Sabine Grönke

Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients

Background Asymptomatic diabetic patients have a high incidence of clinically unrecognized left ventricular dysfunction with an abnormal cardiac response to exercise. We, therefore, examined subclinical defects in the contraction–relaxation cycle and intracellular Ca2+ regulation in myocardium of asymptomatic type 2 diabetic patients. Methods Alterations in the dynamics of the intracellular Ca2+ transient and contractility were recorded in right atrial myocardium of type 2 diabetic patients and non-diabetic control tissue loaded with fura-2. In order to gain an insight into mechanisms underlying the altered Ca2+ handling in diabetic myocardium levels of mRNA, protein expression and phosphorylation of key proteins in sarcoplasmic Ca2+ handling were determined. Results In isolated atrial trabeculae of diabetic myocardium the rise of systolic Ca2+ was significantly prolonged, but relaxation of the Ca2+ transient was unaltered compared to control tissue. Accordingly, the levels of expression of mRNA and protein of the Ca2+ release channel (RyR2) of the sarcoplasmic reticulum were reduced by 68 and 22%, respectively. Endogenous phosphorylation of RyR2 by protein kinases C, however, was increased by 31% in diabetic myocardium, as assessed by the back-phosphorylation technique. Levels of expression of SERCA2 and phospholamban were unaltered between both groups. Conclusions Intracellular Ca2+ release is prolonged in non-failing myocardium of type 2 diabetic patients and this may be primarily due to a decreased expression of RyR2. This defective Ca2+ release may represent an early stage of ventricular dysfunction in type 2 diabetes and would favor the abnormal response to exercise frequently observed in asymptomatic diabetic patients.

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

Aims/hypothesisThe angiotensin II (type 1) (AT1) receptor mediates many biological effects of the renin–angiotensin system (RAS), leading to remodelling of cardiac tissue. The present study was designed to analyse changes in the function and expression of the AT1 receptor as principal effector of the RAS in myocardium from type 2 diabetic patients compared with non-diabetic myocardium as control. In addition, we determined the effect of treatment with ACE inhibitors or AT1 receptor blockers on expression levels of the receptor in diabetic patients.MethodsGene expression of the AT1 receptor was analysed by quantitative RT-PCR and protein expression was determined by immunoblot analysis in human right atrial myocardium. We investigated functional coupling of the receptors by measuring contractility in isolated trabeculae stimulated with increasing concentrations of angiotensin II.ResultsDiabetic myocardium showed a significant increase in protein expression (170 ± 16% of control) and median mRNA expression (186% of control) of the AT1 receptor. The additional receptors were functionally coupled, resulting in a stronger inotropic response upon stimulation with angiotensin II (89 ± 5.5% vs 29 ± 1.6% in controls), whereas receptor affinity was similar in both groups. However, myocardium from diabetic patients treated with ACE inhibitors or AT1 receptor blockers showed no increase in AT1 receptor expression.Conclusions/interpretationAT1 receptor expression in myocardium of type 2 diabetic patients is dynamic, depending on the level of glycaemic control and the activity of the RAS. These findings could at least in part explain the strong therapeutic benefit of RAS inhibition in diabetic patients.

Chirurgische Therapie pulmonaler Metastasen des malignen Melanoms

Results of previous studies question the benefits of pulmonary surgery in patients with pulmonary metastases from malignant melanoma. A systematic literature search and analysis of articles published since 1 January 2000 was carried out to investigate the advantages of metastasectomy and alternative forms of therapy. Patients reached a median survival time of 17-40 months and 5-year survival rates between 18% and 39.4% after metastasectomy. Intrathoracic recurrence occurred in 30 % of patients but could be successfully treated with re-operations in some cases. Various monoclonal antibodies are currently available and achieve a median survival time of up to 17 months. Pulmonary metastasectomy is the treatment of choice in selected patients; however, in the future the benefits should be revalidated in comparison with pharmaceuticals of the current generation.

