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Aims: Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling.
Methods and results: We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4−/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4−/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs. 379 μm2, P < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4−/− mice (+29% vs. −21%, P < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4−/− mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A.
Conclusion: Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.
Systematic protein localization and protein-protein interaction studies to characterize specific protein functions are most effectively performed using tag-based assays. Ideally, protein tags are introduced into a gene of interest by homologous recombination to ensure expression from endogenous control elements. However, inefficient homologous recombination makes this approach difficult in mammalian cells. Although gene targeting efficiency by homologous recombination increased dramatically with the development of designer endonuclease systems such as CRISPR/Cas9 capable of inducing DNA double-strand breaks with unprecedented accuracy, the strategies still require synthesis or cloning of homology templates for every single gene. Recent developments have shown that endogenous protein tagging can be achieved efficiently in a homology independent manner. Hence, combinations between CRISPR/Cas9 and generic tag-donor plasmids have been used successfully for targeted gene modifications in mammalian cells. Here, we developed a tool kit comprising a CRISPR/Cas9 expression vector with several EGFP encoding plasmids that should enable tagging of almost every protein expressed in mammalian cells. By performing protein-protein interaction and subcellular localization studies of mTORC1 signal transduction pathway-related proteins expressed in HEK293T cells, we show that tagged proteins faithfully reflect the behavior of their native counterparts under physiological conditions.
Background: In the emerging era of digitalization and electronic health, various health-related apps have been launched, including apps for sexually transmitted diseases. Until now, little has been known about how patients perceive the value of such apps.
Objective: To investigate patient’s attitudes and awareness toward sexually transmitted disease–related apps in an outpatient sexually transmitted disease clinic setting.
Methods: A cross-sectional study was conducted at a dermatovenereological outpatient unit between April and July 2019. Patients completed a self-administered questionnaire on their perceptions of the popularity and usefulness of sexually transmitted disease–related apps. Descriptive analysis was performed with expression of categorical variables as frequencies and percentages. For continuous variables, the median, range, and interquartile range were indicated. Contingency tables and chi-square tests were used to investigate associations between sociodemographic data and items of the questionnaire.
Results: A total of 226 patients were surveyed (heterosexual: 137/193, 71.0%; homosexual: 44/193, 22.8%; bisexual: 12/193, 6.2%); 11.9% (27/225) had previously used health-related apps. Nearly half of the patients (97/214, 45.3%) specifically considered sexually transmitted disease–related apps useful, 47.8% (100/209) voted that they could supplement or support the consultation of a physician. Interestingly, only 35.1% (74/211) preferred a printed patient brochure on sexually transmitted diseases over downloading and using an app, but 64.0% (134/209) would download a sexually transmitted disease–related app recommended by their physician. General information regarding sexually transmitted diseases (93/167, 55.7%), evaluation of skin diseases based on photos or videos (78/167, 53.3%), information on the prevention of sexually transmitted diseases (76/167, 45.5%), mediation of nearby contact points or test sites (74/167, 44.3%), anonymous medical advice (69/167, 41.3%), and calculation of the risk of having a sexually transmitted disease (63/167, 37.3%) were rated as the most important features. Men were more likely than women to find sexually transmitted disease–related apps useful in general (P=.04; χ2=6.28) and to pay for such apps (P=.01; χ2=9.19). Patients aged <40 years would rather download an app recommended by their physician (P=.03; χ2=7.23), whereas patients aged >40 years preferred reading a patient brochure on sexually transmitted diseases (P=.02; χ2=8.14).
Conclusions: This study demonstrated high general interest in the use of sexually transmitted disease–related apps in this sample of dermatovenereological outpatients. In particular, young age and male sex were significantly associated with a positive perception, underlining the high potential of apps in the prevention and early recognition of sexually transmitted diseases in this group. Future studies are warranted to validate these findings in other populations.
Objective: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. Method: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. Results: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Conclusion: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD. (J. of Att. Dis. 2021; 25(4) 572-583).
Background: Gait kinematics after total hip replacement only partly explain the differences in the joint moments in the frontal plane between hip osteoarthritis patients after hip replacement and healthy controls. The goal of this study was to determine if total hip replacement surgery affects radiological leg alignment (Hip-Knee-Shaft-Angle, femoral offset, Neck-Shaft-Angle and varus/valgus alignment) and which of these parameters can explain the joint moments, additionally to the gait kinematics.
Methods: 22 unilateral hip osteoarthritis patients who were scheduled for total hip replacement were included in the study. Preoperatively and 1 year postoperatively all patients had biplanar radiographic examinations and 3D gait analysis.
Results: The operated leg showed significantly (P < 0.05) more varus (1.1°) as well as a larger femoral offset (+ 8 mm) and a larger Hip-Knee-Shaft-Angle (+ 1.3°) after total hip replacement; however no significant differences in the joint moments in the frontal plane compared to healthy controls were found. The hip moment (first half of stance) and the knee moments (first and second half of stance) were mostly determined by the varus/valgus alignment (29% and respectively 36% and 35%). The combination with a kinematic parameter (knee range of motion, foot progression angle) increased the predictive value for the knee moments.
Conclusion: In our patient group the joint moments after total hip replacement did not differ from healthy controls, whereas radiological leg alignment parameters changed significantly after the total hip replacement. A combination of these radiological leg parameters, especially the varus alignment, and the deviating kinematics explain the joint moments in the frontal plane during gait after total hip replacement surgery. For surgeons it is important not to create too much of a structural varus alignment by implanting the new hip joint as varus alignment can increase the knee adduction moment and the risk for osteoarthritis of the medial knee compartment.
Trial registration: This study was retrospectively registered with DRKS (German Clinical Trials Register) under the number DRKS00015053. Registered 1st of August 2018.
