Biomedical subjects

J Neumann

Publications and source records attributed to J Neumann.

At least 73 records · Page 4Linked to original sources

PubMed1994

Biochemical and electrophysiological mechanisms of the positive inotropic effect of calyculin A, a protein phosphatase inhibitor.

Calyculin A (CyA; 1 microM) increased the force of contraction in isolated guinea pig papillary muscles to 144% of control without affecting contraction parameters. The effect of CyA on L-type calcium channels was assessed in cell-attached patches of guinea pig ventricular cardiomyocytes. Unitary Ba++ current recordings revealed that CyA at micromolar concentrations enhanced channel availability almost 2-fold, whereas the duration of individual openings and closures remained unchanged. In whole-cell recordings with Ca++ as the charge carrier, intracellular dialysis of 1 microM CyA enhanced peak current to a similar extent. In homogenates from guinea pig ventricles, 1 microM CyA completely inhibited phosphorylase phosphatase activity. In isolated [32P]-labeled guinea pig ventricular cardiomyocytes, 1 microM CyA increased the phosphorylation state of phospholamban (to 267% of control), that of the inhibitory subunit of troponin (to 182% of control) and those of various additional proteins. We conclude that the effects of CyA are likely to be mediated by increasing the phosphorylation state of several regulatory proteins.

Animals↗

PubMed1994

[Primary and secondary interventions--a concept in surgical documentation].

Nowadays systematic documentation of surgical procedures is absolutely necessary in all departments of surgery and will soon be required by law. Therefore code systems are essential. Amongst numerous systems the ICPM-GE classification has been chosen as basis. In the department for abdominal and transplantation surgery at Hanover Medical School the ICPM-GE classification has been extended by a concept of coding main and suboperations. This concept considers the fact that in an individual patient the surgical procedure may consist of different and standardized suboperations. This concept widens and simplifies the possibility of documentation considerably.

Cholecystectomy↗

PubMed1994

Effects of adenosine receptor and muscarinic cholinergic receptor agonists on cardiac protein phosphorylation. Influence of pertussis toxin.

In isolated 32P-labeled guinea pig ventricular cardiomyocytes phospholamban (PLB), myosin light chain 2 and the inhibitory subunit of troponin (Tnl) were identified by antibodies. In isolated 32P-labeled guinea pig ventricular cardiomyocytes isoproterenol (0.1 mumol/l) increased phosphorylation of PLB and of the inhibitory subunit of Tnl to 159 and 119% of control, respectively, without effect on the phosphorylation state of myosin light chain 2. Additionally applied carbachol or (-)-N6-phenylisopropyladenosine reduced phosphorylation of PLB and Tnl without reducing cyclic AMP content. After pretreatment of guinea pigs with pertussis toxin (18 micrograms/100 g b.wt.), carbachol or (-)-N6-phenylisopropyladenosine failed to reduce isoproterenol-stimulated phosphorylation of both PLB and Tnl. It is concluded that the reductions by carbachol and (-)-N6-phenylisopropyladenosine of isoproterenol-stimulated PLB phosphorylation and Tnl phosphorylation are pertussis toxin-sensitive.

Animals↗

PubMed1994

[Surgical treatment of large goiters extending into the retrosternal space].

The authors describe the characteristics of primary and secondary goitres reaching as far as the retrosternal space. 154 operations of retrosternal goitres during a five-year period account for 16.7% of all operations of the thyroid gland. The great majority (97.4%) of operations was made from a cervical approach. The authors express also their opinion on sternotomies in these operations; the reasons comprise also extensive goitres which cannot be removed across the upper thoracic aperture where the orientation on the position of major blood vessels is poor, when local invasion of the tumour into the neighbouring tissues is suspected, in some reoperations or when it is necessary to explore the mediastinum to differentiate other lesions. The very rare thoracotomic approach is reserved for large retrosternal goitres located in the posterior mediastinum.

Female↗

PubMed1994

[Elective total hip prosthesis management in patients over 80 years of age].

