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A mouse monoclonal antibody (mAB lu-5) was prepared using a lung cancer cell line as an antigen. The selected clone produces an IgG with a gamma-1 heavy chain and a kappa-light-chain. Immunohistochemical testing of mAB lu-5 on 117 normal tissue biopsies and 474 tumours revealed reactivity with an intracytoplasmic, formaldehyderesistant antigen present in most epithelial and mesothelial cells, but absent in mesenchymal cells. The antibody can therefore be used as a first order, pan-epithelial marker. It proved also useful for fast tumour diagnosis on frozen sections. [ABSTRACT FROM AUTHOR]

Objectives: Administration of gadolinium-based contrast agents (GBCA) in magnetic resonance imaging results in the long-term retention of gadolinium (Gd) in tissues and organs, including the bone, and may affect their function and metabolism. This study aims to investigate the effects of Gd and GBCA on the proliferation/survival, differentiation, and function of bone cell lineages., Materials and Methods: Primary murine osteoblasts (OB) and osteoclast progenitor cells (OPC) isolated from C57BL/6J mice were used to test the effects of Gd 3+ (12.5-100 μM) and GBCA (100-2000 μM). Cultures were supplemented with the nonionic linear Gd-DTPA-BMA (gadodiamide), ionic linear Gd-DTPA (gadopentetic acid), and macrocyclic Gd-DOTA (gadoteric acid). Cell viability and differentiation were analyzed on days 4-6 of the culture. To assess the resorptive activity of osteoclasts, the cells were grown in OPC cultures and were seeded onto layers of amorphous calcium phosphate with incorporated Gd., Results: Gd 3+ did not affect OB viability, but differentiation was reduced dose-dependently up to 72.4% ± 6.2%-73.0% ± 13.2% (average ± SD) at 100 μM Gd 3+ on days 4-6 of culture as compared with unexposed controls ( P < 0.001). Exposure to GBCA had minor effects on OB viability with a dose-dependent reduction up to 23.3% ± 10.2% for Gd-DTPA-BMA at 2000 μM on day 5 ( P < 0.001). In contrast, all 3 GBCA caused a dose-dependent reduction of differentiation up to 88.3% ± 5.2% for Gd-DTPA-BMA, 49.8% ± 16.0% for Gd-DTPA, and 23.1% ± 8.7% for Gd-DOTA at 2000 μM on day 5 ( P < 0.001). In cultures of OPC, cell viability was not affected by Gd 3+ , whereas differentiation was decreased by 45.3% ± 9.8%-48.5% ± 15.8% at 100 μM Gd 3+ on days 4-6 ( P < 0.05). Exposure of OPC to GBCA resulted in a dose-dependent increase in cell viability of up to 34.1% ± 11.4% at 2000 μM on day 5 of culture ( P < 0.001). However, differentiation of OPC cultures was reduced on day 5 by 24.2% ± 9.4% for Gd-DTPA-BMA, 47.1% ± 14.0% for Gd-DTPA, and 38.2% ± 10.0% for Gd-DOTA ( P < 0.001). The dissolution of amorphous calcium phosphate by mature osteoclasts was reduced by 36.3% ± 5.3% upon incorporation of 4.3% Gd/Ca wt/wt ( P < 0.001)., Conclusions: Gadolinium and GBCA inhibit differentiation and activity of bone cell lineages in vitro. Thus, Gd retention in bone tissue could potentially impair the physiological regulation of bone turnover on a cellular level, leading to pathological changes in bone metabolism., Competing Interests: Conflicts of interest: none declared. This work was supported by a CTU Research Grant from the Inselspital, University of Bern (Switzerland) and Gottfried und Julia Bangerter-Rhyner-Foundation to R.J.E., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

One of the most widely used materials for bone graft substitution is β-Tricalcium phosphate (β-TCP; β-Ca 3 (PO 4 ) 2 ). β-TCP is typically produced by sintering in air or vacuum. During this process, evaporation of phosphorus (P) species occurs, leading to the formation of a calcium-rich alkaline layer. It was recently shown that the evaporation of P species could be prevented by co-sintering β-TCP with dicalcium phosphate (DCPA; CaHPO 4 ; mineral name: monetite). The aim of this study was to see how a change of sintering atmosphere could affect the physico-chemical and biological properties of β-TCP. For this purpose, three experimental groups were considered: β-TCP cylinders sintered in air and subsequently polished to remove the surface layer (control group); the same polished cylinders after subsequent annealing at 500 °C in air to generate a calcium-rich alkaline layer (annealed group); and finally, β-TCP cylinders sintered in a monetite-rich atmosphere and subsequently polished (monetite group). XPS analysis confirmed that cylinders from the annealed group had a significantly higher Ca/P molar ratio at their surface than that of the control group while this ratio was significantly lower for the cylinders from the monetite group. Sintering β-TCP in the monetite-rich atmosphere significantly reduced the grain size and increased the density. Changes of surface composition affected the activity of osteoclasts seeded onto the surfaces, since annealed β-TCP cylinders were significantly less resorbed than β-TCP cylinders sintered in the monetite-rich atmosphere. This suggests that an increase of the surface Ca/P molar ratio leads to a decrease of osteoclastic