FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.

The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Protocol of a first-in-human clinical trial to evaluate the safety, tolerability, and preliminary efficacy of the bispecific CD276xCD3 antibody CC-3 in patients with colorectal cancer (CoRe_CC-3).

Introduction: Colorectal cancer (CRC) is the third most common cancer worldwide in men and women. In the metastasized stage, treatment options and prognosis are limited. To address the high medical need of this patient population, we generated a CD276xCD3 bispecific antibody termed CC-3. CD276 is expressed on CRC cells and on tumor vessels, thereby allowing for a "dual" anticancer effect. Methods and analysis: This first-in-human clinical study is planned as a prospective multicenter trial, enrolling patients with metastatic CRC after three lines of therapy. During the dose-escalation part, initially, an accelerated titration design with single-patient cohorts is employed. Here, each patient will receive a fixed dose level (starting with 50 µg for the first patient); however, between patients, dose level may be increased by up to 100%, depending on the decision of a safety review committee. Upon occurrence of any adverse events (AEs) grade ≥2, dose-limiting toxicity (DLT), or reaching a dose level of ≥800 µg, the escalation will switch to a standard 3 + 3 dose design. After maximum tolerated dose (MTD) has been determined, defined as no more than one of the six patients experiencing DLT, an additional 14 patients receive CC-3 at the MTD level in the dose-expansion phase. Primary endpoints are incidence and severity of AEs, as well as the best objective response to the treatment according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints include overall safety, efficacy, survival, quality of life, and pharmacokinetic investigations. Ethics and dissemination: The CD276xCD3 study was approved by the Ethics Committee of the Medical Faculty of the Heinrich Heine University Düsseldorf and the Paul-Ehrlich-Institut (P00702). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: ClinicalTrials.cov Registry (NCT05999396) and EU ClinicalTrials Registry (EU trial number 2022-503084-15-00).

Commissural misalignment independently predicts leaflet thrombosis after transcatheter aortic valve implantation.

AIMS: Transcatheter aortic valve implantation (TAVI) has become a minimally invasive alternative to surgical aortic valve replacement. Hypo-attenuated leaflet thickening (HALT)-a marker of subclinical leaflet thrombosis commonly detected by cardiac computed tomography (CT) after TAVI-may influence valve durability and function. The purpose of this study was to compare commissural alignment of the native and prosthetic aortic valves in cardiac CT in subjects with and without HALT and thereby identify commissural misalignment as potential predictor for leaflet thrombosis after TAVI. METHODS AND RESULTS: In 170 subjects, 85 with and 85 without HALT in post-TAVI CT, commissural orientation of the prosthesis was determined comparing native and prosthetic aortic valve orientation in cardiac CT by measuring the commissural angle relative to the right coronary ostium in the aortic valve plane. For the prosthetic valve, any deviation ≤ 15° compared to the native valve was classified as "aligned"; 16-30° as "mild", 31-45° as "moderate" and ≥ 45° as "severe" misalignment. Among subjects with HALT, median angular deviation was higher (36°, IQR 31°) than in the control group (29°, IQR 29°, p = 0.042). "Severe" misalignment was more frequent in subjects who developed HALT (n = 31, 37%) compared to the control group (n = 17, 20%, p = 0.013). In logistic regression analysis, more severe deviation (p = 0.015, OR = 1.02 per 1° deviation) and "severe" misalignment (p = 0.018, OR = 2.2) represented independent predictors for the occurrence of HALT after TAVI. CONCLUSION: Subclinical leaflet thrombosis after TAVI is associated with commissural misalignment. Potential clinical advantages of obtaining commissural alignment remain to be systematically assessed.

Analysis of Genes Related to Invadopodia Formation and CTTN in Oral Squamous Cell Carcinoma-A Systematic Gene Expression Analysis.

