Abuse of amphetamine-type stimulants is linked to cardiovascular adverse effects like arrhythmias, accelerated atherosclerosis, acute coronary syndromes and sudden cardiac death. Excessive ...catecholamine release following amphetamine use causes vasoconstriction and vasospasms, over time leading to hypertension, endothelial dysfunction or even cardiotoxicity. However, immediate vascular pathomechanisms related to amphetamine exposure, especially endothelial function, remain incompletely understood and were analyzed in this study. Pharmaco-pathological effects of acute d-amphetamine-sulfate (DAM) were investigated ex vivo using contraction-force measurements of rat carotid artery rings and in vitro using label-free, real-time electrochemical impedance spectroscopy (EIS) on endothelial and smooth muscle cells. Specific receptor and target blocking was used to identify molecular targets and to characterize intracellular signaling. DAM induced vasodilation represented by 29.3±2.5% decrease in vascular tone (p<0.001) involving vascular endothelial growth factor receptor (VEGF-R) and protease activated receptor 1 (PAR-1). EIS revealed that DAM induces endothelial barrier disruption (-75.9±1.1% of initial cellular impedance, p<0.001) also involving VEGF-R and PAR-1. Further, in response to DAM, Rho-associated protein kinase (ROCK) mediated reversible contraction of actin cytoskeleton resulting in endothelial barrier disruption. Dephosphorylation of Serine1177 (-50.8±3.7%, p<0.001) and Threonine495 (-44.8±6.5%, p=0.0103) of the endothelial NO synthase (eNOS) were also observed. Blocking of VEGF-R and PAR-1 restored baseline eNOS Threonine495 phosphorylation. DAM induced vasodilation, enhanced vascular permeability and actin cytoskeleton contraction and induced eNOS hypophosphorylation involving VEGF-R, PAR-1 and ROCK. These results may contribute to a better understanding of severe adverse cardiovascular effects in amphetamine abuse.
Endothelial dysfunction and altered nitric oxide (NO) metabolism are considered causal factors in heart failure with preserved ejection fraction (HFpEF). NO synthase activity depends on the ...availability of arginine and its derivatives. Thus, we analyzed arginine, associated metabolites, arginine-metabolizing enzymes and NO turnover in 20-week-old female healthy lean (L-ZSF1) and obese ZSF1 rats (O-ZSF1) with HFpEF. Serum, urine and lysates of liver, kidney and heart were analyzed. There were significantly lower lysine (- 28%), arginine (- 31%), homoarginine (- 72%) and nitrite (- 32%) levels in serum of O-ZSF1 rats. Ornithine (+ 60%) and citrulline (+ 20%) levels were higher. Similar results were found in the heart. Expression of arginine consuming enzymes in liver and kidney was unchanged. Instead, we observed a 5.8-fold higher arginase 1 expression, presumably of granulocyte origin, in serum and > fourfold increased cardiac macrophage invasion in O-ZSF1. We conclude that inflammatory cells in blood and heart consume arginine and probably homoarginine via arginase 1 and inducible NO synthase and release ornithine and citrulline. In combination with evidence for decreased NO turnover in O-ZSF1 rats, we assume lower arginine bioavailability to endothelial NO synthase.
Mechanosensory ion channels are proteins that are sensitive to mechanical forces. They are found in tissues throughout the body and play an important role in bone remodeling by sensing changes in ...mechanical stress and transmitting signals to bone-forming cells. Orthodontic tooth movement (OTM) is a prime example of mechanically induced bone remodeling. However, the cell-specific role of the ion channels Piezo1 and Piezo2 in OTM has not been investigated yet. Here we first identify the expression of PIEZO1/2 in the dentoalveolar hard tissues. Results showed that PIEZO1 was expressed in odontoblasts, osteoblasts, and osteocytes, while PIEZO2 was localized in odontoblasts and cementoblasts. We therefore used a Piezo1
mouse model in combination with Dmp1
to inactivate Piezo1 in mature osteoblasts/cementoblasts, osteocytes/cementocytes, and odontoblasts. Inactivation of Piezo1 in these cells did not affect the overall morphology of the skull but caused significant bone loss in the craniofacial skeleton. Histological analysis revealed a significantly increased number of osteoclasts in Piezo1
;Dmp1
mice, while osteoblasts were not affected. Despite this increased number of osteoclasts, orthodontic tooth movement was not altered in these mice. Our results suggest that despite Piezo1 being crucial for osteoclast function, it may be dispensable for mechanical sensing of bone remodeling.
