI3K)/Akt pathway inhibition, (v) anticancer activity of Dtx E but not Dtx A and B involves disturbance of the intracellular redox balance, (vi) Dtx inhibit the migration and tube formation of human endothelial cells indicating antiangiogenic potential, and (vii) all three Dtx derivatives possess ionophoric properties not differing in conductivity, ion selectivity and single channel kinetics. Thus, Dtx represent feasible, multifunctional anticancer drug candidates for preclinical development especially against colorectal cancer. [Copyright &y& Elsevier]