Successful treatment for any type of carcinoma largely depends on understanding the patterns of invasion and migration. For oral squamous cell carcinoma (OSCC), these processes are not entirely understood as of now. Invadopodia and podosomes, called invadosomes, play an important role in cancer cell invasion and migration. Previous research has established that cortactin (CTTN) is a major inducer of invadosome formation. However, less is known about the expression patterns of CTTN and other genes related to it or invadopodia formation in OSCC during tumor progression in particular. In this study, gene expression patterns of CTTN and various genes (n = 36) associated with invadopodia formation were analyzed to reveal relevant expression patterns and give a comprehensive overview of them. The genes were analyzed from a whole genome dataset of 83 OSCC samples relating to tumor size, grading, lymph node status, and UICC (Union for Internatioanl Cancer Control). The data revealed significant overexpression of 18 genes, most notably CTTN, SRC (SRC proto-onocogene, non-receptor tyrosine kinase), EGFR (epidermal growth factor receptor), SYK (spleen associated tyrosine kinase), WASL (WASP like actin nucleation promotion factor), and ARPC2 (arrestin beta 1) due to their significant correlation with further tumor parameters. This study is one of the first to summarize the expression patterns of CTTN and related genes in a complex group of OSCC samples.

The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial.

INTRODUCTION: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardiovascular protective properties in addition to the metabolic effects and represent a cornerstone of treating patients with chronic heart failure (CHF). We hypothesised that empagliflozin reduces tissue sodium content in patients with CHF. METHODS: In a double-blind, randomised (2:1), placebo-controlled, parallel-group, clinical trial, 74 patients with NYHA class II-III CHF and an ejection fraction of 49% or less received empagliflozin 10 mg once daily or placebo for 3 months. In each patient, tissue sodium content of the lower leg was assessed non-invasively by sodium-MRI (23Na-MRI) at baseline, after 1 and 3 months of treatment. RESULTS: After 1 and 3 months treatment with empagliflozin (n = 48), a significant decrease in skin sodium content was observed (1 month: 22.8 ± 6.1 vs. 21.6 ± 6.0 AU, p = 0.039; 3 months: 22.9 ± 6.1 vs. 21.6 ± 6.1 AU, p = 0.013), while there was no change in muscle sodium and muscle water content. In direct comparison, the change in skin sodium content between baseline and 3 months was - 1.3 ± 3.5 AU in the empagliflozin group versus 0.6 ± 3.5 AU in the placebo group (p for between-group difference = 0.022). No significant difference regarding change in muscle sodium and in muscle water content was observed after 3 months treatment between the two groups. CONCLUSION: This trial showed a significant decrease in skin sodium content after 1 and 3 months of treatment with empagliflozin. The decrease in skin sodium content may reflect a decrease in subclinical micro-oedema or/and in non-osmotic bound tissue sodium, both reported to impair left ventricular function. TRIAL REGISTRATION NUMBER: NCT03128528 ( http://www. CLINICALTRIALS: gov ). TRIAL REGISTRATION DATE: 25th April 2017.

Influence of marginal incision and Le Fort I osteotomy on periodontal tissues: a prospective longitudinal study.

The purpose of this prospective study was to evaluate whether the surgical protocol involving marginal incision and Le Fort I osteotomy affects the periodontal outcome. Twenty-nine patients requiring surgical correction of maxillary dysgnathia were selected for this study. Periodontal conditions of maxillary anterior teeth were assessed prior to the surgery (T0), one month (T1), and 6 months (T2) after the surgical procedure. Interdental papillae loss, periodontal parameters and aesthetic outcomes in the anterior zone were assessed. Statistical analysis was performed with Friedman´s test and within ANOVA (p ≤ 0.05) followed by post-hoc tests. Papilla height decreased from T0 to T1 (p = 0.003), followed by an increase from T1 to T2 (p = 0.040). PPD (T0 = 1.72 ± 0.46; T2 = 2.13 ± 0.43) and CAL (T0 = 1.24 ± 0.55; T2 = 1.99 ± 0.70) increased after 6 months. There were statistically significant differences in aesthetic score among T0, T1 and T2. Periodontal changes after orthognathic surgery were within acceptable biological levels. Although a change in papillae height was reported after the surgery, initial values were recovered after 6 months. Surgical incision design might improve the outcome of Le-Fort I osteotomy. Anterior aesthetic zone may benefit from a marginal incision design, as it respects vascularization principle and may ensure a wound healing without complications.

