EPAC1 inhibition protects the heart from doxorubicin-induced toxicity.

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the exchange protein directly activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administered in vivo, Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 knock-out (KO) mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.

Preoperative visualization of the lingual nerve by 3D double-echo steady-state MRI in surgical third molar extraction treatment.

OBJECTIVES: To assess the lingual nerve (LN) visualization using a 3D double-echo steady-state MRI sequence (3D-DESS). MATERIALS AND METHODS: Three readers prospectively evaluated the LN for its continuous visibility in 3D-DESS MRI in 19 patients with an indication for removal of mandibular impacted third molars, using a 5-point scale (4 = excellent to 0 = none). Six LN anatomical intermediate points (IP) were selected and checked for their detectability by a 4-point scale (4 = yes to1 = no). Inter- and intra-rater agreement was evaluated using intraclass correlation coefficient and percentage of agreement. RESULTS: The average nerve continuity score was 3.3 ± 0.46. In 35% of the cases, the entire course was continuously visible. In 10%, the proximal and 60%, the distal part of the nerve was not continuously visible. Inter- and intra-reader agreement was good (ICC = 0.76, ICC = 0.75). The average detectability score of all IP was 3.7 ± 0.41. From IP1 to IP5, the detectability was excellent; meanwhile, IP6 had lower visibility. The inter- and intra-reader percentage of agreement was 77% and 87%. CONCLUSIONS: The 3D-DESS sequence allowed accurate and continuous visualization of the LN with high reproducibility in more than one-third of the patients. This could improve the preoperative clarification of the LN position and thereby reduce complications during dentoalveolar surgical interventions. CLINICAL RELEVANCE: 3D-DESS MRI might be beneficial in clinical scenarios where the second molar is elongated or presents a difficult rotational position while simultaneously having a close positional relationship to the third molar. Thereby, osteotomy performed more lingually, indicating extended lingual flap detachment may increase the risk of LN damage.

Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension.

INTRODUCTION: A reduction in pulmonary artery relaxation is a key event in the pathogenesis of pulmonary arterial hypertension (PAH). Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in airway epithelial cells plays a central role in cystic fibrosis; CFTR is also expressed in pulmonary arteries and has been shown to control endothelium-independent relaxation. AIM AND OBJECTIVES: We aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models. METHODS AND RESULTS: Reverse-transcriptase quantitative PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in pulmonary arteries from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myography on human, pig and rat pulmonary arteries, we demonstrated that CFTR activation induces pulmonary artery relaxation. CFTR-mediated pulmonary artery relaxation was reduced in pulmonary arteries from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularisation. Pathologic assessment of lungs from patients with severe cystic fibrosis (F508del-CFTR) revealed severe pulmonary artery remodelling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularisation. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats. CONCLUSIONS: CFTR expression is strongly decreased in pulmonary artery smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces pulmonary artery relaxation.

Accuracy of guided biopsy of the jawbone in a clinical setting: A retrospective analysis.

The aim of this study was to investigate the accuracy of a previously described technique for guided biopsy of osseous pathologies of the jawbone in a clinical setting. The data sets of patients who had undergone guided biopsy procedures were retrospectively examined for accuracy. Digital planning of the biopsies and manufacturing of the tooth-supported drilling template were performed with superimposed cone beam computed tomography and intraoral scans using implant planning software. After a trephine biopsy was taken using the template, the postoperative low-dose cone beam computed tomography was analyzed for accuracy using the planning software with the corresponding (digitally-planned) biopsy cylinder. The mean angular deviation was 4.35 ± 2.5°. The mean depth deviation was -1.40 ± 1.41 mm. Guided biopsy seems to be an alternative to a conventional approach for minimally invasive and highly accurate jawbone biopsy.

Cell seeding accelerates the vascularization of tissue engineering constructs in hypertensive mice.