Das adaptive Immunsystem CRISPR (engl. „clustered regularly interspaced short palindromic repeats“) revolutioniert die medizinische Grundlagenforschung. Die Einfachheit, Präzision und Vielseitigkeit der CRISPR-Technologie ermöglicht es nicht nur, Gene gezielt aus- oder einzuschalten, sondern auch zu korrigieren. Die Hoffnung richtet sich auf eine CRISPR-vermittelte Gentherapie, um krebsverursachende Mutationen gezielt zu korrigieren und somit Tumorwachstum zu verhindern oder therapieren zu können. Technisch ist dies zeitnah vorstellbar, doch ethische und rechtliche Rahmenbedingungen sollten dringend vorab geklärt werden. Die durch Gene Editing aufgeworfenen ethischen und rechtlichen Fragen werden zwar schon seit vielen Jahren diskutiert; durch die nun eingetretene rapide technische Entwicklung stellen sie sich jedoch in neuer Dringlichkeit. Eine umfassende ethische Bewertung der Erforschung und möglichen Anwendung ist daher geboten, einschließlich Fragen der Wissenschaftsethik und -kultur sowie längerfristiger potenzieller sozialer Konsequenzen der CRISPR-Technologie. Rechtlich unterliegt die Gentherapie den allgemeinen arzneimittelrechtlichen Regelungen, die Keimbahntherapie dagegen ist in Deutschland verboten. Auf Dauer und angesichts der erwartbaren weltweiten Entwicklung ist dieses Verbot jedoch zu hinterfragen. In der vorliegenden Arbeit erläutern die Autoren technische, ethische und rechtliche Aspekte des Gene Editing in der Krebsforschung und -therapie und diskutieren die daraus resultierenden Fragen: „Was kann, soll und darf gemacht werden?“.
RITA, the RBP‐J interacting and tubulin‐associated protein, has been reported to be related to tumor development, but the underlying mechanisms are not understood. Since RITA interacts with tubulin and coats microtubules of the cytoskeleton, we hypothesized that it is involved in cell motility. We show here that depletion of RITA reduces cell migration and invasion of diverse cancer cell lines and mouse embryonic fibroblasts. Cells depleted of RITA display stable focal adhesions (FA) with elevated active integrin, phosphorylated focal adhesion kinase, and paxillin. This is accompanied by enlarged size and disturbed turnover of FA. These cells also demonstrate increased polymerized tubulin. Interestingly, RITA is precipitated with the lipoma‐preferred partner (LPP), which is critical in actin cytoskeleton remodeling and cell migration. Suppression of RITA results in reduced LPP and α‐actinin at FA leading to compromised focal adhesion turnover and actin dynamics. This study identifies RITA as a novel crucial player in cell migration and invasion by affecting the turnover of FA through its interference with the dynamics of actin filaments and microtubules. Its deregulation may contribute to malignant progression.
Objective: Excessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although α‐synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic α‐synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease.
Methods: We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of α‐synuclein by assessing cytokine release upon exposure.
Results: We show that pathologic α‐synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation‐ dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular α‐synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of α‐synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic α‐synuclein. Furthermore, we demonstrate that α‐synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model.
Interpretation: Taken together, our data suggest that α‐synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to α‐synuclein. ANN NEUROL 2019;86:593–606
The Masquelet technique for the treatment of large bone defects is a two‐stage procedure based on an induced membrane. The size of a scaffold is reported to be a critical factor for bone healing response. We therefore aimed to investigate the influence of the granule size of a bone graft substitute on bone marrow derived mononuclear cells (BMC) supported bone healing in combination with the induced membrane. We compared three different sizes of Herafill® granules (Heraeus Medical GmbH, Wehrheim) with or without BMC in vivo in a rat femoral critical size defect. A 10 mm defect was made in 126 rats and a membrane induced by a PMMA‐spacer. After 3 weeks, the spacer was taken out and membrane filled with different granule sizes. After 8 weeks femurs were taken for radiological, biomechanical, histological, and immunohistochemical analysis. Further, whole blood of the rat was incubated with granules and expression of 29 peptide mediators was assessed. Smallest granules showed significantly improved bone healing compared to larger granules, which however did not lead to an increased biomechanical stability in the defect zone. Small granules lead to an increased accumulation of macrophages in situ which could be assigned to the inflammatory subtype M1 by majority. Increased release of chemotactic respectively proangiogenic active factors in vitro compared to syngenic bone and beta‐TCP was observed. Granule size of the bone graft substitute Herafill® has significant impact on bone healing of a critical size defect in combination with Masquelet's technique in terms of bone formation and inflammatory.
Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann–Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous.
Quantitative T1 mapping indicates tumor infiltration beyond the enhancing part of glioblastomas
(2019)
The aim of this study was to evaluate whether maps of quantitative T1 (qT1) differences induced by a gadolinium‐based contrast agent (CA) are better suited than conventional T1‐weighted (T1w) MR images for detecting infiltration inside and beyond the peritumoral edema of glioblastomas. Conventional T1w images and qT1 maps were obtained before and after gadolinium‐based CA administration in 33 patients with glioblastoma before therapy. The following data were calculated: (i) absolute qT1‐difference maps (qT1 pre‐CA ‐ qT1 post‐CA), (ii) relative qT1‐difference maps, (iii) absolute and (iv) relative differences of conventional T1w images acquired pre‐ and post‐CA. The values of these four datasets were compared in four different regions: (a) the enhancing tumor, (b) the peritumoral edema, (c) a 5 mm zone around the pathology (defined as the sum of regions a and b), and (d) the contralateral normal appearing brain tissue. Additionally, absolute qT1‐difference maps (displayed with linear gray scaling) were visually compared with respective conventional difference images. The enhancing tumor was visible both in the difference of conventional pre‐ and post‐CA T1w images and in the absolute qT1‐difference maps, whereas only the latter showed elevated values in the peritumoral edema and in some cases even beyond. Mean absolute qT1‐difference values were significantly higher (P < 0.01) in the enhancing tumor (838 ± 210 ms), the peritumoral edema (123 ± 74 ms) and in the 5 mm zone around the pathology (81 ± 31 ms) than in normal appearing tissue (32 ± 35 ms). In summary, absolute qT1‐difference maps—in contrast to the difference of T1w images—of untreated glioblastomas appear to be able to visualize CA leakage, and thus might indicate tumor cell infiltration in the edema region and beyond. Therefore, the absolute qT1‐difference maps are potentially useful for treatment planning.
Background: Previous research demonstrated atypical attention in children with attention‐deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Regarding visual orienting, findings suggest a differential impairment: Atypical orienting to relatively unexpected targets in ASD, and atypical processing of alerting cues in ADHD. The locus coeruleus‐norepinephrine (LC‐NE) system plays an important role in exploiting alerting cues to increase attention and task performance. The present study’s aim was to examine differential subcortical processes underlying visual orienting in ASD and ADHD with pupil dilation (PD) as index of LC activity.
Methods: Pupil dilation (PD) progression metrics during visual orienting were calculated for task‐evoked PD locked to cue, stimulus onset, and behavioral response. Group differences in PD and reaction time (RT) were compared between children with ASD without ADHD (ASD‐) (N = 18), ADHD without ASD (ADHD‐) (N = 28), both disorders (ASD + ADHD) (N = 14), and typically developing children (TD) (N = 31) using linear mixed models (LMM). To further explore the modulatory role of the LC‐NE system group differences in the effect of task‐evoked PD metrics on RT were examined exploratively.