Epithelioid Rhabdomyosarcoma at the High Parietal Area of the Head: A Case Report.

Epithelioid rhabdomyosarcoma is a rare condition, which may be clinically misinterpreted as melanoma due to its morphological appearance. Careful morphological and immunohistochemical analysis play an important role in its diagnosis. This case report describes the clinicopathological features of an epithelioid RMS diagnosed at the high parietal area of the head. A 71-year-old male patient presented a red-brown pigmented ulcerative nodule in the high parietal region of the head. Previous biopsy and computer tomography imaging revealed a malignant melanoma in stage I (pT2, sN0, Mx). After tumor operation, histological and immunohistochemical analysis of the tumor were conducted. Histological analysis showed an erosive lesion with a monomorphic cell population containing small cells with prominent nucleoli. A positivity was confirmed for CD10, Vimentin, and Desmin. MyoD1 was detected, as well as a fluctuating signal for p53. Molecular analysis revealed a negativity for Sox-10, and a weak positivity for CK8/18 by absence of p40. Based on the morphological and immunohistochemical findings, the tumor was diagnosed as epithelioid RMS.

Pleiotropic effects on proliferation and mineralization of primary human adipose tissue-derived stromal cells induced by simvastatin.

The circulating low-density lipoprotein concentration in blood can be reduced by the administration of statins. Frequently simvastatin (SV) is prescribed. Due to the reported pleiotropic effects of SV the aim of this study was to evaluate mineralization effects on human adipose tissue-derived stromal cells upon administration of SV. After informed consent human adipose tissue-derived stromal cells were obtained from tissue surplus of regular treatments of 14 individuals. According to established protocols after adding various SV concentrations (0.01 µM, 0.1 µM, 1.0 µM, 2.0 µM), alkaline phosphate (osteoblastic marker), mineralization capability and viability were determined at day 18, 21 and 28. The Kruskal-Wallis test was performed for statistical analysis. After adding SV a dose-dependent significant decreased viability and levels of alkaline phosphatase (p < 0.01) and a significantly increased mineralization (p < 0.01) of the primary cultures was recognized during the late mineralization stage. Mineralization of the human adipose tissue-derived stromal cells was induced by SV, possibly originated from alternative pathways than the alkaline phosphatase pathway. Further investigations should be performed regarding switching into the osteoblastic differentiation and as a possible source of cells that can be used as the basis for a potential bone graft substitute, which may allow an extension of the field of application.

In Vivo Accuracy of a New Digital Planning System in Terms of Jaw Relation, Extent of Surgical Movements and the Hierarchy of Stability in Orthognathic Surgery.

This retrospective cohort study compares the virtual planned and postoperative jaw positions in patients undergoing orthognathic surgery. Surgery was virtually planned with the Digital Münster Model Surgery system (DMMS). Primary outcome: Spatial difference in the maxillo-mandibulo relation between virtual planning and postoperative result. Secondary outcome: Possible relationship between the measured differences and surgical movements as well as the postoperative stability according to Proffit. Ninety female and sixty-one male patients were included in the study. The average translation errors were 0.54 ± 0.50 mm (anteroposterior), 0.37 ± 0.33 mm (mediolateral), and 0.33 ± 0.28 mm (superoinferior). Orientation errors were 0.86 ± 0.79 degrees (yaw), 0.54 ± 0.48 degrees (roll), and 0.90 ± 0.72 degrees (pitch). The surgical procedures do not differ with respect to their error sizes. Maxilla forward and class II maxilla up with mandible forward are the most precise procedures. Most significant differences were found in the anteroposterior direction, whereby the extent of the surgical movement has no effect on the magnitude of the error. The process of planning with the DMMS followed by surgery is highly accurate and shows error values well below the clinically accepted limit of two millimeters in translation and four degrees in rotation.

Effect of Cold Atmospheric Plasma (CAP) on Osteogenic Differentiation Potential of Human Osteoblasts.

