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Background: The differentiation between Gaucher disease type 3 (GD3) and type 1 is challenging because pathognomonic neurologic symptoms may be subtle and develop at late stages. The ophthalmologist plays a crucial role in identifying the typical impairment of horizontal saccadic eye movements, followed by vertical ones. Little is known about further ocular involvement. The aim of this monocentric cohort study is to comprehensively describe the ophthalmological features of Gaucher disease type 3. We suggest recommendations for a set of useful ophthalmologic investigations for diagnosis and follow up and for saccadometry parameters enabling a correlation to disease severity.
Methods: Sixteen patients with biochemically and genetically diagnosed GD3 completed ophthalmologic examination including optical coherence tomography (OCT), clinical oculomotor assessment and saccadometry by infrared based video-oculography. Saccadic peak velocity, gain and latency were compared to 100 healthy controls, using parametric tests. Correlations between saccadic assessment and clinical parameters were calculated.
Results: Peripapillary subretinal drusen-like deposits with retinal atrophy (2/16), preretinal opacities of the vitreous (4/16) and increased retinal vessel tortuosity (3/16) were found. Oculomotor pathology with clinically slowed saccades was more frequent horizontally (15/16) than vertically (12/16). Saccadometry revealed slowed peak velocity compared to 100 controls (most evident horizontally and downwards). Saccades were delayed and hypometric. Best correlating with SARA (scale for the assessment and rating of ataxia), disease duration, mSST (modified Severity Scoring Tool) and reduced IQ was peak velocity (both up- and downwards). Motility restriction occurred in 8/16 patients affecting horizontal eye movements, while vertical motility restriction was seen less frequently. Impaired abduction presented with esophoria or esotropia, the latter in combination with reduced stereopsis.
Conclusions: Vitreoretinal lesions may occur in 25% of Gaucher type 3 patients, while we additionally observed subretinal lesions with retinal atrophy in advanced disease stages. Vertical saccadic peak velocity seems the most promising "biomarker" for neuropathic manifestation for future longitudinal studies, as it correlates best with other neurologic symptoms. Apart from the well documented abduction deficit in Gaucher type 3 we were able to demonstrate motility impairment in all directions of gaze.
Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required. Methodology/Principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of gene-associated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression. Conclusions/Significance: We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes—DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1—that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs.
Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.
Uncalibrated semi-invasive continous monitoring of cardiac index (CI) has recently gained increasing interest. The aim of the present study was to compare the accuracy of CI determination based on arterial waveform analysis with transpulmonary thermodilution. Fifty patients scheduled for elective coronary surgery were studied after induction of anaesthesia and before and after cardiopulmonary bypass (CPB), respectively. Each patient was monitored with a central venous line, the PiCCO system, and the FloTrac/Vigileo-system. Measurements included CI derived by transpulmonary thermodilution and uncalibrated semi-invasive pulse contour analysis. Percentage changes of CI were calculated. There was a moderate, but significant correlation between pulse contour CI and thermodilution CI both before (r(2) = 0.72, P < 0.0001) and after (r(2) = 0.62, P < 0.0001) CPB, with a percentage error of 31% and 25%, respectively. Changes in pulse contour CI showed a significant correlation with changes in thermodilution CI both before (r(2) = 0.52, P < 0.0001) and after (r(2) = 0.67, P < 0.0001) CPB. Our findings demonstrated that uncalibrated semi-invasive monitoring system was able to reliably measure CI compared with transpulmonary thermodilution in patients undergoing elective coronary surgery. Furthermore, the semi-invasive monitoring device was able to track haemodynamic changes and trends.
A comparison of different APTT-reagents, heparin-sensitivity and detection of mild coagulopathies
(1992)
The activated partial thromboplastin time (aPTT) is widely used to detect coagulation abnormalities or to monitor heparin treatment.
Many commercial aPTT-reagents are available which contain different phospholipid reagents and activators. In the present study 3 aPTT-reagents (aPTT-D, Instrumentation Laboratory, Neothromtin, Behring, PTTa, Boehringer) were compared using a computerized centrifugal analyzer. One aPTT-reagent (Pathromtin, Behring) was tested on a semiautomated coagulometer. Instrument precision was evaluated using aPTT-D as reagent.
Comparative tests were performed on plasma samples of 40 healthy donors, 3 patients with mild von Willebrand's disease (vWd), W patients with heaemophilia or subhaemophilia A, 1 patient with subhaemophilia A and vWd, 8 patients treated with subcutaneous injection of unfractionated heparin (UFH) and 14 patients treated with subcutaneous injection of a low molecular weight heparin (LMWH).
aPTT-D was the most sensitive reagent to detect mild vWd while Pathromtin detected none of these defects. In patients with heamophilia A and subhaemophilia A aPTT-D, Neothromtin and PTTa detected the abnormality in nearly all tested samples while Pathromtin was less sensitive.