Rapid blood vessel ingrowth into transplanted constructs represents the key requirement for successful tissue engineering. Seeding three-dimensional scaffolds with suitable cells is an approved technique for this challenge. Since a plethora of patients suffer from widespread diseases that limit the capacity of neoangiogenesis (e.g., hypertension), we investigated the incorporation of cell-seeded poly-L-lactide-co-glycolide scaffolds in hypertensive (BPH/2J, group A) and nonhypertensive (BPN/3J, group B) mice. Collagen-coated scaffolds (A1 and B1) were additionally seeded with osteoblast-like (A2 and B2) and mesenchymal stem cells (A3 and B3). After implantation into dorsal skinfold chambers, inflammation and newly formed microvessels were measured using repetitive intravital fluorescence microscopy for 2 weeks. Apart from a weak inflammatory response in all groups, significantly increased microvascular densities were found in cell-seeded scaffolds (day 14, A2: 192 ± 12 cm/cm2, A3: 194 ± 10 cm/cm2, B2: 249 ± 19 cm/cm2, B3: 264 ± 17 cm/cm2) when compared with controls (A1: 129 ± 10 cm/cm2, B1: 185 ± 8 cm/cm2). In this context, hypertensive mice showed reduced neoangiogenesis in comparison with nonhypertensive animals. Therefore, seeding approved scaffolds with organ-specific or pluripotent cells is a very promising technique for tissue engineering in hypertensive organisms.

Antimicrobial peptide gene expression in medication-related osteonecrosis of the jaw.

Bisphosphonates and denosumab are commonly used antiresorptive therapies in patients with bone metastasis and osteoporosis. Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of these drugs, and infection has been recognized as a contributing factor. Current therapeutic options for MRONJ show limited effectiveness, therefore necessitating novel treatment strategies. Bisphosphonates have recently been reported to induce the expression of antimicrobial peptides (AMPs), an inherent component of the immune system. Therefore, the aim of the present study was to investigate and compare the influence of the anti-RANKL antibody denosumab and bisphosphonates on the gene expression of selected AMPs: human α-defensin-1, human α-defensin-3, human ß-defensin-1, and human ß-defensin-3. Bone specimens were collected from patients with MRONJ who had been treated with bisphosphonates (n = 6) or denosumab (n = 6), and from healthy subjects (n = 6) with no history of treatment with bone metabolism-influencing drugs. Reverse transcription-quantitative polymerase chain reaction was used to quantify the expression levels of selected AMPs. Samples from patients treated with denosumab showed significantly higher mRNA expression of human α-defensin-3 and human ß-defensin-3 than those from healthy subjects. This finding is similar to previously described upregulated expression of human defensins in patients with MRONJ after bisphosphonates treatment. This suggests that the elevated expression of defensins may be at least a part of the mechanism underlying the pathogenesis of osteonecrosis induced by antiresorptive therapies, which can serve as a new target for potential treatment of MRONJ.

Radiologic Analysis of Surgically Treated Fractures of the Condylar Process by an Endoscopic-Assisted Transoral Approach.

PURPOSE: This study analyzed the radiologic outcomes of patients with unilateral mandibular condylar fractures treated with open reduction-internal fixation (ORIF) through a transoral approach. PATIENTS AND METHODS: In this retrospective study, the radiologic images of 40 patients who underwent open reduction-internal fixation through a transoral approach were presented to 2 independent examiners. All patients underwent the surgical procedure between January 2015 and December 2016 at the Department of Cranio-Maxillofacial Surgery at UniversitätsSpital Zürich and were included in a previous functional outcome study. The surgical results were analyzed and graded as poor, acceptable, or good. The examiners declared whether they would have made any intraoperative revisions if the radiologic information had been available. Finally, the examiners estimated the required duration of elastic intermaxillary fixation (IMF) from the radiologic images, which was compared with the actual duration. RESULTS: Fracture reduction was classified as good in 33 cases (82.5%), acceptable in 5 cases, and poor in 2 cases by one examiner and as good in 32 cases (80%), acceptable in 6 cases, and poor in 2 cases by the other examiner. The inter-rater reliability was determined to be good (Cohen κ = 0.92). Correct osteosynthesis placement was found in 19 cases by one examiner and in 21 cases by the other examiner, with good inter-rater reliability (κ = 0.8). Moderate inter-rater reliability (κ = 0.4) was found for the required duration of elastic IMF. Furthermore, the estimated elastic IMF duration matched the actual duration in fewer than half of the cases. CONCLUSIONS: It is feasible to achieve reliably good radiologic results when operating on condylar process fractures by a transoral approach with endoscopic assistance and angled instruments. Intraoperative 3-dimensional imaging enables instant quality control and prompts surgical revision if needed.