Bone regeneration after oral and maxillofacial surgery is a long-term process, which involves various mechanisms. Recently, cold atmospheric plasma (CAP) has become known to accelerate wound healing and have an antimicrobial effect. Since the use of CAP in dentistry is not yet established, the aim of the present study was to investigate the effect of CAP on human calvaria osteoblasts (HCO). HCO were treated with CAP for different durations of time and distances to the cells. Cell proliferation was determined by MTT assay and cell toxicity by LDH assay. Additionally, RT-qPCR was used to investigate effects on osteogenic markers, such as alkaline phosphatase (ALP), bone morphogenic protein (BMP)2, collagen (COL)1A1, osteonectin (SPARC), osteoprotegerin (OPG), osterix (OSX), receptor activator of NF-κB (RANK), RANK Ligand (RANKL), and Runt-related transcription factor (RUNX)2. There were small differences in cell proliferation and LDH release regarding treatment duration and distance to the cells. However, an increase in the expression of RANK and RANKL was observed at longer treatment times. Additionally, CAP caused a significant increase in mRNA expression of genes relevant to osteogenesis. In conclusion, CAP has a stimulating effect on osteoblasts and may thus represent a potential therapeutic approach in the regeneration of hard tissue defects.

The influence of aircraft noise exposure on the systemic and renal haemodynamics.

AIMS: Epidemiological studies found a link between aircraft noise exposure and increased incidence of arterial hypertension and cardiovascular disease, but the underlying pathophysiological mechanisms are not fully understood. Clinical studies have shown that mental stress affects the systemic and renal haemodynamic, but no such study was performed with noise exposure as stress factor. We analysed systemic and renal effects of 25 min standardized aircraft noise in a sham controlled clinical study including 80 healthy men and 34 male patients with hypertension. METHODS AND RESULTS: Systemic haemodynamic parameters were measured using electrocardiography and impedance cardiography. The renal haemodynamic was assessed using steady state input clearance with infusion of para-aminohippuric acid and inulin for glomerular filtration rate and renal plasma flow, respectively. In the systemic circulation of hypertensive patients, there was an increase in total peripheral resistance (TPR) (1420 ± 387 vs. 1640 ± 516 dyn·s·cm-5, P = 0.001) and a decrease in cardiac index (CI) (2.9 ± 0.8 vs. 2.6 ± 0.8 L/(min·m2, P < 0.001) 25 min after the start of noise exposure, which was not present during sham procedure (P = 0.10, P = 0.86). In healthy individuals a procedure induced increase in TPR and decrease in CI was present after noise (TPR: 995 ± 239 vs. 1106 ± 308 dyn·s·cm-5, P = 0.001, CI: 3.6 ± 0.7 vs. 3.3 ± 0.9 L/(min·m2, P < 0.001) and sham application (TPR: P = 0.002, CI: P < 0.001). However, in healthy individuals changes in TPR (P = 0.450) and CI (P = 0.605) from baseline until 25 min after the start of the intervention did not differ between noise and sham exposure. In the renal circulation of hypertensive patients and healthy individuals the response did not differ between noise and sham procedure. CONCLUSIONS: In hypertensive but not healthy men we observed a systemic vasoconstrictive response after aircraft noise exposure accompanied by a decrease in CI. No significant changes were observed in the renal circulation. Our results suggest that male hypertensive patients are more susceptible for noise-induced changes of vascular resistance in the systemic circulation.

Tissue sodium content correlates with hypertrophic vascular remodeling in type 2 diabetes.

