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J Neumann

Publications and source records attributed to J Neumann.

At least 127 records · Page 7Linked to original sources
PubMed1996

Evidence for presence and hormonal regulation of protein phosphatase inhibitor-1 in ventricular cardiomyocyte.

Protein phosphatase inhibitor-1 (PPI-1) has been shown to be present in heart tissue and smooth muscle. Whether PPI-1 is present in cardiomyocytes is not known. The purpose of this study was to determine whether PPI-1 is present and is hormonally regulated in cardiomyocytes. A trichloroacetic acid (TCA) extract enriched in PPI-1 was isolated from guinea pig ventricular cardiomyocytes. The TCA extract inhibited the activity of type 1 protein phosphatase by 20 +/- 4% (n = 3 expts). On phosphorylation by the catalytic subunit of adenosine 3', 5'-cyclic monophosphate-dependent protein kinase, the extent of this inhibition was augmented to 4.5-fold. Dephosphorylation of the phosphorylated TCA extract by type 2 protein phosphatase reduced inhibition to 2 +/- 0.2% (n = 3 expts). To determine whether isoproterenol increases phosphorylation of PPI-1 in cardiomyocytes, the TCA extracts were prepared from cardiomyocytes treated with 1 microM isoproterenol and from untreated cardiomyocytes. The inhibitory activity of the TCA extract in untreated cardiomyocytes was 25 +/- 3% (n = 3 expts) and increased to 75 +/- 2% (n = 3 expts) in isoproterenol-treated cardiomyocytes. With the use of a rabbit skeletal muscle PPI-1 antibody, immunoblots of the TCA extract of cardiomyocytes identified a 28-kDa protein. A 28-kDa protein was also immunoprecipitated from a TCA extract isolated from isoproterenol-treated 32P-labeled cardiomyocytes. The immunoprecipitation was blocked by the addition of excess amounts of purified rabbit skeletal muscle PPI-1. Isoproterenol-treated cardiomyocytes increased the phosphorylation of the 28-kDa protein by 232 +/- 20% (n = 3 expts) compared with untreated cardiomyocytes. We conclude that 1) the 28-kDa protein is PPI-1, 2) PPI-1 is present in ventricular cardiomyocytes, and 3) PPI-1 is hormonally regulated. A decrease in type 1 protein phosphatase activity through phosphorylation of PPI-1 may be an important pathway for augmenting cardiac contractility.

Animals↗
PubMed1996

Relation between contractile function and regulatory cardiac proteins in hypertrophied hearts.

The aim of this study was to examine the mechanism(s) underlying the reduced isoproterenol-induced positive inotropic and lusitropic effects in hypertrophied hearts. Chronic beta-adrenergic stimulation (2.4 mg isoproterenol.kg-1. day-1 for 4 days) induced cardiac hypertrophy by 33 +/- 2% in rats. A parallel downregulation of phospholamban (PLB) and sarcoplasmic reticulum Ca2(+)-ATPase (SERCA2) protein expression by 49 and 40%, respectively, was observed, whereas troponin I (TNI) and C protein remained unchanged. In papillary muscles from chronically beta-adrenergically stimulated rats, the isoproterenol-induced positive inotropic and lusitropic effects, as well as adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, were attenuated compared with those in control animals. Acute exposure to isoproterenol induced phosphate incorporation into PLB, TNI, and C protein of 48 +/- 4.6, 55 +/- 5.0, and 27 +/- 4.9 pmol/mg homogenate protein, respectively, in control animals. In the hypertrophied hearts, phosphate incorporation into PLB was reduced by 76%, whereas phosphate incorporation into TNI or C protein remained unchanged. In conclusion, chronic beta-adrenergic stimulation reduced the isoproterenol-stimulated positive inotropic and lusitropic effects in papillary muscles, which were accompanied by 1) diminished cAMP formation, 2) attenuation of cAMP-mediated PLB phosphorylation, and 3) downregulation of PLB and SERCA2 protein.

Adenosine Triphosphatases↗
PubMed1996

Lack of prognostic relevance of alterations in the epidermal growth factor receptor-transforming growth factor-alpha pathway in human astrocytic gliomas.