Heart failure (HF) is the leading cause of death in western countries. Cardiac dysfunction is accompanied by skeletal alterations resulting in muscle weakness and fatigue. Exercise is an accepted ...interventional approach correcting cardiac and skeletal dysfunction, thereby improving mortality, re-hospitalization and quality of life. Animal models are used to characterize underpinning mechanisms. Transverse aortic constriction (TAC) results in cardiac pressure overload and finally HF. Whether exercise training improves cardiac remodeling and peripheral cachexia in the TAC mouse model was not analyzed yet. In this study, 2 weeks post TAC animals were randomized into two groups either performing a moderate exercise program (five times per week at 60% VO.sub.2 max for 40 min for a total of 8 weeks) or staying sedentary. In both TAC groups HF characteristics reduced ejection fraction (- 15% compared to sham, p < 0.001), cardiac remodeling (+ 22.5% cardiomyocyte cross sectional area compared to sham; p < 0.001) and coronary artery congestion (+ 34% diameter compared to sham; p = 0.008) were observed. Unexpectedly, peripheral cachexia was not detected. Furthermore, compared to sedentary group animals from the exercise group showed aggravated HF symptoms heart area + 9% (p = 0.026), heart circumference + 7% (p = 0.002), right ventricular wall thickness - 30% (p = 0.003) while muscle parameters were unchanged Musculus soleus fiber diameter (p = 0.55), Musculus extensor digitorum longus contraction force (p = 0.90). The severe TAC model is inappropriate to study moderate exercise effects in HF with respect to cardiac and skeletal muscle improvements. Further, the phenotype induced by different TAC procedures should be well documented and taken into account when planning experiments.
Mucopolysaccharidosis VI (MPS VI) is a hereditary lysosomal storage disease caused by the absence of the enzyme arylsulfatase B (ARSB). Craniofacial defects are common in MPS VI patients and manifest ...as abnormalities of the facial bones, teeth, and temporomandibular joints. Although enzyme replacement therapy (ERT) is the treatment of choice for MPS VI, the effects on the craniofacial and dental structures are still poorly understood. In this study, we used an Arsb-deficient mouse model (
Arsb
m/m
) that mimics MPS VI to investigate the effects of ERT on dental and craniofacial structures and compared these results with clinical and radiological observations from three MPS VI patients. Using micro-computed tomography, we found that the craniofacial phenotype of the
Arsb
m/m
mice was characterized by bone exostoses at the insertion points of the masseter muscles and an overall increased volume of the jaw bone. An early start of ERT (at 4 weeks of age for 20 weeks) resulted in a moderate improvement of these jaw anomalies, while a late start of ERT (at 12 weeks of age for 12 weeks) showed no effect on the craniofacial skeleton. While teeth typically developed in
Arsb
m/m
mice, we observed a pronounced loss of tooth-bearing alveolar bone. This alveolar bone loss, which has not been described before in MPS VI, was also observed in one of the MPS VI patients. Interestingly, only an early start of ERT led to a complete normalization of the alveolar bone in
Arsb
m/m
mice. The temporomandibular joints in
Arsb
m/m
mice were deformed and had a porous articular surface. Histological analysis revealed a loss of physiological cartilage layering, which was also reflected in an altered proteoglycan content in the cartilage of
Arsb
m/m
mice. These abnormalities could only be partially corrected by an early start of ERT. In conclusion, our results show that an early start of ERT in
Arsb
m/m
mice achieves the best therapeutic effects for tooth, bone, and temporomandibular joint development. As the MPS VI mouse model in this study resembles the clinical findings in MPS VI patients, our results suggest enzyme replacement therapy should be started as early as possible.
