Short term outcome after left atrial appendage occlusion with the AMPLATZER Amulet and WATCHMAN device: results from the ORIGINAL registry (saxOnian RegIstry analyzinG and followINg left atrial Appendage cLosure).

BACKGROUND: Various randomized multicenter studies have shown that percutaneous left atrial appendage closure (LAAC) is not inferior in stroke prevention compared to vitamin K antagonists (VKA) and can be performed safely and effectively. AIMS: The prospective multicenter ORIGINAL registry in the Free State of Saxony (saxOnian RegIstry analyzinG and followINg left atrial Appendage cLosure) investigated the efficiency and safety of LAAC with Watchman or Amulet device in a real word setting. A special focus was put on the influence of LAAC frequency on periprocedural efficiency and safety. METHODS AND RESULTS: The total of 482 consecutive patients (Abbott Amulet N = 93 and Boston Scientific Watchman N = 389) were included in the periinterventional analyses. After 6 weeks, 353 patients completed the first follow-up including transoesophageal echocardiography (TEE) (73.2%). Successful LAAC could be performed in more than 94%. The complication rate does not significantly differ between device types (p = 0.92) according to Fischer test and comprised 2.2% in the Amulet and 2.3% in the Watchman group. The kind of device and the frequency of LAAC per study center had no influence on the success and complication rates. Device related thrombus could be revealed more frequently in the Watchman group (4.5%) than in the Amulet group (1.4%) but this difference is still not significant in Fisher test (p = 0.14). Same conclusion can be made about residual leakage 1.1% versus 0% [not significant in Fisher test (p = 0.26)]. Dual antiplatelet therapy followed the intervention in 64% and 22% of patients were discharged under a combination of an anticoagulant (VKA/DOAC/Heparin) and one antiplatelet agent. CONCLUSIONS: The ORIGINAL registry supports the thesis from large, randomized trials that LAAC can be performed with a very high procedural success rate in the everyday clinical routine irrespective of the used LAA device (Watchman or Amulet). The postprocedural antithrombotic strategy differs widely among the participating centers. Trial registration Name of the registry: "saxOnian RegIstry analyzinG and followINg left atrial Appendage cLosure", Trial registration number: DRKS00023803; Date of registration: 15/12/2020 'Retrospectively registered'; URL of trial registry record: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023803 .

Long-term symptom improvement and patient satisfaction after AV-node ablation vs. pulmonary vein isolation for symptomatic atrial fibrillation: results from the German Ablation Registry.

BACKGROUND: We aimed to compare patient characteristics and outcome of patients who had either undergone pulmonary vein isolation (PVI) or AV-node ablation (AVN) to control AF-related symptoms. METHODS: From the German Ablation Registry, we analyzed data of 4444 patients (95%) who had undergone PVI and 234 patients (5%) with AVN. RESULTS: AVN patients were on average 10 years older than PVI patients (71 ± 10 vs. 61 ± 10 years, p < 0.001) with 33% aged > 75 years. AVN patients had significantly more cardiovascular comorbidities (diabetes 21% vs. 8%, renal insufficiency 24% vs. 3%, underlying heart disease 80% vs. 36%, severely reduced left ventricular function 28% vs. 1%, all p < 0.001). Significantly more PVI patients had paroxysmal AF (63% vs. 18%, p < 0.001), and more AVN patients had long-standing persistent AF (44% vs. 7%, p < 0.001). At 1-year follow-up, mortality in the AVN group was much higher (Kaplan-Meier estimates 9.8% vs. 0.5%). 20% of PVI patients had undergone another ablation vs. 3% AVN patients (p < 0.001). Symptomatic improvement was equally achieved in about 80%. Re-hospitalization for cardiovascular reasons occurred significantly more often in PVI vs. AVN patients (31% vs. 18%, p < 0.001). CONCLUSION: In the large German Ablation Registry, AVN ablation was performed much less frequently than PVI for symptomatic treatment of AF and typically in older patients with more comorbidity. Symptomatic improvement was similar in both groups. Hospitalizations for cardiovascular reasons were lower in AVN patients despite older age and more cardiovascular comorbidities. 20% of PVI patients had undergone at least one re-ablation.

Effect of Ioxaglate on the cutaneous microcirculation in patients with coronary artery disease: Randomized, double blind, placebo-controlled study.