Alterations in the epidermal growth factor receptor (EGFR) and its main ligand, transforming growth factor-alpha (TGF alpha), were investigated for a possible prognostic relevance in 125 astrocytic gliomas (44 World Health Organization (WHO) Grade II, 19 WHO Grade III, and 62 WHO Grade IV tumors). The TGF alpha and EGFR proteins were detected immunohistochemically using monoclonal antibodies. A positive immunoreaction to TGF alpha was detected in 33 (75%) of 44 WHO Grade II astrocytomas, 18 (95%) of 19 WHO Grade III astrocytoma, and 50 (81%) of 62 WHO Grade IV glioblastomas. No correlation between TGF alpha immunoreaction and duration of survival could be found. A positive EGFR immunoreaction was detected in seven (16%) of 44 WHO Grade II astrocytomas, five (26%) of 19 WHO Grade III astrocytomas, and 32 (52%) of 62 WHO Grade IV glioblastomas. Of these gliomas, 97 (26 WHO Grade II, 17 WHO Grade III, and 54 WHO Grade IV gliomas) were examined for EGFR gene amplification using a differential polymerase chain reaction assay. Amplification of the EGFR gene was detected in none of the WHO Grade II astrocytomas, one (6%) of 17 WHO Grade III astrocytomas, and 18 (33%) of 54 WHO Grade IV glioblastomas. Twenty-two of the tumors investigated showed a positive EGFR immunoreaction without detectable gene amplification (five WHO Grade II, four WHO Grade III, and 13 WHO Grade IV tumors). Gene amplification was invariably associated with a positive EGFR immunoreaction. For the entire study group, a strong correlation between EGFR alterations (gene amplification and positive immunoreaction) and survival could be found. However, this correlation only reflected the higher percentages of cases with EGFR alterations in malignant gliomas and was not an independent prognostic factor as determined by multifactorial analysis. These data demonstrate that EGFR alterations are frequent events in astrocytic gliomas and are largely restricted to glioblastomas. However, within one tumor grade they do not provide prognostic information.

Adult↗
PubMed1996

Positive inotropic effects of the calcium sensitizer CGP 48506 in guinea pig myocardium.

In isolated papillary muscles from reserpinized guinea pigs, CGP 48506 increased force of contraction in a concentration-dependent and reversible manner, starting at 10 mumol/l and reaching 364.14 +/- 46.10% of predrug values at 100 mumol/l. The positive inotropic effect of CGP 48506 was not sensitive to 10 mumol/l carbachol. The positive inotropic effect of CGP 48506 was accompanied by increases in time to peak tension and in time of relaxation amounting to 223.37 +/- 6.87% and 247.10 +/- 9.34% of control, respectively, at 100 mumol/l (n = 10). CGP 48506 sensitized trabeculae from guinea pig hearts to calcium with an EC50 value of 22 mumol/l. However, CGP 48506 (up to 300 mumol/l) did not affect the activity of cardiac PDE isoenzymes I to IV. Likewise, CGP 48506 (up to 100 mumol/l) did not increase phosphorylation of select cardiac regulatory proteins or cyclic AMP content in guinea pig ventricular cardiomyocytes and did not affect cardiac phosphorylase phosphatase activity. CGP 48506 is the first pharmacological agent with noteworthy calcium-sensitizing properties that has been found to be devoid of inhibitory activity on cardiac PDE.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human myocardium.

In trabeculae carneae from failing human myocardium, CGP 48506 increased the force of contraction, which reached 310 +/- 41% of predrug values at 100 mumol/l. Its stereoisomer CGP 48508 did not affect the force of contraction (100 mumol/l). The positive inotropic effect of CGP 48506 was not sensitive to 10 mumol/l carbachol. The positive inotropic effect of CGP 48506 was accompanied by increases in time to peak tension and time of relaxation amounting to 175 +/- 4% and 205 +/- 15% of control, respectively, at 100 mumol/l. CGP 48506 but not CGP 48508 sensitized skinned trabeculae from failing human myocardium to calcium with an EC50 value of 10 mumol/l. However, CGP 48506 and CGP 48508 (up to 300 mumol/l) did not affect the activity of PDE isoenzymes I to IV from failing human myocardium. CGP 48506 is the first inotropic agent with calcium-sensitizing properties in the human heart that has been found to be devoid of inhibitory activity on human cardiac PDE isoenzymes.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Messenger RNA expression and immunological quantification of phospholamban and SR-Ca(2+)-ATPase in failing and nonfailing human hearts.