The age-related maturation of the human midpalatal suture is challenging to predict, but critical for successful non-surgical rapid maxillary expansion (RME). While cone-beam computed tomography ...(CBCT) can be used to categorize the suture into stages, it remains unclear how well the stages predict the actual micromorphology of the palate. To address this clinically relevant question, we used CBCT together with three-dimensional micro-computed tomography (μCT) analysis on 24 human palate specimens from individuals aged 14-34 years. We first classified the specimens into stages (A-E) using CBCT images and then correlated the results with our comprehensive μCT analysis. Our analysis focused on several factors, including bone volume fraction (BV/TV), sutural width, volume, interdigitation, ossification, and their associations with age, CBCT stage, and sex. Our μCT analysis revealed a decrease in sutural width and volume after the age of 20 years, accompanied by sutural closure beginning in the palatal segment. The overall rate of ossification remained low but increased after the age of 20 years. No significant differences were found between males and females. Importantly, we also found no correlation between individual age and CBCT stages. Furthermore, there was no association between CBCT stages and patalal suture volume, ossification and interdigitation. Taken together, our findings cast doubt on the reliability of CBCT stage as a means of predicting skeletal maturity of the palatal suture, as it appears to lack the precision required to accurately assess the true micromorphology of the palatal suture. Future investigations should explore whether alternative CBCT parameters may be more useful in addressing the challenging question of whether RME requires surgical bone weakening.
Objectives
In acute stroke patients with large vessel occlusion, collateral blood flow affects tissue fate and patient outcome. The visibility of collaterals on computed tomography angiography (CTA) ...strongly depends on the acquisition phase, but the optimal time point for collateral imaging is unknown.
Methods
We analysed collaterals in a time-resolved fashion using four-dimensional (4D) CTA in 82 endovascularly treated stroke patients, aiming to determine which acquisition phase best depicts collaterals and predicts outcome. Early, peak and late phases as well as temporally fused maximum intensity projections (tMIP) were graded using a semiquantitative regional leptomeningeal collateral score, compared with conventional single-phase CTA and correlated with functional outcome.
Results
The total extent of collateral flow was best visualised on tMIP. Collateral scores were significantly lower on early and peak phase as well as on single-phase CTA. Collateral grade was associated with favourable functional outcome and the strength of this relationship increased from earlier to later phases, with collaterals on tMIP showing the strongest correlation with outcome.
Conclusions
Temporally fused tMIP images provide the best depiction of collateral flow. Our findings suggest that the total extent of collateral flow, rather than the velocity of collateral filling, best predicts clinical outcome.
Key Points
• Collateral flow visibility on CTA strongly depends on the acquisition phase
• tMIP offers the best visualisation of the extent of collaterals
• Outcome prediction may be better with tMIP than with earlier phases
• Total extent of collaterals seems more important than their filling speed
• If triggered too early, CTA may underestimate collateral flow
Candidemia epidemiology varies significantly by region; thus, local data are essential for evidence-based decision-making in prophylaxis and treatment. Current management strategies are derived from ...large randomized controlled trials mostly executed in large high-volume tertiary care centers. Results may not be entirely transferable to smaller hospitals. This study investigates epidemiology, diagnosis, and treatment standards in six hospitals in the Cologne metropolitan area (number of inhabitants approx. one million). We assessed adherence to the current guideline of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the Infectious Diseases Society of America (IDSA) using the EQUAL Candida Score of the European Confederation of Medical Mycology (ECMM). Data were documented by trained medical students as part of an integrated research and teaching concept at the University of Cologne. Between January 2014 and June 2017, 77 patients had candidemia, corresponding to an incidence of 0.2 cases/1000 admissions. While 55 patients were enrolled, 22 patients were excluded due to incompletely retrievable health records. Fluconazole monotherapy was the preferred first-line treatment in cases with
Candida albicans
infection (21/29). A central vascular catheter was present in 40 patients and was removed in 17 (43%) during treatment. Overall mortality at 30 days was 44%. Patients reached a mean EQUAL Candida Score of 9.9 (range 8–14), which was well below the maximum score of 22 for perfect guideline adherence. In summary, management of candidemia differed from current European recommendations. It remains unclear to what extent enhanced adherence would improve patient outcome. Larger prospective studies need to answer that question.