Results: ASD (+ADHD) showed slower orienting responses to relatively unexpected spatial target stimuli as compared to TD, which was accompanied by higher PD amplitudes relative to ADHD− and TD. In ADHD−, shorter cue‐evoked PD latencies relative to ASD−, ASD + ADHD, and TD were found. Group differences in the effect of cue‐ and stimulus‐evoked PD amplitudes on RT were found in ASD− relative to TD.
Conclusions: Study findings provide new evidence for a specific role of the LC‐NE system in impaired reflexive orienting responses in ASD, and atypical visual processing of alerting cues in ADHD.
Introduction: The number of individuals requesting medical treatment for gender dysphoria has increased significantly within the past years. Our purpose was to examine current biographic and socio‐demographic characteristics and aspects of legal gender reassignment.
Design: Medical files from n = 350 individuals of a German Endocrine outpatient clinic were collected from 2009 to 2017 and analysed retrospectively.
Results: Ratio of transwomen to transmen equates to 1:1.89 with a remarkable increase of transmen by the year 2013, showing a reversal of gender distribution compared with previous studies for the first time. Use of illegal substances or self‐initiated hormone therapy was rare (4.6 and 2.1%). Satisfaction with gender‐affirming hormone therapy was significantly higher in transmen than in transwomen (100% vs 96.2%, P = .005). Use of antidepressants declined significantly after onset of hormone treatment in transmen (13% vs 7%; P = .007). The number of individuals with a graduation diploma was only about half as high as in the general population (14.3% vs 27.3%), whereas unemployment rate was more than twice as high (14% vs 6.9%). Median latency between application for legal gender reassignment and definitive court decision was 9 months.
Conclusions: Our data provide possible indications for a decline of psychosocial burden in individuals diagnosed with gender dysphoria over the last years. However, affected individuals are still limited in their occupational and financial opportunities as well as by a complex and expensive procedure of legal gender reassignment in Germany.
Background In melanoma, preclinical data suggest a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G protein-coupled receptor GPR40, was identified in melanoma cells.
Objectives The aim of this study was to investigate GPR40 expression in human melanocytic tissues and to evaluate its potential as a prognostic marker.
Methods and Results A total of 114 tissue sections of naevi, primary melanoma and melanoma metastasis were immunohistochemically stained with anti-GPR40. The staining was evaluated, using the immunoreactivity scoring system. Compared to naevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR40 (P < 0.05). In primary melanoma, GPR40 expression positively correlated with tumour thickness (P = 0.044) and AJCC level (P = 0.017) and in melanoma metastasis with AJCC level (P = 0.035). Primary melanoma patients with high levels of GPR40 had a significantly poorer overall survival (P = 0.004) and shorter disease-free survival (0.040).
Conclusion The present study identified GPR40 as a novel target molecule in melanoma. First evidence for a potential role of the receptor in tumour progression and metastases was found, and it could be demonstrated that GPR40 expression is negatively correlated with patient’s survival.
In solid tumors, tumor‐associated macrophages (TAMs) commonly accumulate within hypoxic areas. Adaptations to such environments evoke transcriptional changes by the hypoxia‐inducible factors (HIFs). While HIF‐1α is ubiquitously expressed, HIF‐2α appears tissue‐specific with consequences of HIF‐2α expression in TAMs only being poorly characterized. An E0771 allograft breast tumor model revealed faster tumor growth in myeloid HIF‐2α knockout (HIF‐2αLysM−/−) compared with wildtype (wt) mice. In an RNA‐sequencing approach of FACS sorted wt and HIF‐2α LysM−/− TAMs, serine protease inhibitor, Kunitz type‐1 ( Spint1) emerged as a promising candidate for HIF‐2α‐dependent regulation. We validated reduced Spint1 messenger RNA expression and concomitant Spint1 protein secretion under hypoxia in HIF‐2α‐deficient bone marrow–derived macrophages (BMDMs) compared with wt BMDMs. In line with the physiological function of Spint1 as an inhibitor of hepatocyte growth factor (HGF) activation, supernatants of hypoxic HIF‐2α knockout BMDMs, not containing Spint1, were able to release proliferative properties of inactive pro‐HGF on breast tumor cells. In contrast, hypoxic wt BMDM supernatants containing abundant Spint1 amounts failed to do so. We propose that Spint1 contributes to the tumor‐suppressive function of HIF‐2α in TAMs in breast tumor development.
Background: Patients with head and neck cancer (HNC) are at high risk for malnutrition because of tumour localisation and therapy. Prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement is common practice to prevent malnutrition.
Objective: To investigate the benefits of prophylactic PEG tube placement for HNC patients in terms of the influence on patients’ nutritional status, utilisation rate, complications and to identify the predictors of PEG tube utilisation.
Methods: All consecutive HNC patients who underwent prophylactic PEG tube insertion between 1 January 2011 and 31 December 2012 prior to therapy were enrolled. The PEG tube utilisation rate, complications, the patients’ nutritional status and tumour therapy were evaluated with the help of electronic patient charts and telephone interviews.
Results: A total of 181 patients (48 female, median 67.5 years) were included. The PEG utilisation rate in the entire cohort was 91.7%. One hundred and forty‐nine patients (82.3%) used the PEG tube for total enteral nutrition, 17 patients (9.4%) for supplemental nutrition and 15 patients (8.3%) made no use of the PEG tube. Peristomal wound infections were the most common complications (40.3%) in this study. A high Nutritional Risk Screening (NRS) score prior to tube insertion was found to be independently associated with PEG utilisation. No significant weight changes were observed across the three patient subgroups.
Conclusions: The overall PEG tube utilisation rate was high in this study. However, given the high rate of infections, diligent patient selection is crucial in order to determine which patients benefit most from prophylactic PEG tube insertion.
Purpose: To evaluate the prevalence of peri‐implantitis (PI) and peri‐implant mucositis (PM) in a long‐term follow‐up with comparison among different PI and PM definitions, and to report on the incidence of PI.
Materials and Methods: In a retrospective clinical study five different PI and PM definitions were applied onto a population with 274 implants 17 to 23 years postimplant placement. Recommendations by the Eighth European Workshop on Periodontology (EWOP) were used as base reference. Clinical and radiological measurements were considered. Risk factors were evaluated in a regression analysis.