resorption. STATEMENT OF SIGNIFICANCE: Minimal changes of surface and bulk (< 1%) composition have major effects on the ability of osteoclasts to resorb β-tricalcium phosphate (β-TCP), one of the most widely used ceramics for bone substitution. The results presented in this study are thus important for the calcium phosphate community because (i) β-TCP may have up to 5% impurities according to ISO and ASTM standards and still be considered to be "pure β-TCP", (ii) β-TCP surface properties are generally not considered during biocompatibility assessment and (iii) a rationale can be proposed to explain the various inconsistencies reported in the literature on the biological properties of β-TCP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction : Cryopreservation of bipronuclear (2PN) stage zygotes is an integral part of IVF laboratory practice in countries with strict embryo culture legislation. Vitrification of zygotes is compatible with several strategies in infertility treatments holding a freeze-all indication and allows for effective workload management in settings with limited resources. Although it yields high survival rates and clinical outcomes, the ideal timing to commence vitrification of zygotes is elusive while it is empirically practiced in the window between 17 and 21 h post-insemination (hpi). We aimed to deduce the association between pregnancy rate and the time interval from insemination (IVF and ICSI) to vitrification to contribute to the standardization ofzygote cryopreservation. Methods : A retrospective analysis of data on vitrification timings and pregnancy outcomes collected between 2011 and 2019 was performed. All included women received an embryo transfer after warming of vitrified zygotes at the 2PN stage. Results : A total of 468 embryo transfers were included of which 182 (38.9%) resulted in pregnancy and 286 (61.1%) not. Vitrification was on average performed 18.74 ±0.63 hpi in the pregnant group and 18.62 ± 0.64 hpi in the non-pregnant group (OR 1.36, 95% CI 1.01; 1.83, p = 0.045). A multivariate analysis controlling for uterine pathologies, maternal age, AMH, the number of MII oocytes, previous history of pregnancy success, endometriosis, AFC, nicotine intake and male factor infertility showed no predictive value of vitrification timing on pregnancy rate. Three time intervals between insemination and vitrification were defined: 17:00 to 18:00 hpi (Group A), 18:01 to 19:00 hpi (Group B) and 19:01 to 21:00 hpi (Group C). Pregnancy occurred in 40/130 women (30.80%) in Group A, in 115/281 women (40.90%) in Group B and in 27/57 women (47.40%) in Group C. Univariate but not multivariate analysis showed a significantly higher pregnancy rate after the latest time interval between insemination and 2PN vitrification when compared to the earliest (Group C vs . A, OR 2.03, 95% CI 1.07; 3.84, p = 0.031). Discussion: These findings encourage further investigation on the impact of vitrification timing on clinical outcomes and hold the potential to standardize cryopreservation of zygotes from IVF/ICSI cycles to eventually improve the quality of long-term ART outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Makieva, Stähli, Xie, Gil, Sachs and Leeners.)

Purpose: Surgery remains the only treatment allowing for a significant and sustainable weight loss in case of severe obesity. Patients undergo a specific multidisciplinary preparation and selection before the operation. This study aims to correlate the psychosocial profile with the likelihood of undergoing bariatric surgery in patients enrolled in the preparation program of a Swiss reference center., Methods: All patients referred to an obesity center between January 1, 2016, and June 30, 2017, seeking a first bariatric procedure were included. Socio-demographic data, BMI, preoperative psychological and dietary evaluations were collected. Usually, the preoperative process lasts 1 year. Patients who left the preparation or who had not undergone surgery after more than 2 years of follow-up were considered withdrawers. Surgery completion predictors were reviewed with bivariate analysis and socio-demographic clusters established using the K-means method., Results: Out of a total of 221 patients, 99 (45%) patients had not undergone bariatric surgery 2 years after their first consultation. The patients were divided into four distinct socio-demographic clusters, among which a particularly deprived one. Criteria such as unfavorable psychological (p < 0.001) and dietary (p < 0.001) evaluations, and male gender (p < 0.05) were significantly associated with non-operation, unlike socio-demographic indicators and clusters (p > 0.1)., Conclusion: Almost half of the patients starting a bariatric program are not operated on, which is related to an unfavorable psychological or dietary evaluation and to the male gender. This study also demonstrates that a significant share of patients combines several factors of social deprivation, without influencing the likelihood of surgery completion., Level of Evidence: Level V: Descriptive study., (© 2021. The Author(s).)