Radiographic contrast media (RCM) can initiate microcirculatory disorders. This study was performed to investigate effects of Ioxaglate on the cutaneous microcirculation. The investigation was carried out as prospective randomized double-blind comparison in parallel-group design on two groups of n = 10 patients each who had to undergo a diagnostic coronary angiography.The confirmatory parameter of the study was mean erythrocyte capillary velocity [vRBC in mm/sec]. VRBC in the ipsilateral nail-fold capillaries was recorded continuously for 3 min before and 6 min after injection of RCM or isotonic saline solution in the A. axillaris respectively, and was evaluated off-line.VRBC in nailfold capillaries was found to be decreased by Ioxaglate by 34% 150 seconds after injection, while isotonic NaCl solution immediately induced a slight increase of 14%.

[Dyspnea in left-sided heart disease]. / Dyspnoe bei Linksherzerkrankungen.

Shortness of breath (dyspnea) is a common symptom in left-sided heart disease but clinically, patient symptoms show a high variability. Echocardiography is the mainstay for evaluating whether left-sided heart disease is the cause of dyspnea. If left-sided heart failure is diagnosed, this symptom complex must then be subjected to further etiological evaluation. Hypertensive, ischemic and valvular heart diseases are common, as well as atrial fibrillation. If the patient does not have angina pectoris, testing for ischemic heart disease should be done non-invasively by coronary computed tomography or testing for regional myocardial ischemia. Coronary revascularization is indicated only when a prognostically relevant ischemia of more than 10 % of the left ventricle is diagnosed. Diuretics are important for the relief of dyspnea but do not improve the prognosis of patients. In patients with reduced left ventricular function, combination therapy with angiotensin-converting enzyme (ACE) inhibitors, beta blockers and aldosterone antagonists improve the symptoms and prognosis. For treatment of heart failure with preserved ejection fraction evidence-based measures are still lacking. In this case the recommended therapy consists of optimal treatment of comorbidities, regulation of heart rate and blood pressure and participation in structured exercise programs. Angiotensin receptor blockers and aldosterone antagonists can be given in patients with more severe symptoms even though the available data are very sparse.

Nutrition and health in hotel staff on different shift patterns.

BACKGROUND: Limited research is available that examines the nutritional behaviour and health of hotel staff working alternating and regular shifts. AIMS: To analyse the nutritional behaviour and health of employees working in alternating and regular shifts. METHODS: The study used an ex post facto cross-sectional analysis to compare the nutritional behaviour and health parameters of workers with alternating shifts and regular shift workers. Nutritional behaviour was assessed with the Food Frequency Questionnaire. Body dimensions (body mass index, waist hip ratio, fat mass and active cell mass), metabolic values (glucose, triglyceride, total cholesterol and low- and high-density lipoprotein), diseases and health complaints were included as health parameters. RESULTS: Participants worked in alternating (n = 53) and regular shifts (n = 97). The average age of subjects was 35 ± 10 years. There was no significant difference in nutritional behaviour, most surveyed body dimensions or metabolic values between the two groups. However, alternating shift workers had significantly lower fat mass and higher active cell mass but nevertheless reported more pronounced health complaints. Sex and age were also confirmed as influencing the surveyed parameters. CONCLUSIONS: Shift-dependent nutritional problems were not conspicuously apparent in this sample of hotel industry workers. Health parameters did not show significantly negative attributes for alternating shift workers. Conceivably, both groups could have the same level of knowledge on the health effects of nutrition and comparable opportunities to apply this. Further studies on nutritional and health behaviour in the hotel industry are necessary in order to create validated screening programmes.

[Age-related effects on mental ability and their associations with personal characteristics among female teachers]. / Altersbezogene Effekte mentaler Leistungsfähigkeit und deren Zusammenhang zu personenbezogenen Merkmalen bei Lehrerinnen.