Surgical therapy for pulmonary metastases from malignant melanoma

Results of previous studies question the benefits of pulmonary surgery in patients with pulmonary metastases from malignant melanoma. A systematic literature search and analysis of articles published since 1 January 2000 was carried out to investigate the advantages of metastasectomy and alternative forms of therapy. Patients reached a median survival time of 17-40 months and 5-year survival rates between 18% and 39.4% after metastasectomy. Intrathoracic recurrence occurred in 30 % of patients but could be successfully treated with re-operations in some cases. Various monoclonal antibodies are currently available and achieve a median survival time of up to 17 months. Pulmonary metastasectomy is the treatment of choice in selected patients; however, in the future the benefits should be revalidated in comparison with pharmaceuticals of the current generation.

Chirurgische Therapie pulmonaler Metastasen von Kopf-Hals-Tumoren

Pulmonary metastasectomy is an established procedure in oncological therapeutic concepts. A systematic literature search and an analysis of all studies published since 01.01.2000 should evaluate the advantage of pulmonary metastasectomy for patients with primary head and neck cancer. Lung metastases develop in 1.9-13% of head and neck cancer patients. Following metastasectomy, patients reach a median survival of 9.5-78 months and 5-year survival rates of up to 58% are achieved. Intrathoracic recurrence occurs in 18.4-81.8% of patients, selected instances of which can be successfully treated by remetastasectomy. Patients with squamous cell carcinoma have the worst prognosis, but could also become long-term survivors (≥ 60 months). Pulmonary metastasectomy is frequently the only potentially curative therapeutic approach and offers a better long-term survival than nonsurgical therapies. Lung metastasectomy is thus the treatment of choice in selected patients with pulmonary metastases from primary head and neck cancer.

The G protein Gα11 is essential for hypertrophic signalling in diabetic myocardium

AIMS/HYPOTHESIS Pathological cardiac hypertrophy is an early phenotype in both types 1 and 2 diabetes. The primary stimulus for hypertrophic growth in diabetes is yet unknown and may involve neurohumoral stimulation of Gq-coupled receptors as well as direct glucose-dependent mechanisms. To discriminate between these hypertrophic stimuli we analyzed hypertrophic signalling pathways in wildtype and Gα11-knockout mice. METHODS Experimental diabetes was induced in wildtype and knockout mice by intraperitoneal injection of streptozotocin. 8 weeks after induction of diabetes myocardial function and structure was assessed by echocardiography before sacrifice. To identify prohypertrophic signalling pathways expression and translocation of protein kinase C isoforms α, βII, δ, ε and ζ were analyzed by immunohistochemical staining and immunoblot analysis after tissue fractionation. Changes in calcineurin signalling were identified by immunoblot analysis and functional assays. Expression levels of transcription factors GATA4 and NF-κB were quantified by real-time RT-PCR. RESULTS Diabetic wildtype mice developed myocardial hypertrophy with preserved cardiac function. Calcineurin signalling was not different between the two groups. However, diabetic wildtype mice showed increased protein levels of PKC-α and PKC-ζ, translocation of PKC-α, -δ and -ε to cellular membranes and higher levels of NF-κB expression. In contrast, diabetic Gα11-knockout mice showed no altered phenotype and no changes in NF-κB or PKC expression, although translocation of PKC-ε occurred as in wildtypes. CONCLUSIONS Gα11 is essential for the development of cardiac hypertrophy in type 1-diabetes. Stimulation of hypertrophic signalling through PKC-α, PKC-δ, PKC-ζ, and NF-κB appears to be receptor-dependent, whereas PKC-ε is activated by hyperglycemia, independent of Gα11.

Surgical therapy of lung metastases from head and neck cancer

Pulmonary metastasectomy is an established procedure in oncological therapeutic concepts. A systematic literature search and an analysis of all studies published since 01.01.2000 should evaluate the advantage of pulmonary metastasectomy for patients with primary head and neck cancer. Lung metastases develop in 1.9-13% of head and neck cancer patients. Following metastasectomy, patients reach a median survival of 9.5-78 months and 5-year survival rates of up to 58% are achieved. Intrathoracic recurrence occurs in 18.4-81.8% of patients, selected instances of which can be successfully treated by remetastasectomy. Patients with squamous cell carcinoma have the worst prognosis, but could also become long-term survivors (≥ 60 months). Pulmonary metastasectomy is frequently the only potentially curative therapeutic approach and offers a better long-term survival than nonsurgical therapies. Lung metastasectomy is thus the treatment of choice in selected patients with pulmonary metastases from primary head and neck cancer.