Patients treated with subcutaneously applied UFH or LMWH often had a prolonged aPTTt especially when aPTT-D and Neothromtin were used as reagents.
The single nucleotide polymorphism 118A>G of the human micro-opioid receptor gene OPRM1, which leads to an exchange of the amino acid asparagine (N) to aspartic acid (D) at position 40 of the extracellular receptor region, alters the in vivo effects of opioids to different degrees in pain-processing brain regions. The most pronounced N40D effects were found in brain regions involved in the sensory processing of pain intensity. Using the mu-opioid receptor-specific agonist DAMGO, we analyzed the micro-opioid receptor signaling, expression, and binding affinity in human brain tissue sampled postmortem from the secondary somatosensory area (SII) and from the ventral posterior part of the lateral thalamus, two regions involved in the sensory processing and transmission of nociceptive information. We show that the main effect of the N40D micro-opioid receptor variant is a reduction of the agonist-induced receptor signaling efficacy. In the SII region of homo- and heterozygous carriers of the variant 118G allele (n=18), DAMGO was only 62% as efficient (p=0.002) as in homozygous carriers of the wild-type 118A allele (n=15). In contrast, the number of [3H]DAMGO binding sites was unaffected. Hence, the micro-opioid receptor G-protein coupling efficacy in SII of carriers of the 118G variant was only 58% as efficient as in homozygous carriers of the 118A allele (p<0.001). The thalamus was unaffected by the OPRM1 118A>G SNP. In conclusion, we provide a molecular basis for the reduced clinical effects of opioid analgesics in carriers of mu-opioid receptor variant N40D.
Background and Aims: Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians.
Methods: Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235).
Results: The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9–13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6–11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4–1.9; p = 1).
Conclusions: A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches.
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
We explore a combinatorial framework which efficiently quantifies the asymmetries between minima and maxima in local fluctuations of time series. We first showcase its performance by applying it to a battery of synthetic cases. We find rigorous results on some canonical dynamical models (stochastic processes with and without correlations, chaotic processes) complemented by extensive numerical simulations for a range of processes which indicate that the methodology correctly distinguishes different complex dynamics and outperforms state of the art metrics in several cases. Subsequently, we apply this methodology to real-world problems emerging across several disciplines including cases in neurobiology, finance and climate science. We conclude that differences between the statistics of local maxima and local minima in time series are highly informative of the complex underlying dynamics and a graph-theoretic extraction procedure allows to use these features for statistical learning purposes.
Autism spectrum disorders (ASD) have been associated with sensory hypersensitivity. A recent study reported visual acuity (VA) in ASD in the region reported for birds of prey. The validity of the results was subsequently doubted. This study examined VA in 34 individuals with ASD, 16 with schizophrenia (SCH), and 26 typically developing (TYP). Participants with ASD did not show higher VA than those with SCH and TYP. There were no substantial correlations of VA with clinical severity in ASD or SCH. This study could not confirm the eagle-eyed acuity hypothesis of ASD, or find evidence for a connection of VA and clinical phenotypes. Research needs to further address the origins and circumstances associated with altered sensory or perceptual processing in ASD.
Introduction: Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.
Methods: We assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.
Results: Seventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.
Conclusions: We describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.
The discovery of clustered regularly interspaced short palindromic repeats and their associated proteins (Cas) has revolutionized the field of genome and epigenome editing. A number of new methods have been developed to precisely control the function and activity of Cas proteins, including fusion proteins and small-molecule modulators. Proteolysis-targeting chimeras (PROTACs) represent a new concept using the ubiquitin-proteasome system to degrade a protein of interest, highlighting the significance of chemically induced protein-E3 ligase interaction in drug discovery. Here, we engineered Cas proteins (Cas9, dCas9, Cas12, and Cas13) by inserting a Phe-Cys-Pro-Phe (FCPF) amino acid sequence (known as the π-clamp system) and demonstrate that the modified CasFCPF proteins can be (1) labeled in live cells by perfluoroaromatics carrying the fluorescein or (2) degraded by a perfluoroaromatics-functionalized PROTAC (PROTAC-FCPF). A proteome-wide analysis of PROTAC-FCPF-mediated Cas9FCPF protein degradation revealed a high target specificity, suggesting a wide range of applications of perfluoroaromatics-induced proximity in the regulation of stability, activity, and functionality of any FCPF-tagging protein.
Background: One of the most popular and versatile model of murine melanoma is by inoculating B16 cells in the syngeneic C57BL6J mouse strain. A characterization of different B16 modified cell sub-lines will be of real practical interest. For this aim, modern analytical tools like surface enhanced Raman spectroscopy/scattering (SERS) and MTT were employed to characterize both chemical composition and proliferation behavior of the selected cells.