Ninety-five primary elective total hip prosthesis procedures were carried out in patients over 80 years of age (average 82.9 years). The results were studied retrospectively to determine the individual risk-advantage relationship and the general cost-advantage relationship taking the social aspects into consideration. Fractures and emergency procedures were excluded. Ninety-three percent of the patients had preexisting general illnesses. There were no local or general complications in the peri- and postoperative courses of 86% and 85%, respectively. The general complications included urological (6%), cardiovascular (5%) and abdominal (3%) problems. The only death (myocardial infarction) took place 4 weeks after the operation during the rehabilitation phase. The average hospital stay was 23.3 days; 20% of the patients were then able to return home, while 80% were sent to another institution for further care (geriatric department, rehabilitation), where the average stay was 36.7 days. The total inpatient treatment period was on average 52.3 days. At the time of the last follow-up, an average of 4.6 years postoperatively, 75% of the patients were alive with an average age of 87.4 years. Seventy-nine percent were still able to live alone and look after themselves; 81% were independent or only partially dependent (living in a retirement home). Ninety-three percent had no pain or only mild pain. If indicated, the operation risk factor for total hip prostheses in patients over 80 years is obviously low, and the results are good. This operation permits the patient to have many years free of pain, to remain independent, and to achieve a clearly higher quality of life. In this way one can also save on the high cost of many years of nursing care.

Activities of Daily Living↗

PubMed1993

In vivo analysis of the murine beta-myosin heavy chain gene promoter.

The 5' upstream region of the murine beta-myosin heavy chain (MHC) gene has been isolated and tested for its ability to drive gene expression in transgenic mice. Three classes of transgenic mice were generated. The constructs contained approximately 5000, 2500, and 600 base pairs of beta-MHC upstream sequence fused to the chloramphenicol acetyltransferase gene and were termed beta 5, beta 2.5, and beta .6, respectively. Muscle-specific expression was observed with all three constructs. However, only the beta 5 lines directed high levels of muscle-specific transgene expression in both pre- and postbirth mice. Expression driven by the two shorter constructs was two to three orders of magnitude lower when the chloramphenicol acetyltransferase specific activities were compared. These data suggest that a distal-positive element directs high levels of gene expression in the ventricle and in slow skeletal muscles. Analyses of transgene expression during heart maturation revealed that some of the beta 5 lines were not able to respond in an appropriate manner to developmental transcriptional cues. Unlike the endogenous beta-MHC gene, which is down regulated in the ventricles around the time of birth, reporter gene expression in the majority of the lines generated was not shut off in the ventricles of the adult animals. These data indicate that high levels of muscle-specific beta-MHC gene expression are dependent upon the combinatorial interactions of a number of sequence elements that are distributed over a large region of the gene's upstream sequence.

Aging↗

PubMed1993

Transgenic analysis of the thyroid-responsive elements in the alpha-cardiac myosin heavy chain gene promoter.

The role of two putative, cis-acting thyroid hormone-responsive elements, TRE1 and TRE2, located at -129 to -149 and -102 to -120, respectively, on the murine alpha-myosin heavy chain (MHC) gene, has been investigated in transgenic mice. These motifs are present in a 4.5-kilobase fragment lying upstream of the transcriptional start site of the mouse alpha-MHC gene: this fragment directs appropriate expression of a reporter gene in transgenic mice (Subramaniam, A., Jones, W. K., Gulick, J., Wert, S., Neumann, J., and Robbins, J. (1991) J. Biol. Chem. 266, 24613-24620). Here, we independently mutate the TRE1 and TRE2 elements by base substitution. The mice were analyzed for transgene expression in different muscle and non-muscle tissues including the atria and ventricles. Normal levels of transgene expression were observed in euthyroid mice carrying a mutation in TRE1. In contrast to these results, mice in which TRE2 was mutated showed reduced levels of CAT activity in both the atria and ventricles, suggesting a previously undefined role for this element in the constitutive up-regulation of the alpha-MHC gene. In hypothyroid mice carrying either of these mutations, the complete cessation of ventricular expression of the chloramphenicol acetyltransferase transcripts that takes place in the alpha-5.5 (wild type) animals did not occur.

Animals↗

PubMed1993

Pertussis toxin unmasks stimulatory myocardial A2-adenosine receptors on ventricular cardiomyocytes.