Results: After an average observation period of 18.9 years, 40.1% of the implants were diagnosed with PM and 15.0% with PI (Eighth EWOP). PI incidence reached 7.9% on implant level and 13.2% on patient level. Implants diagnosed with PI and progressive bone loss displayed exceptionally vertical bone defect configuration (BDC). Diabetes mellitus, smoking, regular maintenance, or a former periodontal infection did not show significant influence on the prevalence of peri‐implant diseases. Patients with bruxism displayed significantly less PM and PI.
Conclusions: Vertical BDC seems to correspond with active PI, wherefore we estimate such a defining factor of importance. Diagnosis of PM and evaluation of probing pocket depths might be only of descriptive interest as they could lead to false‐positive results.
Paul Ehrlich's concept of the magic bullet, by which a single drug induces pharmacological effects by interacting with a single receptor has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic variability, cellular plasticity, chronobiological rhythms, time, age and disease resolution, sex, drug metabolism, and distribution. We emphasize four existing approaches that can be taken, either singly or in combination, to try to minimize effects of pharmacological plasticity. These are firstly, to enhance specificity using target conditions close to those in diseases, secondly, by simultaneously or thirdly, sequentially aiming at multiple targets, and fourthly, in synchronization with concurrent dietary, psychological, training, and biorhythm‐synchronizing procedures to optimize drug therapy.
Objective: To compare discomfort/pain following periodontal probing around teeth and peri‐implant probing around implants with or without platform switching.
Methods: Two dentists recruited and examined 65 patients, each of them exhibiting a dental implant with a contralateral tooth. Only two types of implants were included: one with and one without platform switching. Periodontal and peri‐implant probing depths (PPD) and probing attachment level (PAL) were assessed. Whether implant or tooth was measured first was randomly assigned. Immediately after probing, patients scored discomfort/pain using a visual analogue scale (VAS). The emergence profiles of implant crowns were assessed as angles between interproximal surfaces on radiographs.
Results: Sixty‐five patients (age 69; 63/76 years [median; lower/upper quartile]; 38 females, 11 smokers) were examined. With the exception of mean PPD and PAL (p < .05) clinical parameters (PPD, PAL, bleeding on probing, suppuration) were well balanced between implants and teeth. Peri‐implant probing (VAS: 10; 0.75/16.25) caused significantly (p < .001) more discomfort/pain than periodontal probing (4; 0/10). Logistic regression analysis identified a larger difference between discomfort/pain for peri‐implant and periodontal probing in the maxilla than the mandible (p = .003). Comparing discomfort/pain between implants maxilla (p = .006) and emergence profile (p = .015) were associated with discomfort/pain. Type of implant (with/without platform switching) had no significant effect on discomfort/pain.
Conclusions: Peri‐implant probing caused significantly more discomfort/pain than periodontal probing. Implant design with/without platform switching failed to have a significant effect on discomfort/pain.
An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
(2019)
Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4‐glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype–phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability.
Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology‐score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule‐associated protein 1A/1B‐light chain 3, p62 and Bcl2‐associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies.
Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology‐score. High morphology‐scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology‐score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine‐kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.‐32‐13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type.
Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Hepatitis B virus (HBV) reactivation in immunosuppressed patients can cause considerable morbidity and mortality. The aim of our study was to evaluate factors associated with acute liver failure (ALF) in HBV reactivation. Clinical, laboratory, and virological data of 87 patients with HBV reactivation were analyzed retrospectively. Teno torque virus (TTV) plasma loads were measured as a measure of immune competence. HBV genomes isolated from 47 patients were analyzed by next-generation sequencing. A functional analysis of identified HBsAg mutants was performed. In patients with ALF the diagnosis was significantly later confirmed than in the non-ALF group. Patients diagnosed during immunosuppression had a milder clinical course compared to later diagnosed patients (p = 0.018, OR = 4.17). TTV viral loads did not differ significantly between the two groups. The HBV genomes isolated from ALF patients had higher viral complexity. A mutation in C-region of HBsAg (L216*), was associated with reduced HBsAg production and secretion. Patients diagnosed with HBV reactivation during immunosuppression had a milder clinical course compared to patients diagnosed during immune reconstitution. ALF was associated with higher viral complexity. An HBsAg mutation (L216*) was found to be more frequent in ALF patients and was associated with reduced HBsAg production and secretion.
Aim: Evaluation of long‐term results after connective tissue graft (CTG) using the envelope technique and the effect on patient‐centred outcomes (Oral Health Impact Profile: OHIP) in a private practice setting.
Materials and Methods: Fifteen patients (11 female, mean age: 45.0 ± 8.88 years) underwent root coverage procedure using a CTG involving maxillary Miller class I teeth. Pre‐operatively, 3 and 120 ± 12 months after surgery, all patients were examined, completed OHIP questionnaire, and were asked to assess improvement and their satisfaction with the results of surgery. All procedures were performed by the same investigator.
Results: Recession depth at 3 months of 1.19 ± 0.93 mm was reduced to that of 0.63 ± 0.64 mm at 120 ± 12 months after surgery (p = .117). Recession width (−1.23 ± 2.27 mm) decreased as well (p = .117), while relative root coverage increased from 48.46 ± 32.18% at 3 months to 71.22 ± 30.86% at 120 months (p = .011). The number of cases with complete root coverage increased from two (15.4%) to six (40.0%) from 3 to 120 months (p = .046). OHIP score (12.07 ± 10.15) did not change after 10 years (12.13 ± 9.86, p = .889). Ten years after surgery, 12 patients (80%) reported they would make the decision again to undergo CTG transplantation.
Conclusions: Within the limitations of the study design with a high risk of bias in a practice setting, long‐term stability of recession reduction, OHIP and patient‐perceived satisfaction remained stable over 10 years.
Aim: To assess the prevalence and severity of periodontitis in patients with moderate chronic kidney disease (CKD) and comparing the results with the self‐reported periodontitis awareness of the study subjects.
Material and methods: The periodontal status of 270 patients with moderate CKD randomly selected from a cohort of 5,217 subjects participating in the prospective observational German Chronic Kidney Disease (GCKD) project was analysed by recording bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment level (CAL). Furthermore, the awareness of the study subjects of their periodontal conditions was evaluated by a self‐reported questionnaire.
Results: 24.4% of the CKD study patients showed no or only mild signs of periodontal disease, 47.6% displayed moderate and 27% severe periodontitis. Questionnaire data revealed that 62.3% of the study subjects with severe periodontitis were not aware of the presence of the disease, 44.4% denied having received any systematic periodontal therapy so far, although 50% of them indicated to visit their dentist regularly for professional tooth cleanings.
