Marginal and internal fit of heat pressed versus CAD/CAM fabricated all-ceramic onlays after exposure to thermo-mechanical fatigue

Objectives

The aim of the study was to evaluate the marginal and internal fit of heat-pressed and CAD/CAM fabricated all-ceramic onlays before and after luting as well as after thermo-mechanical fatigue.

Materials and methods

Seventy-two caries-free, extracted human mandibular molars were randomly divided into three groups (n = 24/group). All teeth received an onlay preparation with a mesio-occlusal–distal inlay cavity and an occlusal reduction of all cusps. Teeth were restored with heat-pressed IPS-e.max-Press* (IP, *Ivoclar-Vivadent) and Vita-PM9 (VP, Vita-Zahnfabrik) as well as CAD/CAM fabricated IPS-e.max-CAD* (IC, Cerec 3D/InLab/Sirona) all-ceramic materials. After cementation with a dual-polymerising resin cement (VariolinkII*), all restorations were subjected to mouth-motion fatigue (98 N, 1.2 million cycles; 5 °C/55 °C). Marginal fit discrepancies were examined on epoxy replicas before and after luting as well as after fatigue at 200× magnification. Internal fit was evaluated by multiple sectioning technique. For the statistical analysis, a linear model was fitted with accounting for repeated measurements.

Results

Adhesive cementation of onlays resulted in significantly increased marginal gap values in all groups, whereas thermo-mechanical fatigue had no effect. Marginal gap values of all test groups were equal after fatigue exposure. Internal discrepancies of CAD/CAM fabricated restorations were significantly higher than both press manufactured onlays.

Conclusions

Mean marginal gap values of the investigated onlays before and after luting as well as after fatigue were within the clinically acceptable range. Marginal fit was not affected by the investigated heat-press versus CAD/CAM fabrication technique. Press fabrication resulted in a superior internal fit of onlays as compared to the CAD/CAM technique.

Clinical relevance

Clinical requirements of 100 μm for marginal fit were fulfilled by the heat-press as well as by the CAD/CAM fabricated all-ceramic onlays. Superior internal fit was observed with the heat-press manufacturing method. The impact of present findings on the clinical long-term behaviour of differently fabricated all-ceramic onlays warrants further investigation.     

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

Alkaloids are a group of natural products with interesting pharmacological properties and a long history of medicinal application. Their complex molecular structures have fascinated chemists for decades, and their total synthesis still poses a considerable challenge. In a previous review, we have illustrated how biocatalysis can make valuable contributions to the asymmetric synthesis of alkaloids. The chemo-enzymatic strategies discussed therein have been further explored and improved in recent years, and advances in amine biocatalysis have vastly expanded the opportunities for incorporating enzymes into synthetic routes towards these important natural products. The present review summarises modern developments in chemo-enzymatic alkaloid synthesis since 2013, in which the biocatalytic transformations continue to take an increasingly ‘central’ role.

This review article discusses developments in the chemo-enzymatic synthesis of alkaloids since 2013, showcasing how modern methods of organic synthesis and biocatalysis are combined to establish novel routes towards these important natural products.     

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10^?3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = ?.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.     

Homozygosity for a partial deletion of apoprotein A-V signal peptide results in intracellular missorting of the protein and chylomicronemia in a breast-fed infant

Deficiency of apoprotein A-V (apoA-V) can cause hypertriglyceridemia. In an 11 months old boy presenting with a severe hypertriglyceridemia, a formerly unknown 24 nucleotide deletion in exon 2 of the APOA5 gene was detected. The homozygous mutation results in an eight amino acid loss in the signal peptide sequence (c.16_39del; p.Ala6_Ala13del). Screening of control persons proved that this deletion is a rare mutation. Hypertriglyceridemia in the patient was only found at the time when he was breast fed, while after weaning, triglyceride levels were close to normal. Under both dietary conditions, apoA-V protein was undetectable in plasma while post-heparin plasma lipoprotein lipase activity was normal.     

Cardiotoxicity from Capecitabine Chemotherapy: Prospective Study of Incidence at Rest and During Physical Exercise

BackgroundPhysical activity may increase the risk of cardiotoxicity (myocardial ischemia, major arrhythmias) of 5-Fluorouracil, but this risk has never been investigated for its prodrug capecitabine.Patients and MethodsOne hundred and ninety-two consecutive patients undergoing capecitabine chemotherapy from December 1, 2010 through July 31, 2016 were prospectively evaluated. The baseline evaluation included electrocardiography (ECG) and echocardiography (2DE); a follow-up evaluation, including ECG and exercise stress testing (2DE in case of ECG abnormalities), was done after ≥10 days of treatment. Cardiotoxicity was suspected from ischemic ECG changes, new kinetic abnormalities at 2DE, Lown classification ≥2 ventricular arrhythmia, symptomatic arrhythmias, or positive stress test, and confirmed by a negative stress test after capecitabine washout.ResultsCardiotoxicity was diagnosed in 32 patients (16.7%): six at rest and 26 during exercise. All 32 patients had ECG abnormalities: ST-segment changes (24 patients), negative T-waves (2) and/or arrhythmias: ventricular arrhythmias (14 cases), supraventricular tachycardia (2), complete heart block (1). Eight patients had typical symptoms, 6 had atypical symptoms, 1 had syncope, 17 (53%) were asymptomatic. Cardiotoxicity was more common in patients with atypical symptoms during daily life (OR = 15.7) and in those on a therapeutic schedule of 5 days/week (OR = 9.44).ConclusionCapecitabine cardiotoxicity is frequent, and often elicited by physical effort. Oncologists, cardiologists, and general practitioners should be aware of this risk. Active cardiotoxicity surveillance with ECG (and echocardiogram and/or stress testing in suspected cases) during therapy is recommended.Clinical Trials registration numberCRO-2010-17.     

JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus

This study was stimulated by the clinical observation of a rapid response of a chilblain lupus patient to treatment with JAK1/2‐kinase inhibitor ruxolitinib. We investigated the in vivo expression of phospho‐JAK2 in CLE skin samples as well as the immunomodulatory in vitro effect of ruxolitinib in cultured immortalized keratinocytes and in a 3D human epidermis model (epiCS). Our results demonstrate that ruxolitinib significantly decreases the production of CLE‐typical cytokines (CXCL10, CXCL9, MxA) and might be a promising drug for future clinical studies in patients with CLE and related autoimmune skin diseases.