Methods: High quality SERS signal was recorded from each of the four types of B16 cell sub-lines: B164A5, B16GMCSF, B16FLT3, B16F10, in order to observe the differences between a parent cell line (B164A5) and other derived B16 cell sub-lines. Cells were incubated with silver nanoparticles of 50–100 nm diameter and the nanoparticles uptake inside the cells cytoplasm was proved by transmission electron microscopy (TEM) investigations. In order to characterize proliferation, growth curves of the four B16 cell lines, using different cell numbers and FCS concentration were obtained employing the MTT proliferation assay. For correlations doubling time were calculated.
Results: SERS bands allowed the identification inside the cells of the main bio-molecular components such as: proteins, nucleic acids, and lipids. An "on and off" SERS effect was constantly present, which may be explained in terms of the employed laser power, as well as the possible different orientations of the adsorbed species in the cells in respect to the Ag nanoparticles. MTT results showed that among the four tested cell sub-lines B16 F10 is the most proliferative and B164A5 has the lower growth capacity. Regarding B16FLT3 cells and B16GMCSF cells, they present proliferation ability in between with slight slower potency for B16GMCSF cells.
Conclusion: Molecular fingerprint and proliferation behavior of four B16 melanoma cell sub-lines were elucidated by associating SERS investigations with MTT proliferation assay.
Serial quantification of BCR–ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR–ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 106, 1.08±0.11 × 105, 1.03±0.10 × 104, 1.02±0.09 × 103, 1.04±0.10 × 102 and 10.0±1.5 copies/μl. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR–ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR–ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/; CRM code ERM-AD623a-f).
We have analyzed a series of eleven mutations in the 49-kDa protein of mitochondrial complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica to identify functionally important domains in this central subunit. The mutations were selected based on sequence homology with the large subunit of [NiFe] hydrogenases. None of the mutations affected assembly of complex I, all decreased or abolished ubiquinone reductase activity. Several mutants exhibited decreased sensitivities toward ubiquinone-analogous inhibitors. Unexpectedly, seven mutations affected the properties of iron-sulfur cluster N2, a prosthetic group not located in the 49-kDa subunit. In three of these mutants cluster N2 was not detectable by electron-paramagnetic resonance spectroscopy. The fact that the small subunit of hydrogenase is homologous to the PSST subunit of complex I proposed to host cluster N2 offers a straightforward explanation for the observed, unforeseen effects on this iron-sulfur cluster. We propose that the fold around the hydrogen reactive site of [NiFe] hydrogenase is conserved in the 49-kDa subunit of complex I and has become part of the inhibitor and ubiquinone binding region. We discuss that the fourth ligand of iron-sulfur cluster N2 missing in the PSST subunit may be provided by the 49-kDa subunit.
During early G1 phase, Rb is exclusively mono-phosphorylated by cyclin D:Cdk4/6, generating 14 different isoforms with specific binding patterns to E2Fs and other cellular protein targets. While mono-phosphorylated Rb is dispensable for early G1 phase progression, interfering with cyclin D:Cdk4/6 kinase activity prevents G1 phase progression, questioning the role of cyclin D:Cdk4/6 in Rb inactivation. To dissect the molecular functions of cyclin D:Cdk4/6 during cell cycle entry, we generated a single cell reporter for Cdk2 activation, RB inactivation and cell cycle entry by CRISPR/Cas9 tagging endogenous p27 with mCherry. Through single cell tracing of Cdk4i cells, we identified a time-sensitive early G1 phase specific Cdk4/6-dependent phosphorylation gradient that regulates cell cycle entry timing and resides between serum-sensing and cyclin E:Cdk2 activation. To reveal the substrate identity of the Cdk4/6 phosphorylation gradient, we performed whole proteomic and phospho-proteomic mass spectrometry, and identified 147 proteins and 82 phospho-peptides that significantly changed due to Cdk4 inhibition in early G1 phase. In summary, we identified novel (non-Rb) cyclin D:Cdk4/6 substrates that connects early G1 phase functions with cyclin E:Cdk2 activation and Rb inactivation by hyper-phosphorylation.