Pertussis toxin-pretreatment abolished the contractility- and cAMP-decreasing effects of the A1-adenosine receptor agonist (-)-N6-phenylisopropyladenosine (R-PIA) in the presence of isoprenaline in isolated ventricular cardiomyocytes from guinea-pigs, indicating that these stimulatory effects of A1-adenosine receptors are mediated via pertussis toxin-sensitive G-proteins. Furthermore, the decrease in contractile response by the A1/A2-adenosine receptor agonist 5'-N-ethylcarboxamidadenosine (NECA) was abolished. Moreover, NECA increased cAMP content in pertussis toxin-pretreated cells. Thus, pertussis toxin unmasked cAMP-augmenting effects of NECA, indicating that NECA can stimulate A2-adenosine receptors on cardiomyocytes. Thereby, the present study provides evidence that besides cAMP- and contractility-decreasing A1-adenosine receptors, cAMP-increasing A2-adenosine receptors coexist on ventricular cardiomyocytes, which do not influence contractile response.

Adenosine↗

PubMed1993

Mechanisms of beta-adrenergic stimulation of cardiac Ca2+ channels revealed by discrete-time Markov analysis of slow gating.

Individual cardiac Ca2+ channels cycle slowly between a mode of gating in which the channel is available to open, and one in which the channel remains silent. The regulation of this multisecond cycling process by isoproterenol was investigated by single-channel recording and the development of a discrete-time Markov model that describes the slow switching among modes in terms of (de) phosphorylation reactions. The results provide evidence that isoproterenol increases Ca2+ channel activity by a reciprocal regulatory mechanism: not only is the phosphorylation rate of the channel increased, but also the dephosphorylation rate decreased. The discrete-time Markov formalism should prove useful as a general tool for understanding the mode switching demonstrated by a number of ionic channels.

1-Methyl-3-isobutylxanthine↗

PubMed1993

Evidence for physiological functions of protein phosphatases in the heart: evaluation with okadaic acid.

Okadaic acid exerts a positive inotropic effect in cardiac preparations. We studied whether the positive inotropic effect of okadaic acid in cardiac preparations could be due to phosphatase inhibition and whether this inhibition affects the phosphorylation of cardiac proteins. In papillary muscles from guinea pigs, 30 microM okadaic acid increased force of contraction to 175% of predrug value. In isolated guinea pig ventricular cardiomyocytes, okadaic acid augmented single Ca(2+)-channel currents by enhancing channel availability. In homogenates from ventricles, 1 microM okadaic acid completely inhibited phosphorylase a phosphatase activity. In isolated 32P-labeled ventricular cardiomyocytes, 30 microM okadaic acid increased phosphorylation of phospholamban (PLB) and troponin inhibitor (TnI) to 325 and 284% of control, respectively. Furthermore, 30 microM okadaic acid increased phosphorylation of a hitherto unknown 23-kDa protein to 352% of control. It is concluded that the effects of okadaic acid could be mediated by increasing the phosphorylation state of several proteins including PLB, a 23-kDa protein, and TnI.

Animals↗

PubMed1993

A1-adenosine receptor-mediated inhibition of isoproterenol-stimulated protein phosphorylation in ventricular myocytes. Evidence against a cAMP-dependent effect.

cAMP content and protein phosphorylation were determined in unlabeled and 32P-labeled guinea pig ventricular myocytes. Isoproterenol (10 nM, 37 degrees C, 10 seconds) increased cAMP content (236%) and phospholamban (265%) and troponin I (135%) phosphorylation in ventricular myocytes. When isoproterenol (0-300 nM) and the A1-adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA, 1 microM) or the A1- and A2-adenosine receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA, 1 microM) were administered simultaneously, both adenosine receptor agonists attenuated phospholamban phosphorylation to approximately the same extent (40%). The EC50 value for isoproterenol to phosphorylate phospholamban was 8 +/- 1 nM (n = 3), which increased to 31 +/- 4 nM (n = 3) in the presence of PIA or NECA. IC50 values for PIA or NECA to decrease the phosphorylation of phospholamban were 30 or 32 nM in 10 nM isoproterenol-stimulated cells and 80 or 85 nM in 30 nM isoproterenol-stimulated cells. Both adenosine receptor agonists failed to inhibit the phosphorylation of troponin I. However, acetylcholine (2 microM) in the presence of 10 nM isoproterenol inhibited phosphorylation of phospholamban as well as troponin I in ventricular cells. These effects were antagonized by 10 microM atropine. The effects of PIA and NECA on phosphorylation were antagonized by the A1-selective adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (1 microM) but not by the A2-selective adenosine receptor antagonist 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4,triazolo(1,5-c)quinazolin -5-imine (1 microM). PIA and NECA did not reduce cAMP levels in isoproterenol-stimulated cells. We conclude that phospholamban phosphorylation was inhibited by A1-adenosine receptor activation and that these effects on phospholamban phosphorylation cannot be explained by a reduction in cAMP levels.