Use of a xenogeneic collagen matrix on extraction sockets: a new approach in ARONJ prevention (in german) / Plastische Deckung von Extraktionsalveolen mit einem xenogenen Bindegewebstransplantat

Antiresorptive drugs are increasingly used for the treatment of osteoporosis, various bone pathologies and malignant tumors. Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a relevant complication, especially in nonhealing extraction sockets. Prescription of antibiotics in combination with a safely guaranteed closure of the extraction socket is considerably reducing the risk of ARONJ development. Full mucosal coverage usually requires the formation of a full thickness flap, which involves periosteal disclosure of the remodeled bone. In this new approach, primary wound closure is performed by covering the extraction socket with a xenogeneic collagen matrix. Ultimately, elevation of a periosteal flap and additional exposure of the surrounding alveolar bone is avoidable. The technique is exemplified on a patient case with a perennial anti resorptive medication history.

A volumetric assessment and follow-up of a granuloma gravidarum in the anterior maxilla.

AIM: Granuloma gravidarum (GG) is a benign lesion of the soft tissue. The aim of this technical note is the volumetric assessment and follow-up 3D measurement of a GG in the anterior maxilla. MATERIALS AND METHODS: A 35-year-old female patient who was 7 months pregnant was referred due to a soft tissue tumor in the papilla of tooth 21. A biopsy verified a pyogenic granuloma gravidarum. Initial and consecutive volumeatric measurements were made with an intraoral scanner during the patient's pregnancy and until 16 months postpartum. RESULTS: The volumetric assessment showed a continuous growth of the tumor and a consecutive volume reduction 16 months postpartum. In comparison with the level of the papilla of the contralateral incisor, there was an almost complete remission at the last follow-up. CONCLUSION: Intraoral scans can serve for the volumetric assessment of soft tissue tumors of the alveolar crest. Image superimposition enables the quantification of changes in morphology. This supports clinical follow-ups and enables the quantification of clinical observations.

Does Zygomatic Complex Symmetry Differ Between Healthy Individuals and Surgically Treated Patients Using Intraoperative 3-Dimensional Cone Beam Computed Tomographic Imaging?

PURPOSE: Reconstruction of symmetry after zygomaticomaxillary complex (ZMC) fractures is essential for esthetic appearance as well as function. Therefore, this study aimed to analyze whether bony facial symmetry in patients surgically treated for unilateral ZMC fractures via intraoperative imaging differs from that of healthy individuals. PATIENTS AND METHODS: Retrospective and cross-sectional radiographic measurements of patients treated for unilateral ZMC fractures via intraoperative cone beam computed tomography (CBCT) were performed to evaluate the postoperative ZMC symmetry. The same number of healthy individuals without any history of midfacial trauma matched for age and gender served as the control group. Asymmetry of the ZMC was determined by measuring bilateral differences in the malar eminence position on CBCT. In addition, demographic statistics, etiology, and fracture type were analyzed. RESULTS: Analysis of 57 surgically treated patients and 57 healthy individuals with a mean age of 29 years was performed. No significant difference in the symmetry of the malar eminence position was observed between healthy individuals and patients treated for a unilateral ZMC fracture (P = .890). In one third of patients, corrections were needed after intraoperative CBCT control. CONCLUSIONS: The results of this study indicate that, on average, a ZMC asymmetry of 1.6 mm is observed in healthy individuals. Furthermore, the use of intraoperative CBCT for the treatment of dislocated ZMC fractures helps to achieve precise anatomic, symmetrical repositioning and is suggested to improve the quality of care.

Right ventricular mitochondrial respiratory function in a piglet model of chronic pulmonary hypertension.