Conclusion: While the clinical study data confirm an increased prevalence of periodontitis in CKD patients, their self‐reported awareness of periodontitis was low.
Atelopus is a species-rich group of Neotropical bufonids. Present knowledge on bioacoustics in this genus is relatively poor, as vocalisations have been described in only about one fifth of the ca. 100 species known. All studied members of the genus produce vocalisations although, with a few exceptions, most species lack a middle ear. Nonetheless, hearing has been demonstrated even in earless Atelopus making bioacoustics in these toads an inspiring research field. So far, three structural call types have been identified in the genus. As sympatry is uncommon in Atelopus, calls of the same type often vary little between species. Based on recordings from the 1980s, we describe vocalisations of three Venezuelan species (A. carbonerensis, A. mucubajiensis, A. tamaense) from the Cordillera de Mérida, commonly known as the Andes of Venezuela and the Tamá Massif, a Venezuelan spur of the Colombian Cordillera Oriental. Vocalisations correspond, in part, to the previously identified call types in Atelopus. Evaluation of the vocalisations of the three species presented in this study leads us to recognise a fourth structural call type for the genus. With this new addition, the Atelopus acoustic repertoire now includes (1) pulsed calls, (2) pure tone calls, (3) pulsed short calls and (4) pure tone short calls. The call descriptions provided here are valuable contributions to the bioacoustics of these Venezuelan Atelopus species, since all of them have experienced dramatic population declines that limit possibilities of further studies.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.
KDEL receptors (KDELRs) represent transmembrane proteins of the secretory pathway which regulate the retention of soluble ER-residents as well as retrograde and anterograde vesicle trafficking. In addition, KDELRs are involved in the regulation of cellular stress response and ECM degradation. For a deeper insight into KDELR1 specific functions, we characterised a KDELR1-KO cell line (HAP1) through whole transcriptome analysis by comparing KDELR1-KO cells with its respective HAP1 wild-type. Our data indicate more than 300 significantly and differentially expressed genes whose gene products are mainly involved in developmental processes such as cell adhesion and ECM composition, pointing out to severe cellular disorders due to a loss of KDELR1. Impaired adhesion capacity of KDELR1-KO cells was further demonstrated through in vitro adhesion assays, while collagen- and/or laminin-coating nearly doubled the adhesion property of KDELR1-KO cells compared to wild-type, confirming a transcriptional adaptation to improve or restore the cellular adhesion capability. Perturbations within the secretory pathway were verified by an increased secretion of ER-resident PDI and decreased cell viability under ER stress conditions, suggesting KDELR1-KO cells to be severely impaired in maintaining cellular homeostasis.
Background: Reports of head and neck ultrasound examinations are frequently written by hand as free texts. Naturally, quality and structure of free text reports is variable, depending on the examiner’s individual level of experience. Aim of the present study was to compare the quality of free text reports (FTR) and structured reports (SR) of head and neck ultrasound examinations.
Methods: Both standard FTRs and SRs of head and neck ultrasound examinations of 43 patients were acquired by nine independent examiners with comparable levels of experience. A template for structured reporting of head and neck ultrasound examinations was created using a web-based approach. FTRs and SRs were evaluated with regard to overall quality, completeness, required time to completion, and readability by four independent raters with different specializations (Paired Wilcoxon test, 95% CI) and inter-rater reliability was assessed (Fleiss’ kappa). A questionnaire was used to compare FTRs vs. SRs with respect to user satisfaction (Mann-Whitney U test, 95% CI).
Results: By comparison, completeness scores of SRs were significantly higher than FTRs’ completeness scores (94.4% vs. 45.6%, p < 0.001), and pathologies were described in more detail (91.1% vs. 54.5%, p < 0.001). Readability was significantly higher in all SRs when compared to FTRs (100% vs. 47.1%, p < 0.001). The mean time to complete a report, however, was significantly higher in SRs (176.5 vs. 107.3 s, p < 0.001). SRs achieved significantly higher user satisfaction ratings (VAS 8.87 vs. 1.41, p < 0.001) and a very high inter-rater reliability (Fleiss’ kappa 0.92).
Conclusions: As compared to FTRs, SRs of head and neck ultrasound examinations are more comprehensive and easier to understand. On the balance, the additional time needed for completing a SR is negligible. Also, SRs yield high inter-rater reliability and may be used for high-quality scientific data analyses.
Acute‐on‐chronic liver failure (ACLF) is a syndrome with high short‐term mortality. Precipitating events, including hemorrhage and infections, contribute to ACLF development, but the role of surgery remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and laboratory data were collected prior to and on days 1‐2, 3‐8, and 9‐28, and at 3 and 12 months after surgery. Surgery type was classified as limited or extensive, as well as liver and nonliver surgery. A total of 39 patients had baseline ACLF. Surgery was performed during acute decompensation in 35% of the rest of the 330 patients, and 81 (24.5%) developed ACLF within 28 days after surgery. Surrogate markers of systemic inflammation were similar in patients who developed ACLF or not. Age, sex, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were independent predictors for the development of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher mortality at 3, 6, and 12 months. Survival did not differ between patients with ACLF at surgery and those developing ACLF after surgery. Development of ACLF within 28 days after surgery and elevated alkaline phosphatase and international normalized ratio were independent predictors of 90‐day mortality. Independent predictors of 1‐year all‐cause mortality were alkaline phosphatase, Model for End‐Stage Liver Disease score, and preoperative hepatic encephalopathy, whereas nonliver surgery was associated with improved survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, especially in those with active bacterial infection, lower serum sodium, and kidney or coagulation dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be carefully managed perioperatively.
Production of free radicals and oxidative damage during physical activity is a topic that is intensively studied and paid a lot of attention, first of all in professional sports. Marathon is categorized as extremely demanding sports discipline, as it induces high energy consumption and also requires special mental self-control. We presented cases of two athletes of different age, who have been on dissimilar level of sports readiness, and also had various approach to physical activity and exercise. During 10 days they ran out 10 marathons, partly on a flat terrain, and partly on hilly, which produced different level of effort in conquering the terrain. Also, both athletes had complex supplementation scheme in order to prevent electrolyte imbalance and excessive production of free radicals. Blood samples were taken in the morning and immediately after the end of the marathon. Measured oxidative stress biomarkers changed without a noticeable pattern, but these changes did not vary greatly among themselves. Catalase activity in both marathon runners was higher after marathon almost after every race for 10 days. On the other hand, amount of reduced glutathione was lower after marathon in both athletes in the same manner. Based on the obtained results we can conclude that adequate supplementation could have crucial role in prevention of oxidative damage.