BACKGROUND: Prospective studies describe a linkage between increased sodium intake and higher incidence of cardiovascular organ damage and end points. We analyzed whether tissue sodium content in the skin and muscles correlate with vascular hypertrophic remodeling, a risk factor for cardiovascular disease. METHODS: In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles. The structural parameters of retinal arterioles assessed by Scanning Laser Doppler Flowmetry were vessel (VD) and lumen diameter (LD), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was measured with a 3.0 T clinical 23Sodium-Magnetic Resonance Imaging (23Na-MRI) system. RESULTS: In patients with type 2 diabetes (N = 52) we observed a significant correlation between muscle sodium content and VD (p = 0.005), WT (p = 0.003), WCSA (p = 0.002) and WLR (p = 0.013). With respect to skin sodium content a significant correlation has been found with VD (p = 0.042), WT (p = 0.023) and WCSA (p = 0.019). Further analysis demonstrated that tissue sodium content of skin and muscle is a significant determinant of hypertrophic vascular remodeling independent of age, gender, diuretic use and 24-hour ambulatory BP. CONCLUSION: With the 23Na-MRI technology we could demonstrate that high tissue sodium content is independently linked to hypertrophic vascular remodeling in type 2 diabetes. TRIAL REGISTRATION: Trial registration number: NCT02383238 Date of registration: March 9, 2015.

Fatal late-onset CAR T-cell-mediated encephalitis after axicabtagene-ciloleucel in a patient with large B-cell lymphoma.

Treatment with CD19-directed (CAR) T cells has evolved as a standard of care for multiply relapsed or refractory large B-cell lymphoma (r/r LBCL). A common side effect of this treatment is the immune effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can occur in up to 30% to 40% of patients treated with axicabtagene-ciloleucel (axi-cel), usually within the first 4 weeks after administration of the dose and usually responding well to steroids. We describe a case of progressive central neurotoxicity occurring 9 months after axi-cel infusion in a patient with r/r LBCL who had undergone a prior allogeneic hematopoietic cell transplant. Despite extensive systemic and intrathecal immunosuppression, neurological deterioration was inexorable and eventually fatal within 5 months. High CAR T-cell DNA copy numbers and elevated levels of interleukin-1 (IL-1) and IL-6 were found in the cerebral spinal fluid as clinical symptoms emerged, and CAR T-cell brain infiltration was observed on autopsy, suggesting that CAR T cells played a major pathogenetic role. This case of unexpected, devastating, late neurotoxicity warrants intensified investigation of neurological off-target effects of CD19-directed CAR T cells and highlights the need for continuous monitoring for late toxicities in this vulnerable patient population.

Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine.

BACKGROUND: Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. METHODS: Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. RESULTS: Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups. CONCLUSIONS: In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016.

Effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function in patients with chronic heart failure.

AIMS: Impairment of vascular function contributes to the progression of chronic heart failure (HF) by increasing the afterload. Treatment with selective sodium-glucose cotransporter 2 (SGLT2) inhibitors improves the prognosis of HF, but the precise mechanisms remain unclear. The aim of this study was to analyse the effect of empagliflozin on vascular function in patients with HF. METHODS AND RESULTS: In an investigator initiated, double-blind, randomized, placebo-controlled, parallel-group, clinical study, patients with HF NYHA II-III and an ejection fraction of 49% or less were randomized 2:1 to receive empagliflozin 10 mg once daily or placebo for 3 months. A total of 74 patients (15% female), aged 66 ± 9 years, with a mean ejection fraction of 39 ± 8% and a median NTproBNP of 558 pg/mL (IQR 219-1051 pg/mL), were included. Vascular parameters such as central systolic blood pressure (cSBP), central pulse pressure (cPP), forward (FPH), and reflected pressure pulse height (RPH) decreased under resting conditions after 1 and 3 months (1 month: cSBP -6.4 ± 8.3 mmHg, P < 0.001, cPP -3.0 ± 6.6 mmHg, P = 0.004, FPH -2.5 ± 4.5 mmHg, P = 0.001, RPH -1.6 ± 3.0 mmHg, P = 0.001; 3 months: cSBP -4.6 ± 8.4 mmHg, P = 0.001, cPP -3.1 ± 4.8 mmHg, P < 0.001, FPH -1.7 ± 3.7 mmHg, P = 0.004, RPH -1.4 ± 2.5 mmHg, P = 0.001) in patients treated with empagliflozin (n = 45). In accordance, cSBP and cPP decreased in patients with empagliflozin treatment under 24 h ambulatory conditions after 1 and 3 months (1 month: cSBP -4.8 ± 10.1 mmHg, P = 0.003, cPP -2.0 ± 5.7 mmHg, P = 0.026; 3 months: cSBP -4.7 ± 9.0 mmHg, P = 0.002, cPP -2.1 ± 6.4 mmHg, P = 0.044). In the placebo group, there was no significant change after 1 and 3 months. The decrease in cSBP under resting conditions (-5.7 ± 2.4 mmHg, P = 0.019) after 1 month and in cSBP (-6.0 ± 2.6, P = 0.027) as well as in pulse wave velocity (-0.5 ± 0.2 m/s, P = 0.021) under 24 h ambulatory conditions after 3 months was greater in the empagliflozin group than in the placebo group. CONCLUSIONS: We found an improvement of vascular function after treatment with empagliflozin that indicates decreased afterload of the left ventricle and may contribute to the beneficial effects of SGLT2 inhibition in HF.