OBJECTIVE: We aimed to assess the mitochondrial respiratory capacities in the right ventricle in the setting of ventricular remodeling induced by pressure overload. METHODS: Chronic thromboembolic pulmonary hypertension was induced in 8 piglets over a 12-week period (chronic thromboembolic pulmonary hypertension model). Right ventricular remodeling, right ventricular function, and mitochondrial respiratory function were assessed at 3, 6, and 12 weeks after induction of pulmonary hypertension and were compared with sham animals (n = 5). Right ventricular cardiomyocytes and mitochondrial structure were studied in transmission electronic microscopy after 12 weeks. RESULTS: As of 3 weeks, chronic pressure overload induced right ventricular dilatation, right ventricular hypertrophy, and right ventricular dysfunction. Maladaptive remodeling in the chronic thromboembolic pulmonary hypertension model was confirmed by the decrease of right ventricular pulmonary artery coupling and right fractional area change. Mitochondrial functional assays in permeabilized right ventricular myocardial fibers revealed that oxidative phosphorylation capacities (complex I, complex II, and IV of the mitochondrial respiratory chain) were degraded. Furthermore, no change in substrate preference of mitochondria was found in the overloaded right ventricle. There was a good correlation between maximal mitochondrial oxygen consumption rate and right ventricular pulmonary artery coupling (Pearson coefficient r = 0.83). Transmission electronic microscopy analysis showed that the composition of cardiomyocytes was no different between the chronic thromboembolic pulmonary hypertension group and the sham group. However, mitochondrial structure anomalies were significantly increased in the chronic thromboembolic pulmonary hypertension group. CONCLUSIONS: Mitochondrial respiratory function impairment is involved early in the development of right ventricular dysfunction in a piglet model of chronic thromboembolic pulmonary hypertension. Underlying mechanisms remain to be elucidated.

Success rate 1 year after apical surgery: a retrospective analysis.

PURPOSE: The aim of the current study was the retrospective analysis of the outcomes of teeth treated with apical surgery after a 1-year follow-up period. Furthermore, potential factors associated with the success rate were investigated. METHODS: All patients were treated at the Clinic of Cranio-Maxillofacial and Oral Surgery at the University of Zurich between 2010 and 2017. To be eligible for inclusion, all patients were required to have undergone apical surgery with a retrograde root-end filling, and a 1-year follow-up examination at the University of Zurich. Treatment success at the 1-year follow-up time-point was defined as an absence of clinical complaints and radiographically determined healing. Parameters that were analysed included tooth localisation, periapical index of the preoperative lesion, administration of antibiotics, smoker status, histopathology of the apical lesion, radiographically determined sufficiency of root canal treatment pain and clinical signs of inflammation at the initial examination. RESULTS: A total of 81 teeth fulfilled all the inclusion criteria. At the 1-year follow-up, 91.4% of the teeth exhibited successful clinical and radiographic healing. The type of tooth was significantly associated with the success of the surgery (p = 0.006), but radiological severity of periapical inflammation, lesion histopathology, administration of antibiotics, smoker status, the quality of the root canal treatment, and preoperative pain and clinical signs of inflammation were not. CONCLUSION: The results of the present study suggest that apical surgery with retrograde root-end filling is a reliable therapy for the preservation of teeth. Furthermore, there are limited factors that affect the treatment outcome.

Guided apicoectomy using a CAD/CAM drilling template.

AIM: Modern microsurgical techniques have increased the success rate of apicoectomy relative to that of traditional approaches. This case report introduces a novel workaround for guided apicoectomy using a patient-specific computer-aided design/computer-aided manufacturing (CAD/CAM) three-dimensional (3D)-printed template. MATERIALS AND METHODS: Apicoectomy was performed on the mesial root of tooth 36 using template-guided trephine drilling, followed by retrograde filling with mineral trioxide aggregate (MTA). Initially, a cone beam computed tomography (CBCT) scan and an intraoral surface scan were imported into the planning software. After superimposition, virtual planning was performed to determine the exact localization for root resection. Subsequently, a tooth-supported drilling template was designed and 3D printed. Endodontic microsurgical approaches, including root-end cavity preparation and root-end filling, completed the surgical treatment. RESULT: The apical resection was easily feasible. There were no postoperative complications. Radiological assessment after a 6-month period showed signs of reossification. CONCLUSION: Guided apicoectomy allowed precise root resection, suggesting that this technique may be advantageous in complex anatomical situations.

Accuracy of Computer-Guided Template-Based Implant Surgery: A Computed Tomography-Based Clinical Follow-Up Study.