Background & Aims: Renal function assessed by creatinine is a key prognostic factor in cirrhotic patients. However, creatinine is influenced by several factors, rendering interpretation difficult in some situations. This is especially important in early stages of renal dysfunction where renal impairment might not be accompanied by an increase in creatinine. Other parameters, such as cystatin C (CysC) and beta‐trace protein (BTP), have been evaluated to fill this gap. However, none of these studies have considered the role of the patient's sex. The present study analysed CysC and BTP to evaluate their prognostic value and differentiate them according to sex.
Patients and methods: CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt (TIPS)‐patients from the NEPTUN‐STUDY(NCT03628807) and analysed their relationship with mortality and sex. Propensity score for age, MELD, etiology and TIPS indication was used.
Results_ Cystatin C and BTP showed excellent correlations with creatinine values at baseline and follow‐up. CysC was an independent predictor of overall mortality (HR = 1.66(1.33‐2.06)) with an AUC of 0.75 and identified a cut‐off of 1.55 mg/L in the whole cohort. Interestingly, CysC was significantly lower in females, also after propensity score matching. In males, the only independent predictor was the creatinine level (HR = 1.54(1.25‐1.58)), while in females CysC levels independently predicted mortality (HR = 3.17(1.34‐7.52)).
Conclusion: This study demonstrates for the first time that in TIPS‐patients creatinine predicts mortality in males better than in females, whereas CysC is a better predictor of mortality in females. These results may influence future clinical decisions on therapeutic options for example, allocation for liver transplantation in TIPS‐patients.
Rationale: The clinical relevance of sensitization to Aspergillus (A) fumigatus in cystic fibrosis (CF) is unclear. Some researchers propose that specific A fumigatus IgE is an innocent bystander, whereas others describe it as the major cause of TH‐2‐driven asthma‐like disease.
Objectives: Lung function parameters in mild CF patients may be different in patients with and without A fumigatus sensitization. We aimed to ascertain whether allergen exposure to A fumigatus by bronchial allergen provocation (BAP) induces TH‐2 inflammation comparable to an asthma‐like disease.
Methods: A total of 35 patients, aged 14.8 ± 8.5 years, and 20 healthy controls were investigated prospectively. The patients were divided into two groups: group 1 (n = 18): specific (s)IgE negative, and group 2 (n = 17): sIgE positive (≥0.7 KU/L) for A fumigatus. Lung function, exhaled NO, and induced sputum were analysed. All sensitized patients with an FEV1 > 75% (n = 13) underwent BAP with A fumigatus, and cell counts, and the expression of IL‐5, IL‐13, INF‐γ, and IL‐8 as well as transcription factors T‐bet, GATA‐3, and FoxP3, were measured.
Results: Lung function parameters decreased significantly compared to controls, but not within the CF patient group. After BAP, 8 of 13 patients (61%) had a significant asthmatic response and increased eNO 24 hours later. In addition, marked TH‐2‐mediated inflammation involving eosinophils, IL‐5, IL‐13, and FoxP3 became apparent in induced sputum cells.
Conclusion: Our study demonstrated the clinical relevance of A fumigatus for the majority of sensitized CF patients. A distinct IgE/TH‐2‐dominated inflammation was found in induced sputum after A fumigatus exposure.
Objective: Fluconazle or posaconazole is a standard of care in antifungal prophylaxis for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). However, many patients need to interrupt standard prophylaxis due to intolerability, drug‐drug interactions, or toxicity. Micafungin has come to prominence for these patients. However, the optimal biological dose of micafungin stays unclear.
Methods: We retrospectively evaluated the efficacy of micafungin as antifungal prophylaxis in HSCT patients. Micafungin was applied as bridging in patients who were not eligible to receive oral posaconazole. Micafungin was either given at a dose of 100 mg or 50 mg SID.
Results: A total of 173 patients received micafungin prophylaxis, 62 in the 100 mg and 111 in the 50 mg dose group. The incidence of probable or proven breakthrough IFDs during the observation period was one in the 100 mg and one in the 50 mg group. Fungal‐free survival after 100 days was 98% and 99% (P = .842), and overall survival after 365 days was 60% and 63% (P = .8) respectively. In both groups, micafungin was well tolerated with no grade 3 or 4 toxicities.
Conclusion: In this retrospective analysis, which was not powered to detect non‐inferiority, micafungin is effective and complements posaconazole as fungal prophylaxis in HSCT.
Background and objectives: Preoperative anaemia is an independent risk factor for a higher morbidity and mortality, a longer hospitalization and increased perioperative transfusion rates. Managing preoperative anaemia is the first of three pillars of Patient Blood Management (PBM), a multidisciplinary concept to improve patient safety. While various studies provide medical information on (successful) anaemia treatment pathways, knowledge of organizational details of diagnosis and management of preoperative anaemia across Europe is scarce.
Materials and methods: To gain information on various aspects of preoperative anaemia management including organization, financing, diagnostics and treatment, we conducted a survey (74 questions) in ten hospitals from seven European nations within the PaBloE (Patient Blood Management in Europe) working group covering the year 2016.
Results: Organization and activity in the field of preoperative anaemia management were heterogeneous in the participating hospitals. Almost all hospitals had pathways for managing preoperative anaemia in place, however, only two nations had national guidelines. In six of the ten participating hospitals, preoperative anaemia management was organized by anaesthetists. Diagnostics and treatment focused on iron deficiency anaemia which, in most hospitals, was corrected with intravenous iron.
Conclusion: Implementation and approaches of preoperative anaemia management vary across Europe with a primary focus on treating iron deficiency anaemia. Findings of this survey motivated the hospitals involved to critically evaluate their practice and may also help other hospitals interested in PBM to develop action plans for diagnosis and management of preoperative anaemia.