Biocompatibility of Lithium Disilicate and Zirconium Oxide Ceramics with Different Surface Topographies for Dental Implant Abutments.

Gingivafibroblasts were cultured on lithium disilicate, on zirconia dioxide, and on titanium with two different surface roughnesses (0.2 µm and 0.07 µm); Proliferation (MTT), Living/Dead staining, cytotoxicity (LDH), proliferation (FGF2), and inflammation (TNFα) were analyzed after 1 day and 21 days. Furthermore, alteration in cell morphology (SEM) was analyzed. The statistical analysis was performed by a Kruskal-Wallis test. The level of significance was set at p < 0.05. There were no distinct differences in cellular behavior between the tested roughness. There were slight differences between tested materials. Cells grown on zirconia dioxide showed higher cytotoxic effects. Cells grown on lithium disilicate showed less expression of TNFα compared to those grown on zirconia dioxide or titanium. These effects persisted only during the first time span. The results indicate that the two tested high-strength ceramics and surface properties are biologically suitable for transmucosal implant components. The findings may help clinicians to choose the most appropriate biomaterial as well as the most appropriate surface treatment to use in accordance with specific clinical dental applications.

Clinical characteristics of oral lichen planus and its causal context with dental restorative materials and oral health-related quality of life.

BACKGROUND: The aim of this study was to investigate the influence of clinical characteristics and dental restorative materials on oral health-related quality of life in patients with oral lichen planus. In particular, the influences of amalgam and metals were investigated. METHODS: A total of 112 patients with clinical and histological features of oral lichen planus from the Department of Cranio-Maxillofacial Surgery at the University Hospital of Münster participated in this prospective study. Clinical parameters of oral lichen planus and the dental restorative materials used were evaluated. Oral health-related quality of life was investigated by using the short form of the German version of the Oral Health Impact Profile (OHIP-14). In addition, physical pain was rated on a visual analogue scale. RESULTS: The average OHIP-14 score was 13.54. A high correlation was seen between OHIP and pain. Likewise, higher OHIP-values were seen for male patients, and such as for those patients with non-reticular forms of oral lichen planus (OLP). A local form of OLP is more often seen on female patients, such as with the presence of reticular lichen. In regard to the restorations, the presence of composite restorations is correlated with a local lichen, whereas the presence of gold restorations is often seen with a generalized lichen. Furthermore, the grading of strength of association between mucosal lesion and amalgam/metal was tested. No significant differences revealed the analysis of the relationship between gender, clinical form of OLP, age, and presentation form between the 4 gradings of Thornhill. CONCLUSIONS: The oral health-related quality of life is significantly limited in patients with oral lichen planus. But these OHIP scores are not influenced by the restorative materials. Here, pain severity is the most important aspect. We found no statistical differences in the clinical parameters between patients with amalgam or metal restoration and patients without these restorations. It is not necessary to replace amalgam fillings that are not in direct contact with mucosal surfaces.

Association of Noise Annoyance with Measured Renal Hemodynamic Changes.