AIM: Mental ability is considered as a resource that supports coping processes among teachers. It consists of fluid speed-orientated components and crystallised precision-orientated components. Both components are subject to differential aging processes and are affected by personal factors. In this context, the effects of age and the correlation between mental ability and personal factors are analysed for a set of younger and older female teachers. METHODS: The data collection was carried out during extended preventive medical examinations at schools in Saxony. The analysis included the data of 252 female teachers. Mental ability was measured with standardised and validated instruments. Data were collected for the verbal and cognitive abilities to respond, to reset, to concentrate, to remember and to orientate as well as for strategy development. These variables were assigned to the speed-orientated and the precision-orientated components on the basis of measurements of time and errors. Personal factors included sense of coherence, susceptibility to stress, incapacity to recover, mental health and health complaints. In order to analyse age effects, the female teachers were divided into 2 age groups (< 45 and 45 years). RESULTS: The fluid components of mental ability showed significant but small effects in favour of the younger age group. No significant difference was found for the crystallised components among the age groups. In both age groups mental ability had a more favourable value for the teachers compared to the general population. The personal factors showed no differences for younger and older teachers, with the exception of physical health complaints which were mentioned more often by older teachers. Only a few very small correlations were detectable between the components of mental ability and personal factors. CONCLUSIONS: Besides the favourable mental ability of the teachers, the hypothesised and expected age effects are confirmed: the fluid abilities decline with age while the crystallised abilities remain stable. This is a starting point for prevention and intervention. Training allows maintenance or an improvement of mental ability at any age. Multidirectional correlations exist between mental ability and personal factors. Since mental ability comprises far more components than those considered in this study, the research approach should be expanded in the future.

[Reflex syncope and syncope secondary to orthostatic hypotension]. / Reflexsynkopen und Synkopen bei orthostatischer Hypotonie.

BACKGROUND: Reflex syncope predominantly occurs in younger patients and is the most common type of syncope. Typical contributors to reflex syncope are orthostatic stress, followed by a delayed and inadequate circulatory response consisting of bradycardia (cardioinhibitory type) and hypotension (vasodepressor type). Comparably, syncope may occur after direct activation of the vagus nerve, after emotional distress or pain, and in specific situations, such as coughing and post-micturition. The latter situations are mediated by indirect vagus nerve activation by usually unknown mediators. Syncope mediated by orthostatic hypotension occurs in elderly patients and is mediated by insufficient sympathoadrenergic vasoconstriction, occurring shortly after the onset of the orthostatic situation. DIAGNOSTICS: A thorough examination of the patient history is the mainstay of diagnostics. Specific testing is only required in uncertain and recurrent cases. In addition to standard diagnostics, tilt table testing can be helpful. A negative tilt test is, however, not definitive. Implanted loop recorders are helpful to diagnose the cardioinhibitory component of reflex syncope and are more sensitive than tilt testing. THERAPY: Treatment of both types of syncope consists of avoiding known situations leading to syncope, early reaction to prodromal syndromes, and physical counterpressure manoeuvers. Drug treatment (e.g. alpha-adrenergic agonists and fludrocortisone) are effective only in patients with orthostatic syncope. In selected patients with reflex syncope of a predominantly cardioinhibitory type, pacemaker implantation may be considered in selected patients.

Calcium dynamics in microbialite-forming exopolymer-rich mats on the atoll of Kiritimati, Republic of Kiribati, Central Pacific.

Microbialite-forming microbial mats in a hypersaline lake on the atoll of Kiritimati were investigated with respect to microgradients, bulk water chemistry, and microbial community composition. O2, H2S, and pH microgradients show patterns as commonly observed for phototrophic mats with cyanobacteria-dominated primary production in upper layers, an intermediate purple layer with sulfide oxidation, and anaerobic bottom layers with sulfate reduction. Ca(2+) profiles, however, measured in daylight showed an increase of Ca(2+) with depth in the oxic zone, followed by a sharp decline and low concentrations in anaerobic mat layers. In contrast, dark measurements show a constant Ca(2+) concentration throughout the entire measured depth. This is explained by an oxygen-dependent heterotrophic decomposition of Ca(2+)-binding exopolymers. Strikingly, the daylight maximum in Ca(2+) and subsequent drop coincides with a major zone of aragonite and gypsum precipitation at the transition from the cyanobacterial layer to the purple sulfur bacterial layer. Therefore, we suggest that Ca(2+) binding exopolymers function as Ca(2+) shuttle by their passive downward transport through compression, triggering aragonite precipitation in the mats upon their aerobic microbial decomposition and secondary Ca(2+) release. This precipitation is mediated by phototrophic sulfide oxidizers whose action additionally leads to the precipitation of part of the available Ca(2+) as gypsum.

[Anticoagulation in high thromboembolic risk after catheter ablation for atrial fibrillation: results from the German Ablation Registry]. / Antikoagulationssituation bei hohem thromboembolischem Risiko nach Vorhofflimmerablation: Daten des Ablations-Qualitätsregisters.