Acetylcholine↗

PubMed1993

[A multidisciplinary approach in the treatment of endocrine orbitopathy].

Despite the knowledge of immunological mechanisms of Graves-Basedow's disease the pathogenesis of endocrine orbitopathy remains obscure. Apart from the most frequent association with GB disease it may occur also in patients with primary hypothyroidism, Hashimoto's thyroiditis or in rare instances in euthyroid patients not suffering from thyroid disease. Endocrine orbitopathy is a typical example of a disease with a multidisciplinary approach to its diagnosis and treatment. In the submitted paper the authors demonstrate the collaboration of four clinics of the Faculty Hospital when dealing with this problem. Complete or almost complete removal of the thyroid gland leads within 1-4 years to regression of the protrusion of the bulbus by 1 mm. In combination with decompression of the orbit by a modification of Ogura's and Walsh's method improvement of visual acuity by 50% was achieved and the mean value of the exophthalmus diminished by 3.5 mm.

Exophthalmos↗

PubMed1993

Comparison of adenosine and muscarinic receptor-mediated effects on protein phosphatase inhibitor-1 activity in the heart.

Langendorff-perfused guinea pig ventricles were used to examine the effects of the adenosine agonists, (-)-N-6-phenylisopropyl-adenosine (PIA) and 5'-N-ethylcarboxamidoadenosine and the muscarinic cholinergic agonist, acetylcholine, on the rate of tension development, protein phosphatase inhibitor-1 (PPI-1) activity, and cyclic AMP-dependent protein kinase (PKA) activity ratio. Isoproterenol (10 nM) and forskolin (1 microM) stimulated rate of tension development, PKA activity ratio and PPI-1 activity each approximately 2-fold. Acetylcholine (1 microM) by itself was not effective, but when administered with isoproterenol for forskolin reduced the rate of tension development and PPI-1 activity without decreasing PKA activity ratio. Similarly, both PIA and 5'-N-ethylcarboxamidoadenosine alone were ineffective, but when simultaneously applied with isoproterenol attenuated the isoproterenol-stimulated rate of tension development and PPI-1 activity. PIA reduced PKA activity ratio, whereas 5'-N-ethylcarboxyamidoadenosine failed to do so. However, the effect of PIA on PKA activity ratio was smaller than those seen on rate of tension development and PPI-1 activity. Hence, the present data do not support a cyclic AMP-dependent regulation of PPI-1 activity by adenosine and muscarinic agonists. It is tempting to speculate that adenosine and muscarinic agonists reduce PPI-1 activity by a cyclic AMP-independent mechanism.

Acetylcholine↗

PubMed1993

[The significance of the ultrasound examination in surgery of the thyroid gland].

The authors emphasize the importance of ultrasonographic examination of the thyroid gland for the diagnosis of disease as well as for planning and implementation of the operation. They evaluate the importance of 154 sonographic examinations which were made during the last three years in 545 operations of the thyroid. For the surgeon anatomical parameters of the pathological tissue are important with special emphasis on the relation with surrounding tissues and affection of the lymphatic system. The examination is irreplaceable, in particular in reoperations of the thyroid gland and nodular syndrome.

Humans↗

PubMed1992

Phosphodiesterase inhibition and positive inotropy in failing human myocardium.