Rheumatoid arthritis (RA) is a chronic inflammatory disease with a heritability of 60%. Genetic contributions to RA are made by multiple genes, but only a few gene associations have yet been confirmed. By studying animal models, reduced capacity of the NADPH-oxidase (NOX) complex, caused by a single nucleotide polymorphism (SNP) in one of its components (the NCF1 gene), has been found to increase severity of arthritis. To our knowledge, however, no studies investigating the potential role played by reduced reactive oxygen species production in human RA have yet been reported. In order to examine the role played by the NOX complex in RA, we investigated the association of 51 SNPs in five genes of the NOX complex (CYBB, CYBA, NCF4, NCF2, and RAC2) in a Swedish case-control cohort consisting of 1,842 RA cases and 1,038 control individuals. Several SNPs were found to be mildly associated in men in NCF4 (rs729749, P = 0.001), NCF2 (rs789181, P = 0.02) and RAC2 (rs1476002, P = 0.05). No associations were detected in CYBA or CYBB. By stratifying for autoantibody status, we identified a strong association for rs729749 (in NCF4) in autoantibody negative disease, with the strongest association detected in rheumatoid factor negative men (CT genotype versus CC genotype: odds ratio 0.34, 95% confidence interval 0.2 to 0.6; P = 0.0001). To our knowledge, this is the first genetic association identified between RA and the NOX complex, and it supports previous findings from animal models of the importance of reactive oxygen species production capacity to the development of arthritis.
The pathophysiology of Takotsubo Syndrome (TTS) is not completely understood and the trigger of sudden cardiac death (SCD) in TTS is not clear either. We therefore sought to find an association between TTS and primary electrical diseases. A total of 148 TTS patients were analyzed between 2003 and 2017 in a bi-centric manner. Additionally, a literature review was performed. The patients were included in an ongoing retrospective cohort database. The coexistence of TTS and primary electrical diseases was confirmed in five cases as the following: catecholaminergic polymorphic ventricular tachycardia (CPVT, 18-year-old female) (n = 1), LQTS 1 (72-year-old female and 65-year-old female) (n = 2), LQTS 2 (17-year-old female) (n = 1), and LQTS in the absence of mutations (22-year-old female). Four patients suffered from malignant tachyarrhythmia and recurrent syncope after TTS. Except for the CPVT patient and one LQTS 1 patient, all other cases underwent subcutaneous ICD implantation. An event recorder of the CPVT patient after starting beta-blocker did not detect arrhythmias. The diagnosis of primary electrical disease was in 80% of cases unmasked on a TTS event. This diagnosis triggered a family clinical and genetic screening confirming the diagnosis of primary electrical disease. A subsequent literature review identified five cases as the following: a congenital atrioventricular block (n = 1), a Jervell and Lange-Nielsen Syndrome (n = 1), and a family LQTS in the absence of a mutation (n = 2), LQTS 2 (n = 1). A primary electrical disease should be suspected in young and old TTS patients with a family history of sudden cardiac death. In suspected cases, e.g., ongoing QT interval prolongation, despite recovery of left ventricular ejection fraction a family screening is recommended.
Vaccination represents one of the fundamentals in the fight against SARS-CoV-2. Myocarditis has been reported as a rare but possible adverse consequence of different vaccines, and its clinical presentation can range from mild symptoms to acute heart failure. We report a case of a 29-year-old man who presented with fever and retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance imaging and laboratory data revealed typical findings of acute myocarditis.
A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer
(2019)
Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions.
Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms.
Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.
Knowledge discovery in biomedical data using supervised methods assumes that the data contain structure relevant to the class structure if a classifier can be trained to assign a case to the correct class better than by guessing. In this setting, acceptance or rejection of a scientific hypothesis may depend critically on the ability to classify cases better than randomly, without high classification performance being the primary goal. Random forests are often chosen for knowledge-discovery tasks because they are considered a powerful classifier that does not require sophisticated data transformation or hyperparameter tuning and can be regarded as a reference classifier for tabular numerical data. Here, we report a case where the failure of random forests using the default hyperparameter settings in the standard implementations of R and Python would have led to the rejection of the hypothesis that the data contained structure relevant to the class structure. After tuning the hyperparameters, classification performance increased from 56% to 65% balanced accuracy in R, and from 55% to 67% balanced accuracy in Python. More importantly, the 95% confidence intervals in the tuned versions were to the right of the value of 50% that characterizes guessing-level classification. Thus, tuning provided the desired evidence that the data structure supported the class structure of the data set. In this case, the tuning made more than a quantitative difference in the form of slightly better classification accuracy, but significantly changed the interpretation of the data set. This is especially true when classification performance is low and a small improvement increases the balanced accuracy to over 50% when guessing.