OBJECTIVE: The aim of this clinical study was to analyze the accuracy of computer-guided implant surgery. MATERIALS AND METHODS: Assisted by computed tomography (CT)-based planning software and navigational templates, 16 patients successfully received 26 dental implants. Each implant parameter (a-d) was calculated based on superimposed preoperative and postoperative cone beam CT scans: (a) deviation at entry point; (b) deviation at apex; (c) angular deviation; and (d) depth deviation. RESULTS: Mean central deviation at implant entry point and apex was 0.91 mm (standard error [SE] = 0.11 mm; 95% confidence interval [CI]: 0.69-1.13) and 1.22 mm (SE = 0.11 mm; 95% CI: 0.99-1.45), respectively. Mean angulation deviation was 4.11 degrees (SE = 0.52 degrees; 95% CI: 3.04-5.17) and the average depth deviation was 0.65 mm (SE = 0.11 mm; 95% CI: 0.42-0.87). For the total number of implants placed, the maximum error was 2.34 mm at entry point, 2.71 mm at apex, 9.44 degrees in angular deviation, and 2.00 mm in depth deviation. CONCLUSION: Great accuracy was reached even in advanced cases with prior bone augmentation and complex traumas. This leads to the conclusion that particularly in advanced cases, computer-guided implantation can be beneficial.

Change of saliva composition with radiotherapy.

OBJECTIVE: The aim of this study was to analyze the physiological and microbiological changes of saliva from patients with head and neck cancer during and after intensity-modulated radiotherapy (IMRT). DESIGN: In this prospective clinical trial saliva samples and oral candida swabs were collected from patients receiving IMRT due to head and neck cancer (examination group). The first measurement was scheduled before radiotherapy, the other measurements during and after radiotherapy up to a one year follow-up. Additionally samples from healthy controls were collected over six weeks. Salivary flow rate and pH were measured. Microbiological analysis of cariogenic and periodontopathogenic taxa was performed by fluorescence in situ hybridization and oral Candida spp occurrence was evaluated by swab tests. RESULTS: 11 patients and 19 controls were included. The salivary flow rate and the unstimulated pH of the examination group were significantly reduced during radiotherapy compared with the measurement before radiotherapy and to the control group. Total bacteria, streptococci and lactobacilli numbers slightly increased after radiotherapy, resuming baseline levels after one year. Mutans streptococci, Porphyromonas gingivalis and Treponema denticola were barely detectable, whereas Tannerella forsythia slightly increased following radiotherapy. No differences in Candida levels were observed in the study. CONCLUSIONS: Salivary changes in quantitative, qualitative and microbial composition occur during and after radiotherapy, with resumption of the measurements towards baseline levels after one year. While low levels of cariogenic and periodontopathogenic species were detected, the lower pH and salivary flow combined with increased numbers of aciduric and acidogenic lactobacilli corroborates a higher risk for caries, necessitating prevention.

Synergic PDE3 and PDE4 control intracellular cAMP and cardiac excitation-contraction coupling in a porcine model.

AIMS: Cyclic AMP phosphodiesterases (PDEs) are important modulators of the cardiac response to ß-adrenergic receptor (ß-AR) stimulation. PDE3 is classically considered as the major cardiac PDE in large mammals and human, while PDE4 is preponderant in rodents. However, it remains unclear whether PDE4 also plays a functional role in large mammals. Our purpose was to understand the role of PDE4 in cAMP hydrolysis and excitation-contraction coupling (ECC) in the pig heart, a relevant pre-clinical model. METHODS AND RESULTS: Real-time cAMP variations were measured in isolated adult pig right ventricular myocytes (APVMs) using a Förster resonance energy transfer (FRET) biosensor. ECC was investigated in APVMs loaded with Fura-2 and paced at 1 Hz allowing simultaneous measurement of intracellular Ca2+ and sarcomere shortening. The expression of the different PDE4 subfamilies was assessed by Western blot in pig right ventricles and APVMs. Similarly to PDE3 inhibition with cilostamide (Cil), PDE4 inhibition with Ro 20-1724 (Ro) increased cAMP levels and inotropy under basal conditions. PDE4 inhibition enhanced the effects of the non-selective ß-AR agonist isoprenaline (Iso) and the effects of Cil, and increased spontaneous diastolic Ca2+ waves (SCWs) in these conditions. PDE3A, PDE4A, PDE4B and PDE4D subfamilies are expressed in pig ventricles. In APVMs isolated from a porcine model of repaired tetralogy of Fallot which leads to right ventricular failure, PDE4 inhibition also exerts inotropic and pro-arrhythmic effects. CONCLUSIONS: Our results show that PDE4 controls ECC in APVMs and suggest that PDE4 inhibitors exert inotropic and pro-arrhythmic effects upon PDE3 inhibition or ß-AR stimulation in our pre-clinical model. Thus, PDE4 inhibitors should be used with caution in clinics as they may lead to arrhythmogenic events upon stress.