OBJECTIVES: Human heart failure is associated with prolonged relaxation and prolonged Ca2+ transients which indicates an impaired function of the sarcoplasmic reticulum (SR) and may be detrimental for cardiac function. Controversy exists whether the altered SR function is accompanied by changes in the expression of phospholamban (PLB) and cardiac SR-Ca(2+)-ATPase (SERCA2) on mRNA and/or protein levels. METHODS: We determined mRNA and/or protein levels for PLB and SERCA2 in the same left ventricular tissue of patients undergoing heart transplantation due to idiopathic dilated cardiomyopathy (IDC) or ischemic cardiomyopathy (ICM) in comparison to left ventricular tissue from nonfailing human hearts (NF). Total protein extracts were prepared and subjected to SDS gel electrophoresis. PLB and SERCA2 were identified with specific antibodies. Total RNA was isolated and hybridized with 32P-labeled cDNAs for human PLB and rat SERCA2. RESULTS: Hybridization revealed the three expected mRNAs with the PLB probe (3.3 kb, 1.9 kb and 0.6 kb) and a single band with the SERCA2 probe (4.5 kb). Determination of respective proteins by immunoblotting revealed unchanged protein levels for PLB and SERCA2, whereas the mRNA levels for PLB and SERCA2 were reduced by about 30% and 50%, respectively. CONCLUSIONS: These data show the level of SERCA2 and PLB protein and mRNA in the same hearts. The reduced mRNA level of SERCA2 and PLB is in accordance with previous data. However, the unchanged protein levels may indicate that the diminished RNA expression is not accompanied by a corresponding decrease for these proteins in human heart failure. These data also show that the altered SR function in human heart failure cannot be explained by altered protein levels of PLB and SERCA2. Furthermore, it is suggested that extrapolations from cardiac mRNA levels to protein expression may be misleading.

Adenosine Triphosphate↗
PubMed1996

[Acute treatment of non-metabolic complications after surgery of the thyroid gland].

Non-metabolic complications after surgery of the thyroid gland must be known because of their specific character. Frequently not only the health but also the patient's life depend on an early and correct solution. The authors discuss different complications and recommend a solution. They conclude that satisfactory anatomical knowledge, adequate surgical training and an experienced anaesthesiologist are with regard to the frequency of complications in thyroid surgery much more important than the type of operation.

Female↗
PubMed1996

[An unusual cause of death after the Whipple operation].

The authors describe and discuss the sudden death of a patient 22 days after curative resection of a tumour of the head of the pancreas. The previous quite uncomplicated postoperative development was terminated by massive haemorrhage into the upper digestive tract. As a result of this haemorrhage the patient died in shock before the source of the haemorrhage could be investigated. On necropsy an obvious source of haemorrhage was not detected. Only three minor submucous venectasias in the blind stump of an excluded jejunal loop. One with a minor mucosal defect, may have been the cause of this fatal complication.

Fatal Outcome↗
PubMed1995

Sodium fluoride attenuates the negative inotropic effects of muscarinic M2 and adenosine receptor agonists.

Sodium fluoride increased the force of contraction in isolated guinea-pig papillary muscles concentration dependently, starting at 3 mmol/1. Sodium fluoride inhibited phosphorylase phosphatase activity in homogenates from guinea pig hearts, starting at 1 mmol/1. The positive inotropic effect of 3 mmol/1 sodium fluoride was not accompanied by an increase in cAMP content in guinea-pig papillary muscles. In papillary muscles, carbachol or (-)-N(6)-phenylisopropyladenosine reduced the positive inotropic effect of isoprenaline (10 nmol/1) or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (60 mu mol/1). These negative inotropic effects of carbachol and (-)-N(6)-phenylisopropyladenosine were attenuated by additional sodium fluoride (3 mmol/l). It is concluded that sodium fluoride can impair the signal transduction of muscarinic M2 (carbachol) and adenosine receptor (-)-N(6)-phenylisopropyladenosine) agonists. This effect of sodium fluoride could support the hypothesis that the cardiac effects of muscarinic M2 and adenosine receptor agonists involve, at least in part, the activation of phosphatases.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Molecular and physiological effects of overexpressing striated muscle beta-tropomyosin in the adult murine heart.