Child maltreatment remains a major health threat globally that requires the understanding of socioeconomic and cultural contexts to craft effective interventions. However, little is known about research agendas globally and the development of knowledge-producing networks in this field of study. This study aims to explore the bibliometric overview on child maltreatment publications to understand their growth from 1916 to 2018. Data from the Web of Science Core Collection were collected in May 2018. Only research articles and reviews written in the English language were included, with no restrictions by publication date. We analyzed publication years, number of papers, journals, authors, keywords and countries, and presented the countries collaboration and co-occurrence keywords analysis. From 1916 to 2018, 47,090 papers (53.0% in 2010–2018) were published in 9442 journals. Child Abuse & Neglect (2576 papers; 5.5%); Children and Youth Services Review (1130 papers; 2.4%) and Pediatrics (793 papers, 1.7%) published the most papers. The most common research areas were Psychology (16,049 papers, 34.1%), Family Studies (8225 papers, 17.5%), and Social Work (7367 papers, 15.6%). Among 192 countries with research publications, the most prolific countries were the United States (26,367 papers), England (4676 papers), Canada (3282 papers) and Australia (2664 papers). We identified 17 authors who had more than 60 scientific items. The most cited papers (with at least 600 citations) were published in 29 journals, headed by the Journal of the American Medical Association (JAMA) (7 papers) and the Lancet (5 papers). This overview of global research in child maltreatment indicated an increasing trend in this topic, with the world’s leading centers located in the Western countries led by the United States. We called for interdisciplinary research approaches to evaluating and intervening on child maltreatment, with a focus on low-middle income countries (LMICs) settings and specific contexts.
Multimodal therapy of glioblastoma (GBM) reveals inter-individual variability in terms of treatment outcome. Here, we examined whether a miRNA signature can be defined for the a priori identification of patients with particularly poor prognosis.
FFPE sections from 36 GBM patients along with overall survival follow-up were collected retrospectively and subjected to miRNA signature identification from microarray data. A risk score based on the expression of the signature miRNAs and cox-proportional hazard coefficients was calculated for each patient followed by validation in a matched GBM subset of TCGA. Genes potentially regulated by the signature miRNAs were identified by a correlation approach followed by pathway analysis.
A prognostic 4-miRNA signature, independent of MGMT promoter methylation, age, and sex, was identified and a risk score was assigned to each patient that allowed defining two groups significantly differing in prognosis (p-value: 0.0001, median survival: 10.6 months and 15.1 months, hazard ratio = 3.8). The signature was technically validated by qRT-PCR and independently validated in an age- and sex-matched subset of standard-of-care treated patients of the TCGA GBM cohort (n=58). Pathway analysis suggested tumorigenesis-associated processes such as immune response, extracellular matrix organization, axon guidance, signalling by NGF, GPCR and Wnt. Here, we describe the identification and independent validation of a 4-miRNA signature that allows stratification of GBM patients into different prognostic groups in combination with one defined threshold and set of coefficients that could be utilized as diagnostic tool to identify GBM patients for improved and/or alternative treatment approaches.
Purpose: Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study.
Methods: We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS.
Results: IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p < 0.01) but not for oligodendroglioma (p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p < 0.001/ = 0.06; OS data immature) the effect, mainly in combination with temozolomide, was weaker in astrocytomas (median radiochemotherapy 6.7/chemotherapy 2.3/radiotherapy 2.0 years; p < 0.001/ = 0.11) and did not translate to improved OS (median 8.4 years).
Conclusion: This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.
On 26th November 2010 around 3000 psychiatrists rose up for a minute's silence in the great hall of the International Congress Centrum in Berlin. What they had heard before, was deeply impressive and memorable to the audience. Professor Frank Schneider, president of the German Society for Psychiatry, Psychotherapy and Neurology (DGPPN) asked the psychiatric victims and their relatives of the Nazi era for forgiveness to an extent as only a few German Doctors done before. ...
[Abstract] Occurrence of hepatitis B virus (HBV) reactivation following kidney transplantation
(2004)
Only a few Methyl-[11C]-l-methionine (MET) positron emission tomography (PET) studies have focused on children and young adults with brain neoplasm. Due to radiation exposure, long scan acquisition time, and the need for sedation in young children MET-PET studies should be restricted to this group of patients when a decision for further therapy is not possible from routine diagnostic procedures alone, e.g., structural imaging. We investigated the diagnostic accuracy of MET-PET for the differentiation between tumorous and non-tumorous lesions in this group of patients. Forty eight MET-PET scans from 39 patients aged from 2 to 21 years (mean 15 ± 5.0 years) were analyzed. The MET tumor-uptake relative to a corresponding control region was calculated. A receiver operating characteristic (ROC) was performed to determine the MET-uptake value that best distinguishes tumorous from non-tumorous brain lesions. A differentiation between tumorous (n = 39) and non-tumorous brain lesions (n = 9) was possible at a threshold of 1.48 of relative MET-uptake with a sensitivity of 83% and a specificity of 92%, respectively. A differentiation between high grade malignant lesions (mean MET-uptake = 2.00 ± 0.46) and low grade tumors (mean MET-uptake = 1.84 ± 0.31) was not possible. There was a significant difference in MET-uptake between the histologically homogeneous subgroups of astrocytoma WHO grade II and anaplastic astrocytoma WHO grade III (P = 0.02). MET-PET might be a useful tool to differentiate tumorous from non-tumorous lesions in children and young adults when a decision for further therapy is difficult or impossible from routine structural imaging procedures alone. Keywords Brain tumor - Children - PET - Methionine - Molecular imaging
Background and Aims: The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated.