Differential expression of protein kinase C isoforms in coronary arteries of diabetic mice lacking the G-protein Gα11

BackgroundDiabetes mellitus counts as a major risk factor for developing atherosclerosis. The activation of protein kinase C (PKC) is commonly known to take a pivotal part in the pathogenesis of atherosclerosis, though the influence of specific PKC isozymes remains unclear. There is evidence from large clinical trials suggesting excessive neurohumoral stimulation, amongst other pathways leading to PKC activation, as a central mechanism in the pathogenesis of diabetic heart disease. The present study was therefore designed to determine the role of Gq-protein signalling via Gα11 in diabetes for the expression of PKC isozymes in the coronary vessels.MethodsThe role of Gα11 in diabetes was examined in knockout mice with global deletion of Gα11 compared to wildtype controls. An experimental type 1-diabetes was induced in both groups by injection of streptozotocin. Expression and localization of the PKC isozymes α, βII, δ, ε, and ζ was examined by quantitative immunohistochemistry.Results8 weeks after induction of diabetes a diminished expression of PKC ε was observed in wildtype animals. This alteration was not seen in Gα11 knockout animals, however, these mice showed a diminished expression of PKCζ. Direct comparison of wildtype and knockout control animals revealed a diminished expression of PKC δ and ε in Gα11 knockout animals.ConclusionThe present study shows that expression of the nPKCs δ and ε in coronary vessels is under control of the g-protein Gα11. The reduced expression of PKC ζ that we observed in coronary arteries from Gα11-knockout mice compared to wildtype controls upon induction of diabetes could reduce apoptosis and promote plaque stability. These findings suggest a mechanism that may in part underlie the therapeutic benefit of RAS inhibition on cardiovascular endpoints in diabetic patients.

Chirurgische Therapie pulmonaler Metastasen des malignen Melanoms@@@Surgical therapy for pulmonary metastases from malignant melanoma

Results of previous studies question the benefits of pulmonary surgery in patients with pulmonary metastases from malignant melanoma. A systematic literature search and analysis of articles published since 1 January 2000 was carried out to investigate the advantages of metastasectomy and alternative forms of therapy. Patients reached a median survival time of 17-40 months and 5-year survival rates between 18% and 39.4% after metastasectomy. Intrathoracic recurrence occurred in 30 % of patients but could be successfully treated with re-operations in some cases. Various monoclonal antibodies are currently available and achieve a median survival time of up to 17 months. Pulmonary metastasectomy is the treatment of choice in selected patients; however, in the future the benefits should be revalidated in comparison with pharmaceuticals of the current generation.

Chirurgische Therapie pulmonaler Metastasen von Kopf-Hals-Tumoren@@@Surgical therapy of lung metastases from head and neck cancer

Pulmonary metastasectomy is an established procedure in oncological therapeutic concepts. A systematic literature search and an analysis of all studies published since 01.01.2000 should evaluate the advantage of pulmonary metastasectomy for patients with primary head and neck cancer. Lung metastases develop in 1.9-13% of head and neck cancer patients. Following metastasectomy, patients reach a median survival of 9.5-78 months and 5-year survival rates of up to 58% are achieved. Intrathoracic recurrence occurs in 18.4-81.8% of patients, selected instances of which can be successfully treated by remetastasectomy. Patients with squamous cell carcinoma have the worst prognosis, but could also become long-term survivors (≥ 60 months). Pulmonary metastasectomy is frequently the only potentially curative therapeutic approach and offers a better long-term survival than nonsurgical therapies. Lung metastasectomy is thus the treatment of choice in selected patients with pulmonary metastases from primary head and neck cancer.