Tropomyosins comprise a family of actin-binding proteins that are central to the control of calcium-regulated striated muscle contraction. To understand the functional role of tropomyosin isoform differences in cardiac muscle, we generated transgenic mice that overexpress striated muscle-specific beta-tropomyosin in the adult heart. Nine transgenic lines show a 150-fold increase in beta-tropomyosin mRNA expression in the heart, along with a 34-fold increase in the associated protein. This increase in beta-tropomyosin message and protein causes a concomitant decrease in the level of alpha-tropomyosin transcripts and their associated protein. There is a preferential formation of the alpha beta-heterodimer in the transgenic mouse myofibrils, and there are no detectable alterations in the expression of other contractile protein genes, including the endogenous beta-tropomyosin isoform. When expression from the beta-tropomyosin transgene is terminated, alpha-tropomyosin expression returns to normal levels. No structural changes were observed in these transgenic hearts nor in the associated sarcomeres. Interestingly, physiological analyses of these hearts using a work-performing model reveal a significant effect on diastolic function. As such, this study demonstrates that a coordinate regulatory mechanism exists between alpha- and beta-tropomyosin gene expression in the murine heart, which results in a functional correlation between alpha- and beta-tropomyosin isoform content and cardiac performance.

Animals↗
PubMed1995

Human heart-infiltrating T-cell clones from rheumatic heart disease patients recognize both streptococcal and cardiac proteins.

BACKGROUND: beta-Hemolytic streptococcal infection in developing countries still causes thousands of causes of rheumatic heart disease, demanding surgical valve correction. Antigenic mimicry between self and streptococcal components has been proposed as the triggering factor leading to autoimmunity in individuals with genetic susceptibility. Although heart streptococcal-M protein cross-reactive antibodies have been demonstrated, heart tissue damage seems to be T lymphocyte-dependent. We studied the infiltrating T lymphocytes in rheumatic heart lesions with the aim of understanding the role of cellular immune response at the site of the lesions. METHODS AND RESULTS: We obtained 107 T-cell clones from surgical fragments of cardiac tissue from four rheumatic heart disease patients. We tested their capacity to recognize streptococcal M protein-derived synthetic peptides and heart proteins. We found eight infiltrating T-cell clones from all four patients that simultaneously recognize streptococcal M and heart proteins. Among the M-protein sequences tested, only synthetic peptides corresponding to regions 1 through 25, 81 through 103, and 163 through 177 were simultaneously recognized with heart protein fractions. Interestingly, regions 81 through 103 and 163 through 177 have been known to bear heart cross-reactive epitopes at the antibody level. Five of these clones are CD4+, and one is CD8+. CONCLUSIONS: The presence of heart-M protein cross-reactive T-cell clones in rheumatic heart lesions suggests their direct involvement in the pathogenesis of this disease. The dissection of protective and pathogenic epitopes of streptococcal M protein is an important step in allowing the development of a safe anti-streptococcal synthetic vaccine.

Amino Acid Sequence↗
PubMed1995

[Surgical therapy of carcinoma of the thyroid gland].

BACKGROUND: Thyroid carcinoma comprises tumours with a wide spectrum of aggressiveness. The method of first choice is surgery, however, views on its extent and technique are frequently controversial. The objective of the present work was to demonstrate and justify the procedure used at the author's department in treatment of this tumour. METHODS AND RESULTS: During 1988-1992 a total of 919 patients with thyroid disease were operated. The female:male ratio was 4.13:1; a benign finding was confirmed in 76.4% and a malignant one in 23.6%. The female:male ratio in patients with a malignant findings was 3.24:1. Most frequently a papillary carcinoma was confirmed--in 59.9%, followed by follicular carcinoma in 23.11%, medullary carcinoma in 7.0%, Hürtle's carcinoma in 4.25%, anaplastic carcinoma in 1.42% and epidermoid carcinoma in 0.47%. Metastases in the thyroid were present in 0.94% and a myeloma or sarcoma both in 0.47%. In retrosternal goitres papillary carcinoma was most frequent (19 patients) followed by follicular (7 patients). As to surgical operations, total thyroidectomy was performed in 47.6%, total lobectomy in 20.3%, subtotal thyroidectomy in 15.1% and subtotal lobectomy in 2.4% of the operated patients. A palliative resection was made in 11.8% and lymphadenectomy in 2.8% patients with a malignant finding on the thyroid gland. Permanent complications (paresis of the recurrent nerve, hypoparathyroidism) occurred in 0.95% of the patients, temporary complications (abscess in the scar, transient hypoparathyroidism, oedema of the vocal cords) in 8.66% of the operations. None of the patients died. CONCLUSIONS: Surgical results and experience of the clinic for nuclear medicine support a radical approach to all types of thyroid carcinoma in adults as well as in adolescents.