Objectives: Mandibular collum fractures among growing patients can lead to abnormal growth, function, esthetics and ultimately quality of life. Among the proposed treatment alternatives, orthopaedic treatment with functional appliances has been suggested, with encouraging results. Aim of the present systematic review was to critically appraise existing evidence on the outcome of functional appliance treatment among growing patients with mandibular collum fractures., Materials and Methods: Eight databases were searched up to October 2020 for randomised and non-randomised clinical studies assessing functional appliance treatment outcome for children with mandibular fractures. After duplicate study selection, data extraction and risk of bias assessment, random effects meta-analyses of mean differences (MD) and their 95% confidence intervals (CIs) were performed, followed by assessment of the quality of evidence with GRADE., Results: A total of 8 unique studies (one prospective and nine retrospective non-randomised) with 223 children could be identified. Functional appliance treatment was associated with greater anteroposterior condyle dimensions of the injured condyle compared with the contralateral healthy condyle (3 studies; MD = 0.87 mm; 95% CI = 0.30 to 1.45 mm; p = .003). No difference was found in the mesiodistal condyle size between the injured and the contralateral healthy joint (3 studies; MD = -0.05 mm; 95% CI = -1.05 to 0.95 mm; p = .92), but collum length was smaller at the injured side compared with the contralateral one (1 study; MD = -2.89 mm; 95% CI = -5.29 to -0.49 mm; p = .02). Treatment outcome might be influenced by patient age, patient sex and severity/localisation of the fracture, but the quality of evidence for all analyses was very low due to methodological limitations leading to bias., Conclusions: While some evidence exists that functional appliances might lead to good clinical rehabilitation of fractured mandibular condyles, including considerable bone remodelling, available studies are small and have methodological weaknesses., (© 2021 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Biomaterials can interact with cells directly, that is, by direct contact of the cells with the material surface, or indirectly, through soluble species that can be released to or uptaken from the surrounding fluids. However, it is difficult to characterise the relevance of this fluid-mediated interaction separately from the topography and composition of the substrate, because they are coupled variables. These fluid-mediated interactions are amplified in the case of highly reactive calcium phosphates (CaPs) such as biomimetic calcium deficient hydroxyapatite (CDHA), particularly in static in vitro cultures. The present work proposes a strategy to decouple the effect of ion exchange from topographical features by adjusting the volume ratio between the cell culture medium and biomaterial (V CM /V B ). Increasing this ratio allowed mitigating the drastic ionic exchanges associated to the compositional changes experienced by the material exposed to the cell culture medium. This strategy was validated using rat mesenchymal stem cells (rMSCs) cultured on CDHA and beta-tricalcium phosphate (β-TCP) discs using different V CM /V B ratios. Whereas in the case of β-TCP the cell response was not affected by this ratio, a significant effect on cell adhesion and proliferation was found for the more reactive CDHA. The ionic exchange, produced by CDHA at low V CM /V B , altered cell adhesion due to the reduced number of focal adhesions, caused cell shrinkage and further rMCSs apoptosis. This was mitigated when using a high V CM /V B , which attenuated the changes of calcium and phosphate concentrations in the cell culture medium, resulting in rMSCs spreading and a viability over time. Moreover, rMSCs showed an earlier expression of osteogenic genes on CDHA compared to sintered β-TCP when extracellular calcium fluctuations were reduced., Statement of Significance: Fluid mediated interactions play a significant role in the bioactivity of calcium phosphates. Ionic exchange is amplified in the case of biomimetic hydroxyapatite, which makes the in vitro characterisation of cell-material interactions especially challenging. The present work proposes a novel and simple strategy to explore the mechanisms of interaction of biomimetic and sintered calcium phosphates with mesenchymal stem cells. The effects of topography and ion exchange are analysed separately by modifying the volume ratio between cell culture medium and biomaterial. High ionic fluctuations interfered in the maturation of focal adhesions, hampering cell adhesion and leading to increased apoptosis and reduced proliferation rate., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Introduction: Intravenous lacosamide (LCM) is increasingly used in the treatment of status epilepticus (SE), but optimal loading dose and target serum levels are unclear. We analysed the correlation between LCM serum levels after intravenous loading dose and clinical response., Materials and Methods: Retrospective study in two centres from December 2014 to May 2016 including consecutive SE patients treated with LCM, in which trough serum levels after intravenous loading dose were available. Trough levels were correlated with the loading dose and the clinical response, defined as LCM introduction terminating SE without the need of further treatment. Correlations were adjusted for other SE characteristics., Results: Among 40 patients, 16 (40%) responded to LCM. LCM serum concentrations within the reference interval (10-20mg/l) were associated with loading doses of >9mg/kg (p=0.003; χ2). However, we observed no difference between LCM serum levels in responders (median 10.4mg/l) versus non-responders (median 9.5mg/l; p=0.36; U test), even after adjusting for other predictors of clinical outcome (SE severity, aetiology, and number of previous treatment)., Discussion: High intravenous LCM loading doses (>9mg/kg) were associated with serum levels within the reference interval, there was however no correlation with the clinical response. Prospective studies are needed to evaluate the benefit of increasing the LCM loading dose in SE., (Copyright © 2017 Elsevier B.V. All rights reserved.)