BACKGROUND: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. METHODS: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. RESULTS: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 ± 106 vs. 663 ± 124 mL/min, p = 0.009), lower renal blood flow (1,068 ± 203 vs. 1,172 ± 225 mL/min, p = 0.047), higher filtration fraction (22.7 ± 3.3 vs. 21.3 ± 3.0, p = 0.012), higher renal vascular resistance (88.9 ± 25.6 vs. 75.8 ± 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 ± 1,253.4 vs. 1,849.9 ± 1,242.0 dyn s-1 cm-5, p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 ± 11.8 vs. 138 ± 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 ± 472.2 vs. 2,245.8 ± 370.3 dyn s-1 cm-5, p = 0.060), and intraglomerular pressure (64.0 ± 3.1 vs. 64.6 ± 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. CONCLUSION: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated.

Hypertrophic remodelling of retinal arterioles in patients with congestive heart failure.

AIMS: Analysis of microvascular parameters in the retinal circulation-known to reflect those in the systemic circulation-allows us to differentiate between eutrophic and hypertrophic remodelling of small arteries. This study aimed to examine microvascular changes in patients with congestive heart failure (CHF) and reduced as well as mid-range ejection fraction. METHODS AND RESULTS: Forty subjects with CHF underwent measurement of retinal capillary flow (RCF), wall-to-lumen ratio (WLR), vessel and lumen diameter, wall thickness, and wall cross-sectional area (WCSA) of retinal arterioles of the right eye by scanning laser Doppler flowmetry (SLDF). Applying a matched pair approach, we compared this group with reference values of age-matched controls from a random sample in the population of Pilsen, Czech Republic. There was no significant difference in RCF and WLR between the groups (RCF: P = 0.513; WLR: P = 0.106). In contrast, wall thickness and WCSA, indicators of hypertrophic remodelling, were higher in CHF subjects (WT: 15.0 ± 4.2 vs. 12.7 ± 4.2 µm, P = 0.021; WCSA: 4437.6 ± 1314.5 vs. 3615.9 ± 1567.8 µm2 , P = 0.014). Similarly, vessel (109.4 ± 11.1 vs. 100.5 ± 14.4 µm, P = 0.002) and lumen diameter (79.0 ± 7.9 vs. 75.2 ± 8.5 µm, P = 0.009) were increased in CHF. CONCLUSIONS: In CHF subjects, we observed hypertrophic remodelling of retinal arterioles indicative of similar changes of small resistance arteries in the systemic circulation. Microvascular structure and function assessed by SLDF may thereby represent a useful, non-invasive method for monitoring of microvascular damage in patients with CHF and may offer innovative treatment targets for new CHF therapies.

Detection of Changes in Renal Blood Flow Using Arterial Spin Labeling MRI.

BACKGROUND: Alteration in kidney perfusion is an early marker of renal damage. The purpose of this study was to evaluate if changes in renal blood flow (RBF) could be detected using MRI with arterial spin labeling (ASL) technique. METHODS: RBF as assessed by cortical (CRBF), medullary, and total renal blood flow (TRBF) were measured by MRI with arterial spin labeling (ASL-MRI) using flow-sensitive alternating inversion recovery true fast imaging with steady-state precession sequence. In 11 normotensive healthy individuals (NT) and 11 hypertensive patients (HT), RBF was measured at baseline and after both feet were covered with cold ice packs (cold pressor test) that activates the sympathetic nervous system. In another experiment, RBF was measured in 10 patients with CKD before and after a pharmacological intervention. We compared RBF measurements between the 3 study populations. RESULTS: A significant reduction in CRBF (p = 0.042) and a trend in TRBF (p = 0.053) were observed in response to the activation of the sympathetic nervous system. A trend toward reduction of CRBF (p = 0.051) and TRBF (p = 0.059) has been detected after pharmacological intervention. TRBF was significantly lower in patients with HT and CKD patients compared to NT individuals (NT vs. HT, p = 0.014; NT vs. CKD, p = 0.004). TRBF was lower in patients with CKD compared to HT (p = 0.047). CONCLUSION: Our data indicate that both acute and short-term changes in RBF could be detected using ASL-MRI. We were able to detect differences in RBF between healthy and diseased individuals by needing only small sample size per group. Thus, ASL-MRI offers an advantage in conducting clinical trials compared to other technologies.