Purpose: There is a need to identify lung cancer prevention mechanisms. All- trans -retinoic acid (RA) was reported previously to inhibit N -nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone ...(NNK) carcinogenic transformation of BEAS-2B human bronchial epithelial
cells (J. Langenfeld et al ., Oncogene, 13: 1983–1990, 1996). This study was undertaken to identify pathways targeted during this chemoprevention.
Experimental Design: Because epidermal growth factor receptor (EGFR) overexpression is frequent in non-small cell lung cancers (NSCLC) and bronchial
preneoplasia, BEAS-2B cells, carcinogen-transformed BEAS-2B NNK cells, and retinoid chemoprevented BEAS-2B NNK RA cells were each examined for EGFR expression. Whether RA treatment regulated directly EGFR expression or reporter plasmid
activity was studied. RA effects on epidermal growth factor (EGF) induction of EGFR-phosphotyrosine levels, cyclin D1 expression
and mitogenesis were examined in BEAS-2B cells.
Results: Findings reveal that NNK-mediated transformation of BEAS-2B cells increased EGFR expression. RA treatment repressed EGFR
expression and reporter plasmid activity in these cells. This treatment reduced EGF-dependent mitogenesis as well as EGFR-associated
phosphotyrosine levels and cyclin D1 expression. These findings extend prior work by highlighting EGFR as a chemoprevention
target in the lung. Notably, RA treatment prevented transformation as well as outgrowth of EGFR overexpressing bronchial epithelial
cells, despite NNK exposure. After acute NNK exposure, p53-induced species that appear after DNA damage or oxidative stress
were evident before an observed increase in EGFR expression.
Conclusions: These findings indicate how effective chemoprevention prevents carcinogenic transformation of bronchial epithelial cells
when repair of genomic damage does not select against EGFR overexpressing cells. This implicates EGFR as a chemoprevention
target in the carcinogen-exposed bronchial epithelium.
This open access book presents the exciting research results of the BMBF funded project iCity carried out at University of Applied Science Stuttgart to help cities to become more liveable, ...intelligent and sustainable, to become a LIScity. The research has been pursued with industry partners and NGOs from 2017 to 2020. A LIScity is increasingly digitally networked, uses resources efficiently, and implements intelligent mobility concepts. It guarantees the supply of its grid-bound infrastructure with a high proportion of renewable energy. Intelligent cities are increasingly human-centered, integrative, and flexible, thus placing the well-being of the citizens at the center of developments to increase the quality of life. The articles in this book cover research aimed to meet these criteria. The book covers research in the fields of energy (i.e. algorithms for heating and energy storage systems, simulation programs for thermal local heating supply, runtime optimization of combined heat and power (CHP), natural ventilation), mobility (i.e. charging distribution and deep learning, innovative emission-friendly mobility, routing apps, zero-emission urban logistics, augmented reality, artificial intelligence for individual route planning, mobility behavior), information platforms (i.e. 3DCity models in city planning: sunny places visualization, augmented reality for windy cities, internet of things (IoT) monitoring to visualize device performance, storing and visualizing dynamic energy data of smart cities), and buildings and city planning (i.e. sound insulation of sustainable facades and balconies, multi-camera mobile systems for inspection of tunnels, building-integrated photovoltaics (BIPV) as active façade elements, common space, the building envelopes potential in smart sustainable cities).
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