Guided biopsy of osseous pathologies in the jaw bone using a 3D-printed, tooth-supported drilling template.

Suspicious radiological findings in the jaw bone require histopathological examination for the confirmation of a diagnosis. As pathologies in this region are difficult to reach or are in close proximity to relevant anatomical structures, e.g. tooth roots or nerves, they often represent a challenge. Such factors may adversely affect the predictability of the surgical outcome of a biopsy of the osseous tissues. This technical note introduces a novel method for performing a digitally planned, guided biopsy. For this purpose, a cone beam computed tomography scan and an intraoral scan are superimposed using specific planning software. The resulting three-dimensionally printed, tooth-supported drilling template is designed for a trephine biopsy. It allows a precise, minimally invasive approach, with an exact three-dimensional determination of the biopsy location prior to surgery. The risk of devitalization of the neighbouring teeth or possible damage to the nerve structures can be minimized. Furthermore, a small access flap can be sufficient. In summary, the method of bone biopsy presented here allows high precision and greater predictability for biopsy sampling and is minimally invasive for the patient.

The BET Bromodomain Inhibitor I-BET-151 Induces Structural and Functional Alterations of the Heart Mitochondria in Healthy Male Mice and Rats.

The bromodomain and extra-terminal domain family inhibitors (BETi) are a promising new class of anticancer agents. Since numerous anticancer drugs have been correlated to cardiomyopathy, and since BETi can affect non-cancerous tissues, we aimed to investigate in healthy animals any ultrastructural BETi-induced alterations of the heart as compared to skeletal muscle. Male Wistar rats were either treated during 3 weeks with I-BET-151 (2 or 10 mg/kg/day) (W3) or treated for 3 weeks then allowed to recover for another 3 weeks (W6) (3-weeks drug washout). Male C57Bl/6J mice were only treated during 5 days (50 mg/kg/day). We demonstrated the occurrence of ultrastructural alterations and progressive destruction of cardiomyocyte mitochondria after I-BET-151 exposure. Those mitochondrial alterations were cardiac muscle-specific, since the skeletal muscles of exposed animals were similar in ultrastructure presentation to the non-exposed animals. I-BET-151 decreased the respiration rate of heart mitochondria in a dose-dependent manner. At the higher dose, it also decreased mitochondrial mass, as evidenced by reduced right ventricular citrate synthase content. I-BET-151 reduced the right and left ventricular fractional shortening. The concomitant decrease in the velocity-time-integral in both the aorta and the pulmonary artery is also suggestive of an impaired heart function. The possible context-dependent cardiac side effects of these drugs have to be appreciated. Future studies should focus on the basic mechanisms of potential cardiovascular toxicities induced by BETi and strategies to minimize these unexpected complications.

CO2 laser application in stomatology / Der CO2-Laser und seine Anwendung in der Stomatologie

The CO2 laser has found great acceptance in the stomatologic field of dentistry. This article gives an overview of the most important bene fits. The absorption of the laser light produces photothermal effects such as coagulation, vaporization and photoablation. The main indications in stomatology are pain alleviation and prevention of recurences in aphthae and cold sores (minor aphthae, herpes simplex), ablation of benign and irritant tissue excess (stimulus fibroma), lip and tongue band correction and soft tissue hemostasis. One great advantage is the minimal bleeding in the surgical field, which allows for optimal visibility. In addition, the CO2 laser offers high patient comfort since no primary wound closure with sutures are required. However, in suspect of malignancy a sharp excision with a scalpel is still preferred due to possible compromisation of the histopathologic evaluation.