Female↗
PubMed1995

Effects of the phosphatase inhibitor calyculin A on the phosphorylation of C-protein in mammalian ventricular cardiomyocytes.

The effects of inhibitors of protein phosphatase activity on C-protein phosphorylation were studied in preparations from mammalian ventricles. Calyculin A (CyA), an inhibitor of type 1 and 2A protein phosphatases, was studied. CyA concentration- and time-dependency increased the phosphorylation state of C-protein in isolated 32P-labelled guinea pig ventricular cardiomyocytes. C-protein was identified by its reaction with a polyclonal antibody and immunoprecipitation. It is concluded that C-protein in intact cardiomyocytes could be a substrate for type 1 and 2A protein phosphatases.

Animals↗
PubMed1995

Mechanisms of the contractile effects of flosequinoxan.

In guinea-pig papillary muscles the positive inotropic effect of flosequinoxan (BTS) starting at 100 mumol/l amounted to 287.6 +/- 34.2% at 300 mumol/l without any effects on time to peak tension (103.9 +/- 2%) and relaxation time (107.1 +/- 6.7% of predrug value, respectively). 10 mumol/l carbachol attenuated the positive inotropic effect of 300 mumol/l to 166.5 +/- 11.6% (n = 10). The phosphorylation state of the inhibitory subunit of troponin (TnI) and phospholamban (PLB) in [32P]-labeled guinea-pig ventricular myocytes was increased starting at 100 mumol/l amounting to 142.5 +/- 12.6% and 130.9 +/- 2.2% at 300 mumol/l, respectively (n = 5). Furthermore, BTS (300 mumol/l) decreased phosphorylase phosphatase activity by 23.1%. It is concluded that the contractile effects of BTS are accompanied by enhanced phosphorylation of regulatory proteins which could in part be due to inhibition of phosphorylase phosphatase activity.

Adenosine Triphosphatases↗
PubMed1995

[Requirements for a surgical documentation system and its realization].

Adequate documentation of all surgical procedures is now essential. High demands in terms of quality and quantity mean that computerized databases and evaluation procedures are required. In the Department of Abdominal and Transplantation Surgery within Hanover Medical School a standardized but individually adaptable documentation system has been greated using standard hardware and software. A hierarchical code system has been established for surgical procedures, and this also offers the options of automatic online coding and translation into the coding used in the International Classification of Procedures in Medicine. The advantages and limitations of this system are discussed.

Database Management Systems↗
PubMed1995

Stimulation of protein phosphatases as a mechanism of the muscarinic-receptor-mediated inhibition of cardiac L-type Ca2+ channels.

Acetylcholine decreases currents through cardiac L-type Ca2+ channels after stimulation with agents which elevate levels of cyclic adenosine monophosphate, such as isoproterenol, but there is still a controversy over the mechanisms of this muscarinic effect. We tested the hypothesis of whether, after isoproterenol stimulation, protein phosphatases are activated by acetylcholine. Whole-cell currents were recorded from guinea-pig ventricular myocytes. The effect of 10(-5) M acetylcholine on currents induced by 10(-8) M isoproterenol was studied in the absence or presence of protein phosphatase inhibitors. Three agents reduced the acetylcholine response: okadaic acid (3 or 9 x 10(-6) M) and cantharidin (3 x 10(-6) M) added to the pipette solution, and bath-applied fluoride (3 mM). In contrast, pipette application of other phosphatase inhibitors, namely the inhibitor PPI2 (1000 U/ml), ciclosporin (10(-5) M), or calyculin A (10(-6) M) did not significantly diminish the acetylcholine effect. Interestingly, there was no correlation between the effects of the compounds on basal Ca2+ current and their interference with the muscarinic response. An activation of type 2A phosphatases by acetylcholine would explain these findings. Indeed, okadaic acid is 3 orders of magnitude more potent in vitro in its inhibition of this isoform (purified from cardiac myocytes) than is calyculin A, while type-1 phosphatases are inhibited equally. The data support the attractive possibility that stimulation of protein phosphatases is part of the signal transduction cascade of Ca2+ channel inhibition by acetylcholine.

Acetylcholine↗