β-Tricalcium phosphate (β-TCP) platelets synthesized in ethylene glycol offer interesting geometries for nano-structured composite bone substitutes but were never crystallographically analyzed. In this study, powder X-ray diffraction and Rietveld refinement revealed a discrepancy between the platelet structure and the known β-TCP crystal model. In contrast, a model featuring partial H for Ca substitution and the inversion of P1O 4 tetrahedra, adopted from the whitlockite structure, allowed for a refinement with minimal misfits and was corroborated by HPO 4 2- absorptions in Fourier-transform IR spectra. The Ca/P ratio converged to 1.443 ± 0.003 (n = 36), independently of synthesis conditions. As a quantitative verification, the platelets were thermally decomposed into hydrogen-free β-TCP and β-calcium pyrophosphate which resulted in a global Ca/P ratio in close agreement with the initial β-TCP Ca/P ratio (ΔCa/P = 0.003) and with the chemical composition measured by inductively coupled plasma (ΔCa/P = 0.003). These findings thus describe for the first time a hydrogen-substituted β-TCP structure, i.e. a Mg-free whitlockite, represented by the formula Ca 21 - x (HPO 4 ) 2x (PO 4 ) 14 - 2x , where x = 0.80 ± 0.04, and may have implications for resorption properties of bone regenerative materials.

Calcium phosphate (CaP) ceramics are extensively used for bone regeneration; however, their clinical performance is still considered inferior to that of patient's own bone. To improve the performance of CaP bone graft substitutes, it is important to understand the effects of their individual properties on a biological response. The aim of this study is to investigate the effects of the crystal phase and particle morphology on the behavior of human mesenchymal stromal cells (hMSCs). To study the effect of the crystal phase, brushite, monetite, and octacalcium phosphate (OCP) are produced by controlling the precipitation conditions. Brushite and monetite are produced as plate-shaped and as needle-shaped particles, to further investigate the effect of particle morphology. Proliferation of hMSCs is inhibited on OCP as compared to brushite and monetite in either morphology. Brushite needles consistently show the lowest expression of most osteogenic markers, whereas the expression on OCP is in general high. There is a trend toward a higher expression of the osteogenic markers on plate-shaped than on needle-shaped particles for both brushite and monetite. Within the limits of CaP precipitation, these data indicate the effect of both crystal phase and particle morphology of CaPs on the behavior of hMSCs., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: In 2015, the International League Against Epilepsy (ILAE) issued a new status epilepticus (SE) classification, including a detailed semiologic axis. This study assesses frequencies of SE forms in a cohort of adult patients, and explores differences and practical implications as compared to a seizure-type-bound classification., Methods: The prospective adult SE registry of the Lausanne University Hospital (CHUV) was considered over 5 years (2011-2015); each SE episode was retrospectively reclassified for its semiology according to the new ILAE scheme. Mortality rates were retrieved for each subgroup of SE., Results: Among 488 SE episodes, according to the seizure-type-bound classification, 230 (47%) had a generalized convulsive, and 29 (6%) had a nonconvulsive SE in coma; both categories overlapped almost perfectly between the two classifications. However, the 84 episodes with focal SE without consciousness impairment and the 141 episodes with consciousness impairment were each translated into two major (and five sub-) categories of the new ILAE classification, having markedly different mortality rates. In addition, of 140 episodes labeled as focal motor SE according to the new classification, 54% had concomitant consciousness impairment, whereas 46% did not; again, mortality rates were heterogeneous., Significance: Although generalized convulsive and nonconvulsive SE in coma show an almost perfect correspondence across SE semiologic classifications, focal SE is markedly heterogeneous and appears to be better reflected in the new classification, offering more clinically relevant subdivisions, also differing in mortality rates. This refined knowledge may allow the development of clinical prognostic scores that are more precise than existing tools, and should be taken into account for epidemiologic studies., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Over the last years a new type of tubular plug flow reactor, the segmented flow tubular reactor (SFTR), has proven its versatility and robustness through the water-based synthesis of precipitates as varied as CaCO3, BaTiO3, Mn(1-x)NixC2O4·2H2O, YBa oxalates, copper oxalate, ZnS, ZnO, iron oxides, and TiO2 produced with a high powder quality (phase composition, particle size, and shape) and high reproducibility. The SFTR has been developed to overcome the classical problems of powder production scale-up from batch processes, which are mainly linked with mass and heat transfer. Recently, the SFTR concept has been further developed and applied for the synthesis of metals, metal oxides, and salts in form of nano- or micro-particles in organic solvents. This has been done by increasing the working temperature and modifying the particle carrying solvent. In this paper we summarize the experimental results for four materials prepared according to the polyol synthesis route combined with the SFTR. CeO2, Ni, Ag, and Ca3(PO4)2 nanoparticles (NPs) can be obtained with a production rate of about 1-10 g per h. The production was carried out for several hours with constant product quality. These findings further corroborate the reliability and versatility of the SFTR for high throughput powder production.

Both silicate-based bioactive glasses and copper ions have demonstrated angiogenic activity and therefore represent promising bioinorganic agents for the promotion of vascularization in tissue-engineered scaffolds. This study examined the effect of ionic release products from 45S5 Bioglass® doped with 0 and 2.5 wt.% CuO (BG and Cu-BG respectively) on the formation of capillary-like networks by SVEC4-10 endothelial cells (ECs) seeded in a three-dimensional (3D) type I collagen matrix. Copper and silicon release following 24h dissolution increased non-proportionally with Cu-BG concentration in cell culture medium, while calcium levels were decreased below the initial medium concentration. EC network length, connectivity, branching, quantified by means of a 3D morphometric image analysis method, as well as proliferation and metabolic activity were reduced in a dose-dependent fashion by BG and Cu-BG ionic release products. This reduction was less prominent for BG compared to an equivalent concentration of Cu-BG, which was attributed to a lower extent of silicon release and calcium consumption. Moreover, a CuCl2 dose equivalent to the highest concentration of Cu-BG exhibited no effect on ECs. In conclusion, while the previously reported pro-angiogenic activity of both Bioglass® and copper may not be reflected in a direct response of ECs, this study provides a maximum glass concentration for non-harmful angiogenic stimulation to be examined in future work., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: Therapeutic coma is advocated in guidelines for management of refractory status epilepticus; this is, however, based on weak evidence. We here address the specific impact of therapeutic coma on status epilepticus outcome., Design: Retrospective assessment of a prospectively collected cohort., Setting: Academic hospital., Patients: Consecutive adults with incident status epilepticus lasting greater than or equal to 30 minutes, admitted between 2006 and 2013., Measurements and Main Results: We recorded prospectively demographics, clinical status epilepticus features, treatment, and outcome at discharge and retrospectively medical comorbidities, hospital stay, and infectious complications. Associations between potential predictors and clinical outcome were analyzed using multinomial logistic regressions. Of 467 patients with incident status epilepticus, 238 returned to baseline (51.1%), 162 had new disability (34.6%), and 67 died (14.3%); 50 subjects (10.7%) were managed with therapeutic coma. Therapeutic coma was associated with poorer outcome in the whole cohort (relative risk ratio for new disability, 6.86; 95% CI, 2.84-16.56; for mortality, 9.10; 95% CI, 3.17-26.16); the effect was more important in patients with complex partial compared with generalized convulsive or nonconvulsive status epilepticus in coma. Prevalence of infections was higher (odds ratio, 3.81; 95% CI, 1.66-8.75), and median hospital stay in patients discharged alive was longer (16 d [range, 2-240 d] vs 9 d [range, 1-57 d]; p < 0.001) in subjects managed with therapeutic coma., Conclusions: This study provides class III evidence that therapeutic coma is associated with poorer outcome after status epilepticus; furthermore, it portends higher infection rates and longer hospitalizations. These data suggest caution in the straightforward use of this approach, especially in patients with complex partial status epilepticus.