BACKGROUND: Catheter ablation (CA) for atrial fibrillation (AF) is an effective therapeutic option for the treatment of symptomatic drug-refractory AF. According to current guidelines, the prevention of stroke and embolism is the most important therapeutic goal in AF and the recommendations for anticoagulation (OAC) after successful CA are based upon the CHA2DS2-VASc-Score 3. The aim of this study was to evaluate the use of OAC in patients with a high risk for thromboembolic events 1 year after CA and to identify predictor variables for discontinuation of OAC. METHODS: Between January 2007 and January 2010 13092 patients were enrolled in the study. A total of 52 German electrophysiological centers agreed to participate in this prospective multicenter registry. 41 centers included patients undergoing CA for AF. Analysis included patients who were discharged with OAC after CA and had a CHA2DS2-VASc-Score ≥ 2. A centralized 1 year follow-up (FU) was conducted via telephone. RESULTS: 1300 patients fulfilled the inclusion criteria. One year after CA 51.8 % of these patients were on OAC. Factors significantly associated with discontinuation of OAC included no AF recurrence in FU (adjusted odds ratio (OR): 2.14, [95 % confidence interval (CI): 1.73-2.66], P < 0.001) and paroxysmal AF (OR: 1.53 [95 % CI: 1.29-1.81], P < 0.001). Factors associated with continuation of OAK were patient age (OR per 10 years: 0.79 [95 % CI: 0.68-0.91], P = 0.002), valvular heart disease (OR: 0.67 [95 % CI: 0.48-0.92], P = 0.013), an implanted pacemaker, defibrillator or a cardiac resynchronization therapy system (OR: 0.55 [95 % CI: 0.41-0.74], P < 0.001) and neurological events in hospital or during FU (OR: 0.40 [95 % CI: 0.18-0.88], P < 0.022). CONCLUSION: Almost half of the patients with an indication for OAC are not adequately anticoagulated one year after CA for AF. Paroxysmal AF or freedom from AF is significantly associated with discontinuation of OAC.

[Percutaneous coronary intervention versus bypass surgery in patients with diabetes and multivessel coronary disease. Coronary revascularization after FREEDOM]. / Perkutane koronare Intervention versus Bypass-Operation bei Patienten mit Diabetes und koronarer Mehrgefäßerkrankung. Koronarrevaskularisation nach FREEDOM.

Is coronary revascularization required in a patient with chronic stable coronary artery disease or can optimized medical therapy (OMT) alone be a sufficient alternative? This question has been controversially discussed for non-diabetics as well as for diabetics since the COURAGE and BARI 2D trials. According to our present knowledge, a patient will benefit from coronary revascularization only when either a non-invasive test method, such as single photon emission computed tomography (SPECT) or positron emission tomography (PET) myocardial scintigraphy, stress echocardiography or stress nuclear magnetic resonance imaging, can detect relevant, objective evidence of ischemia >10% of the left ventricular myocardium or when a pathological fractional flow reserve (FFR) <0.80 can be measured in an invasive procedure for an angiographically detectable coronary stenosis. If similar relevant ischemia can be non-invasively or invasively objectified in a patient with chronic stable multivessel coronary artery disease, the often controversially discussed question arises particularly in diabetics whether a percutaneous coronary intervention (PCI) with implantation of drug-eluting stents or coronary artery bypass surgery should be favored. The FREEDOM study (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease), published in November 2012, was the first prospective randomized study to examine this issue in diabetic patients with multivessel coronary artery disease. Despite a higher rate of stroke in the surgical cohort, after an average follow-up time of 3.8 years a significant prognostic advantage in favor of bypass surgery was detected for a combined primary endpoint of all-cause mortality, nonfatal myocardial infarction and nonfatal stroke. Thus, in the new ESC guidelines on diabetes, pre-diabetes and cardiovascular diseases developed with the EASD of the European Society of Cardiology and published in 2013, coronary bypass surgery has a class I, level of evidence A recommendation for patients with diabetes mellitus, chronic stable multivessel coronary disease and a synergy between PCI with taxus and cardiac surgery (SYNTAX) score >22. The decision for or against a PCI/stent implantation or coronary bypass surgery in a diabetic patient with chronic stable multivessel coronary artery disease should therefore be made with the patient only after a detailed informed consent discussion and comprehensive explanation of both treatment options. In controversial cases, particularly with an equivocal SYNTAX score around 22, relevant comorbidities or anticipated method-specific complications, a one-stage ad hoc intervention during the diagnostic coronary angiography should be rejected in favor of a two-stage procedure with prior discussion of both treatment options in the heart team comprising noninvasive cardiologists, interventional cardiologists and cardiac surgeons.

Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells.

There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found up-regulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by re-isoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway.

[Prevalence of undetected diabetes mellitus in invasive and interventional cardiology. Silent diabetes in the catheterization laboratory]. / Prävalenz unentdeckter Glukosestoffwechselstörungen in der invasiven und interventionellen Kardiologie. "Silent diabetes" im Herzkatheterlabor.

In most randomized controlled trials on revascularization therapy for patients with ischemic coronary artery disease (CAD), the diabetes prevalence ranges between 15% and 35%. However, the true prevalence of diabetes is probably considerably underestimated in these trials. The European heart survey diabetes and the heart published in 2004 supplied strong evidence that there are many additional cases of undetected prediabetics and diabetics in any cardiology patient cohort. The long-term outcome of newly detected diabetics was found to be comparable to patients with already known diabetes mellitus. With this in mind, the Dresden silent diabetes study investigated the prevalence of undetected diabetes mellitus by oral glucose tolerance testing (OGTT) and comparative HbA1c sampling in 1,015 patients admitted for coronary angiography. Patients with known diabetes were excluded from the study.According to the OGTT only 513 patients (51%) were classified with normal glucose tolerance (NGT), 10 (1%) with isolated impaired fasting glucose (IFG), 349 (34%) with impaired glucose tolerance (IGT) and 143 (14%) were diagnosed with newly detected diabetes mellitus (DM). According to the HbA1c measurements 588 patients (58%) were classified as normal, 385 (38%) as borderline and only 42 (4%) were diagnosed with diabetes (DM). There was a significant correlation between the extent of CAD and glycemic status as defined by the OGTT. The number of patients with IGT and diabetes increased with the extent of CAD (IGT group p<0.001, diabetes group p=0.01). However, no such correlation was observed when glycemic status was defined by HbA1c testing.Based on these results an OGTT should be routinely performed in patients with known or suspected coronary artery disease undergoing coronary angiography for diagnosis of diabetes, as HbA1c measurements alone appear to miss a substantial proportion of patients. These findings are of high clinical relevance with regard to optimal coronary revascularization procedure chosen in catheterization laboratories, preferably drug-eluting stents in cases of diabetes mellitus or newly detected diabetes mellitus and preferably coronary bypass surgery in diabetics with multi-vessel disease and high SYNTAX scores.

[Outpatient rehabilitation after myocardial infarction or for heart failure]. / Ambulante Rehabilitation nach Herzinfarkt und bei Herzinsuffizienz.

Reducing cardiac mortality and improving quality of life are the main objectives of cardiac rehabilitation. In recent years, outpatient rehabilitation within easy patient reach has achieved the same status as inpatient rehabilitation. Outpatient rehabilitation permits close involvement of the patient's family and social environment, thus easing reintegration into everyday life. However, the health care system is not yet utilizing outpatient rehabilitation to its full potential. This contribution illustrates the principles of rehabilitation following myocardial infarction or for heart failure in an outpatient setting, as well as its potential and future development.

Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography: [corrected] the Silent Diabetes Study.

AIMS/HYPOTHESIS: The primary aim of this study was to compare the results of HbA(1c) measurements with those of an OGTT for early diagnosis of 'silent diabetes' in patients with coronary artery disease (CAD) undergoing angiography without prediagnosed diabetes. A secondary aim was to investigate the correlation between the extent of CAD and the glycaemic status of the patient. METHODS: Data from 1,015 patients admitted for acute (n = 149) or elective (n = 866) coronary angiography were analysed. Patients with known diabetes were excluded from the study. Using the OGTT results, patients were classified as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. According to the results of the HbA(1c) measurements, patients were classified into three groups: normal (HbA(1c) <5.7% [<39 mmol/mol]), borderline (HbA(1c) 5.7-6.4% [39-47 mmol/mol]) and diabetes (HbA(1c) ≥6.5% [≥48 mmol/mol]). RESULTS: Based on the OGTT, 513 patients (51%) were classified with NGT, 10 (1%) with IFG, 349 (34%) with IGT and 149 (14%) were diagnosed with diabetes. According to HbA(1c) measurements, 588 patients (58%) were classified as normal, 385 (38%) as borderline and 42 (4%) were diagnosed with diabetes. The proportion of patients with IGT and diabetes increased with the extent of CAD (IGT ρ = 0.14, p < 0.001, diabetes ρ = 0.09, p = 0.01). No differences in HbA(1c) were seen among the groups with different extents of CAD (p = 0.652). CONCLUSIONS/INTERPRETATION: An OGTT should be performed routinely for diagnosis of diabetes in patients with CAD undergoing coronary angiography, since HbA(1c) measurement alone appears to miss a substantial proportion of patients with silent diabetes. A limitation of the study is that the OGTT was not performed before the angiography.