Cardiac reactions to emotional words in adolescents and young adults with PTSD after child abuse
(2019)
Post‐traumatic stress disorder (PTSD) is associated with alterations in cardiac reactivity to threat cues. Meta‐analyses have summarized that adults with PTSD have increased heart rates in response to trauma‐related stimuli. However, the opposite effect (i.e., cardiac hyporeactivity) has recently been reported in subgroups of PTSD patients. In children and adolescents with PTSD, reports of cardiac alterations are rare and ambiguous. So far, most studies in adolescents and young adults are restricted to victims of accidents, even though PTSD is highly prevalent in victims of child maltreatment. The present study aimed at investigating cardiac reactions in adolescents and young adults with PTSD after child abuse. Cardiac responses to standardized emotional words were studied in 39 adolescent and young adult PTSD patients after childhood sexual and/or physical abuse as compared to 39 healthy control subjects (age range: 15–20 years). The experimental paradigm consisted of a passive reading task with neutral, positive, physically threatening, and socially threatening (swear) words. Results showed that cardiac reactions to negative stimuli, particularly physically threatening stimuli, were less pronounced in PTSD patients than in controls. Moreover, cardiac reactions in response to socially threatening words were less variable in the PTSD group. No differences between and within groups were present in reaction to neutral or positive stimuli. Findings suggest that a physiologically blunted subtype of PTSD may already manifest during adolescence and young adulthood. Moreover, the results of the present study emphasize the relevance of individual trauma history for physiological reactions.
Health economics of Patient Blood Management: a cost‐benefit analysis based on a meta‐analysis
(2019)
Background and Objectives: Patient Blood Management (PBM) is the timely application of evidence‐based medical and surgical concepts designed to improve haemoglobin concentration, optimize haemostasis and minimize blood loss in an effort to improve patient outcomes. The focus of this cost‐benefit analysis is to analyse the economic benefit of widespread implementation of a multimodal PBM programme.
Materials and Methods: Based on a recent meta‐analysis including 17 studies (>235 000 patients) comparing PBM with control care and data from the University Hospital Frankfurt, a cost‐benefit analysis was performed. Outcome data were red blood cell (RBC) transfusion rate, number of transfused RBC units, and length of hospital stay (LOS). Costs were considered for the following three PBM interventions as examples: anaemia management including therapy of iron deficiency, use of cell salvage and tranexamic acid. For sensitivity analysis, a Monte Carlo simulation was performed.
Results: Iron supplementation was applied in 3·1%, cell salvage in 65% and tranexamic acid in 89% of the PBM patients. In total, applying these three PBM interventions costs €129·04 per patient. However, PBM was associated with a reduction in transfusion rate, transfused RBC units per patient, and LOS which yielded to mean savings of €150·64 per patient. Thus, the overall benefit of PBM implementation was €21·60 per patient. In the Monte Carlo simulation, the cost savings on the outcome side exceeded the PBM costs in approximately 2/3 of all repetitions and the total benefit was €1 878 000 in 100·000 simulated patients.
Conclusion: Resources to implement a multimodal PBM concept optimizing patient care and safety can be cost‐effectively.
Objective: Novel treatments are needed to control treatment‐resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE).
Methods: A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation.
Results: In total, TPM was used in 106 of 854 patients having a mean age of 67.4 ± 18.1 years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5 days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100 mg/d, which was uptitrated to a median maintenance dose of 400 mg/d. Treatment with TPM was continued for a median time of 12 days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment‐emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty‐four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n = 24).
Significance: The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than 8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.
Post‐traumatic stress disorder (PTSD) is associated with a hypersensitivity to potential threat. This hypersensitivity manifests through differential patterns of emotional information processing and has been demonstrated in behavioral and neurophysiological experimental paradigms. However, the majority of research has been focused on adult patients with PTSD. To examine possible differences in underlying neurophysiological patterns for adolescent patients with PTSD after childhood sexual and/or physical abuse (CSA/CPA), ERP correlates of emotional word processing in 38 healthy participants and 40 adolescent participants with PTSD after experiencing CSA/CPA were studied. The experimental paradigm consisted of a passive reading task with neutral, positive (e.g., paradise), physically threatening (e.g., torment), and socially threatening (i.e., swearing, e.g., son of a bitch) words. A modulation of P3 amplitudes by emotional valence was found, with positive words inducing less elevated amplitudes over both groups. Interestingly, in later processing, the PTSD group showed augmented early late positive potential (LPP) amplitudes for socially threatening stimuli, while there were no modulations within the healthy control group. Also, region‐specific emotional modulations for anterior and posterior electrode clusters were found. For the anterior LPP, highest activations have been found for positive words, while socially and physically threatening words led to strongest modulations in the posterior LPP cluster. There were no modulations by group or emotional valence at the P1 and EPN stage. The findings suggest an enhanced conscious processing of socially threatening words in adolescent patients with PTSD after CSA/CPA, pointing to the importance of a disjoined examination of threat words in emotional processing research.
Objectives: Whereas stationary stability of implants has been postulated for decades, recent studies suggested a phenomenon termed implant migration. This describes a change in position of implants as a reaction to applied forces. The present study aims at employing image registration of in vivo micro‐CT scans from different time points and to assess (a) if migration of continuously loaded implants is possible and (b) migration correlates with the force magnitude.
Material and methods: Two customized machined implants were placed in the dorsal portion of caudal vertebrae in n = 61 rats and exposed to standardized forces (0.5 N, 1.0 N, and 1.5 N) applied through a flat nickel–titanium contraction spring, or no forces (control). Micro‐CT scans were performed at 0, 1, 2, 4, 6, and 8 weeks after surgery. The baseline image was registered with the forthcoming scans. Implant migration was measured as the Euclidean distance between implant tips. Bone remodeling was assessed between the baseline and the forthcoming scans.
Results: The findings confirmed a positional change of the implants at 2 and 8 weeks of healing, and a linear association between applied force and velocity of movement (anterior implant: χ2 = 12.12, df = 3, and p = .007 and posterior implant: χ2 = 20.35, df = 3, and p < .001). Bone apposition was observed around the implants and accompanied by formation of load‐bearing trabeculae and a general cortical thickening close and also distant to the implants.
Conclusion: The present analysis confirmed that implants can migrate in bone. The applied forces seemed to stimulate bone thickening, which could explain why implants migrate without affecting stability.
The detection of cortical malformations in conventional MR images can be challenging. Prominent examples are focal cortical dysplasias (FCD), the most common cause of drug‐resistant focal epilepsy. The two main MRI hallmarks of cortical malformations are increased cortical thickness and blurring of the gray (GM) and white matter (WM) junction. The purpose of this study was to derive synthetic anatomies from quantitative T1 maps for the improved display of the above imaging characteristics in individual patients.
On the basis of a T1 map, a mask comprising pixels with T1 values characteristic for GM is created from which the local cortical extent (CE) is determined. The local smoothness (SM) of the GM‐WM junctions is derived from the T1 gradient. For display of cortical malformations, the resulting CE and SM maps serve to enhance local intensities in synthetic double inversion recovery (DIR) images calculated from the T1 map.