Methods: A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52.
Results: 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52.
Conclusions: Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B.
Trial Registration: ClinicalTrials.gov NCT00651209
Leukotrienes constitute a group of bioactive lipids generated by the 5-lipoxygenase (5-LO) pathway. An increasing body of evidence supports an acute role for 5-LO products already during the earliest stages of pancreatic, prostate, and colorectal carcinogenesis. Several pieces of experimental data form the basis for this hypothesis and suggest a correlation between 5-LO expression and tumor cell viability. First, several independent studies documented an overexpression of 5-LO in primary tumor cells as well as in established cancer cell lines. Second, addition of 5-LO products to cultured tumor cells also led to increased cell proliferation and activation of anti-apoptotic signaling pathways. 5-LO antisense technology approaches demonstrated impaired tumor cell growth due to reduction of 5-LO expression. Lastly, pharmacological inhibition of 5-LO potently suppressed tumor cell growth by inducing cell cycle arrest and triggering cell death via the intrinsic apoptotic pathway. However, the documented strong cytotoxic off-target effects of 5-LO inhibitors, in combination with the relatively high concentrations of 5-LO products needed to achieve mitogenic effects in cell culture assays, raise concern over the assignment of the cause, and question the relationship between 5-LO products and tumorigenesis. Keywords: leukotriene, apoptosis, cell proliferation, mitogenic effects, cytotoxicity
5-Lipoxygenase contributes to PPAR [gamma] activation in macrophages in response to apoptotic cells
(2012)
Background: One hallmark contributing to immune suppression during the late phase of sepsis is macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells (AC). Taking the important role of the nuclear receptor PPARγ for this phenotype switch into consideration, it remains elusive how AC activate PPARγ in macrophages. Therefore, we were interested to characterize the underlying principle.
Methods: Apoptosis was induced by treatment of Jurkat T cells for 3 hours with 0.5 μg/ml staurosporine. Necrotic cells (NC) were prepared by heating cells for 20 minutes to 65°C. PPARγ activation was followed by stably transducing RAW264.7 macrophages with a vector encoding the red fluorescent protein mRuby after PPARγ binding to 4 × PPRE sites downstream of the reporter gene sequence. This readout was established by treatment with the PPARγ agonist rosiglitazone (1 μM) and AC (5:1). Twenty-four hours after stimulation, mRuby expression was analysed by fluorescence microscopy. Lipid rafts of AC, NC, as well as living cells (LC) were enriched by sucrose gradient centrifugation. Fractions were analysed for lipid raft-associated marker proteins. Lipid rafts were incubated with transduced RAW264.7 macrophages as described above. 5-Lipoxygenase (5-LO) involvement was verified by pharmacological inhibition (MK-866, 1 μM) and overexpression.
Results: Assuming that the molecule responsible for PPARγ activation in macrophages is localized in the cell membrane of AC, most probably associated to lipid rafts, we isolated lipid rafts from AC, NC and LC. Mass spectrometric analysis of lipid rafts of AC showed the expression of 5-LO, whereas lipid rafts of LC did not. Moreover, incubating macrophages with lipid rafts of AC induced mRuby expression. In contrast, lipid rafts of NC and LC did not. To verify the involvement of 5-LO in activating PPARγ in macrophages, Jurkat T cells were incubated for 30 minutes with the 5-LO inhibitor MK-866 (1 μM) before apoptosis induction. In line with our hypothesis, these AC did not induce mRuby expression. Finally, although living Jurkat T cells overexpressing 5-LO did not activate PPARγ in macrophages, mRuby expression was significantly increased when AC were generated from 5-LO overexpressing compared with wild-type Jurkat cells.
Conclusion: Our results suggest that induction of apoptosis activates 5-LO, localizing to lipid rafts, necessary for PPARγ activation in macrophages. Therefore, it will be challenging to determine whether 5-LO activity in AC, generated from other cell types, correlates with PPARγ activation, contributing to an immune-suppressed phenotype in macrophages.