Mospd1, a new player in mesenchymal versus epidermal cell differentiation.

Mospd1 codes for a small protein with unknown physiological function, which is part of a family of genes, including Mospd2 and Mospd3, defined by the presence of the major sperm protein domain and two transmembrane domains. This work characterizes the Mospd1 gene, the intracellular location of the protein and its expression in different mouse tissues and mesenchymal cell lines during differentiation. The role of Mospd1 in mesenchymal cellular differentiation was studied by siRNA knockdown experiments in mouse osteoblastic MC3T3-E1 cells. Transfection experiments of the targeted cDNA show MOSPD1 located in the endoplasmatic reticulum and in the Golgi apparatus. Removal of the last exon of the gene resulted in localization of the protein in the nucleus, which was attributed to a nuclear export sequence in the N-terminal part. In mouse tissues the gene was generally strongly expressed while mesenchymal tissues showed the highest expression. In mesenchymal cell lines Mospd1 mRNA was higher expressed in cells with advanced differentiation status. In osteoblastic, myoblastic, and adipocytic cell lines Mospd1 was up-regulated during differentiation. Genome-wide gene expression analysis after knockdown of Mospd1 by siRNA in MC3T3-E1 cells revealed a shift in the gene expression pattern from mesenchymal to epithelial genes featuring up-regulation of the epithelial cadherin Cdh1 and down-regulation of its inhibitors Snail1 and 2 and the mesenchymal cadherin Cdh11, suggesting a mesenchymal to epithelial transition. From these data we conclude that Mospd1 plays a pivotal role in the developmental regulation at the switch between mesenchymal and epithelial cells.

T3 affects expression of collagen I and collagen cross-linking in bone cell cultures.

Thyroid hormones (T3,T4) have a broad range of effects on bone, however, its role in determining the quality of bone matrix is poorly understood. In-vitro, the immortalized mouse osteoblast-like cell line MC3T3-E1 forms a tissue like structure, consisting of several cell layers, whose formation is affected by T3 significantly. In this culture system, we investigated the effects of T3 on cell multiplication, collagen synthesis, expression of genes related to the collagen cross-linking process and on the formation of cross-links. T3 compared to controls modulated cell multiplication, up-regulated collagen synthesis time and dose dependently, and stimulated protein synthesis. T3 increased mRNA expressions of procollagen-lysine-1,2-oxoglutarate 5-dioxygenase 2 (Plod2) and of lysyloxidase (Lox), both genes involved in post-translational modification of collagen. Moreover, it stimulated mRNA expression of bone morphogenetic protein 1 (Bmp1), the processing enzyme of the lysyloxidase-precursor and of procollagen. An increase in the collagen cross-link-ratio Pyr/deDHLNL indicates, that T3 modulated cross-link maturation in the MC3T3-E1 culture system. These results demonstrate that T3 directly regulates collagen synthesis and collagen cross-linking by up-regulating gene expression of the specific cross-link related enzymes, and underlines the importance of a well-balanced concentration of thyroid hormones for maintenance of bone quality.

Collagen cross-linking influences osteoblastic differentiation.