The resulting CE‐ and/or SM‐enhanced DIR images appear hyperintense at the site of cortical malformations, thus facilitating FCD detection in epilepsy patients. However, false positives may arise in areas with naturally elevated CE and/or SM, such as large GM structures and perivascular spaces.
In summary, the proposed method facilitates the detection of cortical abnormalities such as cortical thickening and blurring of the GM‐WM junction which are typical FCD markers. Still, subject motion artifacts, perivascular spaces, and large normal GM structures may also yield signal hyperintensity in the enhanced synthetic DIR images, requiring careful comparison with clinical MR images by an experienced neuroradiologist to exclude false positives.
Progression of pupil dilation (PD) in response to visual stimuli may indicate distinct internal processes. No study has been performed on PD progression during a social cognition task. Here, we describe PD progression during the Movie for the Assessment of Social Cognition (MASC) test in n = 23 adolescents with Autism Spectrum Disorder (ASD) and n = 24 age, IQ and sex‐matched neurotypical controls (NTC). The MASC consists of 43 video sequences depicting human social interactions, each followed by a multiple‐choice question concerning characters' mental states. PD progression data were extracted by eye tracking and controlled for fixation behavior. Segmenting PD progression during video sequences by principal component analysis, three sequential PD components were unveiled. In ASD compared with NTC, a distinct PD progression was observed with increased constriction amplitude, increased dilation latency, and increased dilation amplitude that correlated with PD progression components. These components predicted social cognition performance. The first and second PD components correlated positively with MASC behavioral performance in ASD but negatively in NTC. These PD components may be interpreted as indicators of sensory‐perceptual processing and attention function. In ASD, aberrant sensory‐perceptual processing and attention function could contribute to attenuated social cognition performance. This needs to be tested by additional studies combining the respective cognitive tests and the outlined PD progression analysis. Phasic activity of the locus coeruleus–norepinephrine system is discussed as putatively shared underlying mechanism.
Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.
Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
Uncertainty is a central theme in the illness experiences of older cancer patients throughout their illness trajectory. Mishel’s popular theory on uncertainty during illness approaches uncertainty as an outcome and is characterized by the patient’s inability to find meaning in illness events. This study used the concepts of liminality and subjunctivity to explore uncertainty throughout the illness trajectory of cancer patients. We interviewed 18 older (age range = 57–92 years) patients with breast cancer or gastro-intestinal cancer 3 to 4 years post diagnosis. Our analysis is based on the QUAGOL guide that draws on elements of grounded theory such as constant comparison. We found that liminality and subjunctivity provide a useful frame for understanding uncertainty with a specific focus on its productive potential and meaning making. Health care professionals should be open to acquiring a complete picture of patients’ diverse and dynamic experiences of uncertainty in the different stages of their illness trajectory.
This paper aims at reconstructing the development and role of German neurology between 1840 and 1940. Therefore a couple of original sources as well as selected material form the scattered secondary literature were assessed and reviewed. Since the middle of the nineteenth century, an intricate process of separation from internal medicine and psychiatry gradually led to forming a self-conscious community of German neurologists. While Moritz Heinrich Romberg had constructed a cognitive basis for neurology, scientific founders such as Wilhelm Erb, Carl Wernicke, Alois Alzheimer, Hermann Oppenheim, Max Nonne, and many others established the new discipline within modern medicine. In 1891, the first generation of “pure” neurologists succeeded in founding the German Journal for Neurology (Deutsche Zeitschrift für Nervenheilkunde) followed by an autonomous professional organisation, the Society of German Neurologists (Gesellschaft Deutscher Nervenärzte) in 1907. A variety of external factors, however, hampered the institutional evolution and thus the implementation of chairs and departments remained quite modest. In 1935, only 2 years after the National Socialists had seized power, the regulatory merger with the psychiatristsʼ society caused the cautious attempts of German neurologists for autonomy to end in complete failure. The imprisonment, murder and expulsion of neuroscientists declared as Jewish or non-Aryan caused profound changes in neurology, medicine, academic life, and health care in general. Further historical research is needed to reconstruct in detail the involvement of German neurologists in racial-hygienic and eugenic research as well as the institutional and scientific development of German neurology after World War II.
Mutations in blood stem cells do not necessarily have to result in leukaemia. It was only recently discovered that clones of mutated blood cells can be identified in many healthy people in old age. Nonetheless, clonal haematopoiesis, as scientists baptised this finding, is far from innocent. It is a formidable risk factor for cardiovascular diseases – on par with smoking, excess weight or high blood pressure. Why this is, is still a riddle to be solved.
You are what you eat!
(2019)
Nowadays almost everyone is aware of the link between high blood cholesterol levels and cardiovascular disease. There are effective treatments that target blood cholesterol. his overview highlights some well known and some new mediators implicated in cardiovascular disease with the common theme that all of them can be influenced by the diet.
University hospital research
(2019)
Heart and vessels form a highly complex organ system in which extremely diverse cells have to work together correctly to provide all organs with blood. In past decades, heart biology placed its focus on whole tissues or cell isolates. Now, however, new technologies allow the tracing of a diversity of cell types and their individual responses to signals down to the level of proteins and genes. Researchers hope this will help them better support the regeneration of diseased hearts.
Objective: Cerebral vasospasm (CVS) after a ruptured arteriovenous malformation (AVM) is rarely reported. This study is aimed at evaluating the predictive variables in AVM hemorrhage for CVS. Methods: A total of 160 patients with ruptured AVMs were admitted to our neurosurgical department from 2002 to 2018. The frequency of cerebral vasospasm after AVM hemorrhage and the impact of AVM-associated aneurysms were evaluated. We compared different bleeding patterns, such as intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) or a combination of both (ICH + SAH) and evaluated predictive variables for outcome in last follow-up. Results: A total of 62 (39%) patients had AAA, mostly located prenidal (75.8%). AVMs with ruptured aneurysms often resulted in ICH with SAH component (p < 0.001). Eighty-two patients (51%) presented a SAH component, and CVS occurred in 6 patients (7.3%), mostly due to a ruptured infratentorial AVM (p < 0.03). Infratentorial location and the amount of SAH component (p < 0.001) predicted the incidence of CVS significantly. Cerebral infarction was significantly associated with CVS (p < 0.02). Conclusion: SAH component and infratentorial location of ruptured AVMs may harbor a higher risk for CVS. Follow-up with angiographic imaging should be considered in patients with infratentorial AVM hemorrhage and delayed neurologic deterioration to rule out CVS.