5-iodotubercidin sensitizes cells to RIPK1-dependent necroptosis by interfering with NFκB signaling
(2023)
Receptor-interacting protein kinases (RIPK) −1 and −3 are master regulators of cell fate decisions in response to diverse stimuli and are subjected to multiple checkpoint controls. Earlier studies have established the presence of distinct IKK1/2 and p38/MK2-dependent checkpoints which suppress RIPK1 activation by directly phosphorylating it at different residues. In the present study, we investigated TNF-induced death in MAPK-activated protein kinase 2 (MK2)-deficient cells and show that MK2-deficiency or inactivation predominantly results in necroptotic cell death, even in the absence of caspase inhibition. While MK2-deficient cells can be rescued from necroptosis by RIPK1 inhibitors, RIPK3 inhibition seems to revert the process triggering apoptosis. To understand the mechanism of this necroptosis switch, we screened a 149-compound kinase inhibitor library for compounds which preferentially sensitize MK2-deficient MEFs to TNF-induced cell death. The most potent inhibitor identified was 5-Iodotubericidin, an adenosine analogue acting as adenosine kinase and protein kinase inhibitor. 5-ITu also potentiated LPS-induced necroptosis when combined with MK2 inhibition in RAW264.7 macrophages. Further mechanistic studies revealed that 5-Iodotubericidin induces RIPK1-dependent necroptosis in the absence of MK2 activity by suppressing IKK signaling. The identification of this role for the multitarget kinase inhibitor 5-ITu in TNF-, LPS- and chemotherapeutics-induced necroptosis will have potential implications in RIPK1-targeted therapies.
The stimulation of the AMP-activated kinase (AMPK) by 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) has been associated with antihyperalgesia and the inhibition of nociceptive signaling in the spinal cord in models of paw inflammation. The attenuated nociception comes along with a strongly reduced paw edema, indicating that peripheral antiinflammatory mechanisms contribute to antinociception. In this study, we investigated the impact of AICAR on the immune cell composition in inflamed paws, as well as the regulation of inflammatory and resolving markers in macrophages. By using fluorescence-activated cell sorting (FACS) analysis and immunofluorescence, we found a significantly increased fraction of proresolving M2 macrophages and anti-inflammatory interleukin (IL)-10 in inflamed tissue, while M1 macrophages and proinflammatory cytokines such as IL-1 were decreased by AICAR in wild type mice. In AMPKα2 knock-out mice, the M2 polarization of macrophages in the paw was missing. The results were supported by experiments in primary macrophage cultures which also showed a shift to a proresolving phenotype with decreased levels of proinflammatory mediators and increased levels of antiinflammatory mediators. However, in the cell cultures, we did not observe differences between the AMPKα2+/+ and −/− cells, thus indicating that the AICAR-induced effects are at least partially AMPK-independent. In summary, our results indicate that AICAR has potent antiinflammatory and proresolving properties in inflammation which are contributing to a reduction of inflammatory edema and antinociception.
Patient therapy is based mainly on a combination of diagnosis, suitable monitoring or support devices and drug treatment and is usually employed for a pre-existing disease condition. Therapy remains predominantly symptom-based, although it is increasingly clear that individual treatment is possible and beneficial. However, reasonable precision medicine can only be realized with the coordinated use of diagnostics, devices and drugs in combination with extensive databases (4Ds), an approach that has not yet found sufficient implementation. The practical combination of 4Ds in health care is progressing, but several obstacles still hamper their extended use in precision medicine.
Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.
Purpose of the study: There is a clinical need for antiretroviral therapy (ART) regimens that simplify dosing and make adherence easier for specific patient groups such as former intravenous drug users (IVDU) receiving opiate substitution. Availability of tenofovir DF (TDF) and other once-daily (OD) agents could offer a viable OD regimen. The 3OD study was designed to evaluate the use of OD HAART in IVDU patients.
Methods: 3OD was a single-arm, multicentre, 48-weeks trial to assess efficacy, tolerability and adherence to a OD TDF-containing HAART regimen in former IVDU patients receiving opiate substitution. Of 67 patients enrolled, 27 were antiretroviral treatment naïve, 10 were virologically suppressed (<400 copies/mL), and 30 were re-starting HAART without prior virological failure. Opiate substitution was adjusted according to subject symptoms of opiate overdosing or withdrawal. Various methods were used to assess adherence: besides pill count, patients were asked to fill in a MASRI (Medication Adherence Self-Report Inventory) questionnaire and an electronic log pad diary. Calculation of adherence by pill count assumed that unreturned pills had been taken by the subjects.
Summary of results: Overall, 55% (n = 37, ITT, M = F) of patients had viral load <400 copies/mL at week 48. Using an ITT, M = E analysis, 90% (37/41) of patients reached undetectable VL (<400 copies/mL), 56% (23/41 patients) had plasma HIV-1 RNA concentrations <50 copies/mL at week 48. Only 30 patients (45%) completed the full study and the follow-up period. In 51% of patients, TDF adherence was >100% using pill count. MASRI showed adherence rates of 80–100% in 83–85% of patients; however, 15 patients never entered any data. Diary data were entered by 57 patients; diary data were entered for fewer days than patients received treatment (mean difference 113 days, calculated from treatment start and stop dates).