Osteoblasts synthesize collagen matrix, which itself regulates the differentiation of precursor cells into mature osteoblasts. They express lysyl oxidase (LOX), which is involved in the collagen cross-linking process. Lathyrogens, like ss-aminopropionitrile (ssAPN), inhibit the formation of a stable matrix. The aim of the present study was to investigate the influence of cross-linking on osteoblastic differentiation. MC3T3-E1 cells were seeded and treated with or without 400 muM ssAPN for 1 week. Thereafter, living cells were removed and, on this extracellular matrix, new MC3T3-E1 cells were seeded and cultured for 1 week without ssAPN. RNA was isolated, and expression of specific marker genes was determined by quantitative reverse transcription-polymerase chain reaction. Changes in specific cross-links after ssAPN treatment were measured with Fourier-transform infrared spectroscopy. The collagen matrix that formed showed a significant reduction of two major cross-links of bone collagen, deH-DHLNL and pyr, compared to control cultures. Gene expression studies showed an increase of collagen alpha1 (I) (COL1A1) to 150%. Expression of LOX and osteocalcin (OCN) mRNA was significantly downregulated to about 75%. When fresh MC3T3-E1 cells were seeded on this altered matrix without ssAPN, COL1A1 mRNA expression was upregulated (140%), OCN was downregulated (60%), and LOX mRNA expression remained unaffected. These results indicate that ssAPN treatment not only disrupts collagen cross-link formation but also affects osteoblastic activity and expression. In conclusion, the disrupted matrix produced in the presence of lathyrogen influences, even in its absence, the expression of osteoblastic genes.

Lysyl oxidase (LOX) mRNA expression and genes of the differentiated osteoblastic phenotype are upregulated in human osteosarcoma cells by suramin.

It is well known that suramin influences proliferation and differentiation of tumour cells. To study whether and how suramin effects osteosarcoma (OS) cells, proliferation, differentiation, LOX mRNA expression and telomerase activity (TA) was analysed in the human MG-63 and U-2 OS, and the rat UMR-106 OS cell lines. Data show that suramin inhibited proliferation in the human cell lines and upregulated alkaline phosphatase activity. TA was attenuated in the human cells while in UMR-106 it was not changed. In UMR-106 suramin had no influence on osteocalcin and LOX expression, in the human cells however, both genes were upregulated.

Relations between parents' interactive style in dyadic and triadic play and toddlers' symbolic capacity.

Play has a major role in the evaluation and treatment of young children referred to mental health clinicians. The present study examined parental correlates of preschoolers' symbolic play during dyadic and triadic play interactions. Boys' play contained more aggressive themes, and girls' contained more nurturing themes. Mothers displayed more caring themes during play with both sons and daughters, and fathers displayed more repair and construction themes. Mothers' and fathers' facilitative- creative interaction style in dyadic play predicted the level of the child's symbolic play. Co-parenting style marked by cooperation and autonomy predicted symbolic play during a triadic family session. Child intelligence predicted symbolic play beyond the parent's style during triadic but not dyadic interactions. The findings have implications for early intervention directed at increasing symbolic play in young children.

Triiodothyronine (T3) and 1,25-dihydroxyvitamin D3 (1,25D3) inversely regulate OPG gene expression in dependence of the osteoblastic phenotype.

Both thyroid hormones and 1,25-dihydroxyvitamin D3 (1,25D3) are essential for normal development and maintenance of the skeleton. They regulate osteoblastic differentiation by influencing expression of osteoblast specific genes like osteocalcin (OCN). Mice deficient in OCN, the most abundant noncollagenous protein of the bone matrix, develop a phenotype characterized by higher bone mass and bone of improved quality. Osteoprotegerin (OPG), another protein important for bone metabolism, protects bone and is a regulator of the osteoclast development. 1,25D3 down regulates the basal expression of these two proteins in osteoblasts and osteoblast-like cells. The involvement of these hormones and proteins in the bone metabolism guided us to compare their regulation in cell lines with different osteoblastic phenotypes. We found that T3 increased OCN mRNA levels in MC3T3-E1 osteoblastic cells independent from their phenotype albeit with different potency but not in the bone marrow-derived stromal cell line ST2. OPG mRNA expression levels were only stimulated by T3 in mature MC3T3-E1 cells, which have the capacity to mineralize, but not in pre-osteoblastic MC3T3-E1 cells or in ST2 cells. In the mineralizing osteoblastic cells 1,25D3 inhibited T3-induced expression for OPG mRNA but not OCN mRNA. In the pre-osteoblastic cell line with undetectable OPG mRNA levels, either basal or T3-stimulated, 1,25D3 inhibited OCN mRNA expression completely. Our results emphasize the importance of balanced regulation of mRNA transcript levels for OPG and OCN, by both hormones and probably other systemic factors to enable a fine-tuning of bone metabolism at specific skeletal sites.