Conclusion: TDF in combination with other OD antiretrovirals in former IVDU patients showed comparable efficacy to that seen in the average HIV-1 infected population. However, measurement of adherence to self-administered HAART via pill count, MASRI or diary may be misleading in this population.
Background: Recent advances in 3D printing technology have enabled the emergence of new educational and clinical tools for medical professionals. This study provides an exemplary description of the fabrication of 3D‐printed individualised patient models and assesses their educational value compared to cadaveric models in oral and maxillofacial surgery.
Methods: A single‐stage, controlled cohort study was conducted within the context of a curricular course. A patient's CT scan was segmented into a stereolithographic model and then printed using a fused filament 3D printer. These individualised patient models were implemented and compared against cadaveric models in a curricular oral surgery hands‐on course. Students evaluated both models using a validated questionnaire. Additionally, a cost analysis for both models was carried out. P‐values were calculated using the Mann‐Whitney U test.
Results: Thirty‐eight fourth‐year dental students participated in the study. Overall, significant differences between the two models were found in the student assessment. Whilst the cadaveric models achieved better results in the haptic feedback of the soft tissue, the 3D‐printed individualised patient models were regarded significantly more realistic with regard to the anatomical correctness, the degree of freedom of movement and the operative simulation. At 3.46 € (compared to 6.51 €), the 3D‐printed patient individualised models were exceptionally cost‐efficient.
Conclusions: 3D‐printed patient individualised models presented a realistic alternative to cadaveric models in the undergraduate training of operational skills in oral and maxillofacial surgery. Whilst the 3D‐printed individualised patient models received positive feedback from students, some aspects of the model leave room for improvement.
In Bone Tissue Engineering (BTE), autologous bone-regenerative cells are combined with a scaffold for large bone defect treatment (LBDT). Microporous, polylactic acid (PLA) scaffolds showed good healing results in small animals. However, transfer to large animal models is not easily achieved simply by upscaling the design. Increasing diffusion distances have a negative impact on cell survival and nutrition supply, leading to cell death and ultimately implant failure. Here, a novel scaffold architecture was designed to meet all requirements for an advanced bone substitute. Biofunctional, porous subunits in a load-bearing, compression-resistant frame structure characterize this approach. An open, macro- and microporous internal architecture (100 µm–2 mm pores) optimizes conditions for oxygen and nutrient supply to the implant’s inner areas by diffusion. A prototype was 3D-printed applying Fused Filament Fabrication using PLA. After incubation with Saos-2 (Sarcoma osteogenic) cells for 14 days, cell morphology, cell distribution, cell survival (fluorescence microscopy and LDH-based cytotoxicity assay), metabolic activity (MTT test), and osteogenic gene expression were determined. The adherent cells showed colonization properties, proliferation potential, and osteogenic differentiation. The innovative design, with its porous structure, is a promising matrix for cell settlement and proliferation. The modular design allows easy upscaling and offers a solution for LBDT.
Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures—namely the ER surface and the membranous webs—based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results deccribed in the present study.
Popular media now often present 3D printing as a widely employed technology for the production of dental prostheses. This article aims to show, based on factual information, to what extent 3D printing can be used in dental laboratories and dental practices at present. It attempts to present a rational evaluation of todays´ applications of 3D printing technology in the context of dental restorations. In addition, the article discusses future perspectives and examines the ongoing viability of traditional dental laboratory services and manufacturing processes. It also shows which expertise is needed for the digital additive manufacturing of dental restorations.
Introduction: The treatment of carious lesions is one of the most fundamental competencies in daily dental practice. However, many commercially available training models lack in reality regarding the simulation of pathologies such as carious lesions. 3D printed models could provide a more realistic simulation. This study provides an exemplary description of the fabrication of 3D printed dental models with carious lesions and assesses their educational value compared to commercially available models in conservative dentistry.
Materials and Methods: A single-stage, controlled cohort study was conducted within the context of a curricular course. A stereolithographic model was obtained from an intraoral scan and then printed using fused deposition modelling. These models were first piloted by experts and then implemented and compared against commercial models in a conservative dentistry course. Experts and students evaluated both models using a validated questionnaire. Additionally, a cost analysis for both models was carried out.
Results: Thirteen dentists and twenty-seven 5th year dental students participated in the study. The 3D printed models were rated significantly more realistic in many test areas. In particular, the different tactility and the distinction in colour was rated positively in the 3D printed models. At 28.29€ (compared to 112.36€), the 3D printed models were exceptionally cost-efficient.
Conclusions: 3D printed dental models present a more realistic and cost-efficient alternative to commercial models in the undergraduate training of conservative dentistry.