Positive inotropic effects of phosphodiesterase inhibitors like 3-isobutyl-1-methylxanthine (IBMX), pimobendan, adibendan, milrinone, saterinone, and enoximone are greatly diminished in isolated heart muscle preparations from human failing myocardium as compared to nonfailing myocardium. This is accompanied by a reduced increase in cAMP content in intact isometrically contracting human trabeculae. With anion exchange chromatography four peaks of phosphodiesterase activities (PDE I-IV) could be separated from both nonfailing and failing human myocardium. Substrate specificity, Km, and Vmax were similar in nonfailing and failing myocardium. Furthermore, the PDE inhibitors investigated exhibited similar IC50-values in both tissues, indicating that the sensitivity of the enzymes from nonfailing and failing tissue was unchanged. Thus, changes in PDE are probably not responsible for the reduced positive inotropic and cAMP-increasing effects of PDE inhibitors in human failing heart muscle preparations. Instead, an increase in signal transducing inhibitory G-proteins may keep the adenylyl cyclase at reduced activity, resulting in an attenuated formation of cAMP, even in the presence of PDE inhibitors.

Benzimidazoles↗

PubMed1992

Reduced alpha 1- and beta 2-adrenoceptor-mediated positive inotropic effects in human end-stage heart failure.

1. alpha 1-Adrenoceptor (phenylephrine in the presence of propranolol) and beta 2-adrenoceptor (fenoterol)-mediated positive inotropic effects were investigated in human ventricular preparations isolated from five non-failing (prospective organ donors) and from eight explanted failing hearts with end-stage idiopathic dilative cardiomyopathy (NYHA IV). 2. For comparison, the nonselective beta-adrenoceptor agonist isoprenaline, the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), the cardiac glycoside dihydroouabain, and calcium were studied. 3. Furthermore, the influence of IBMX on adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE activity as well as total beta-adrenoceptor density, beta 1- and beta 2-adrenoceptor subtype distribution, and alpha 1-adrenoceptor density were compared in nonfailing and failing human heart preparations. The radioligands (-)-[125I]-iodocyanopindolol for beta-adrenoceptor binding and [3H]-prazosin for alpha 1-adrenoceptor binding were used. 4. The inotropic responses to calcium and dihydroouabain in failing human hearts were unchanged, whereas the maximal alpha 1- and beta 2-adrenoceptor-mediated positive inotropic effects were greatly reduced. The inotropic effects of the other cyclic AMP increasing compounds, i.e. isoprenaline and IBMX, were also reduced to about 60% of the effects observed in nonfailing controls. The potency of these compounds was decreased by factors 4-10. 5. The basal PDE activity and the PDE inhibition by IBMX were similar in nonfailing and failing preparations. 6. The total beta-adrenoceptor density in nonfailing hearts was about 70 fmol mg-1 protein. In failing hearts the total number of beta-adrenoceptors was markedly reduced by about 60%. The betal/beta2-adrenoceptor ratio was shifted from about 80/20% in nonfailing to approximately 60/40% in failing hearts which was due to a selective reduction of beta1-adrenoceptors. The beta2-adrenoceptor population remaining unchanged. alpha-Adrenoceptor density was increased from about 4 fmol mg-' protein in nonfailing to 10 fmol mgprotein in failing hearts.7. Changes in PDE activity and adrenoceptor downregulation cannot completely explain the reduced positive inotropic effects of alpha 1- and beta 2-adrenoceptor agonists in failing human hearts. This supports the hypothesis that impairment of other processes such as the coupling between receptor and effector system, i.e. the respective G-proteins, are equally important in end-stage heart failure.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1992

Regular physical exercise and low-fat diet. Effects on progression of coronary artery disease.

BACKGROUND: Significant regression of coronary and femoral atherosclerotic lesions has been documented by angiographic studies using aggressive lipid-lowering treatment. This study tested the applicability and effects of intensive physical exercise and low-fat diet on coronary morphology and myocardial perfusion in nonselected patients with stable angina pectoris. METHODS AND RESULTS: Patients were recruited after routine coronary angiography for stable angina pectoris; they were randomized to an intervention group (n = 56) and a control group on "usual care" (n = 57). Treatment comprised intensive physical exercise in group training sessions (minimum, 2 hr/wk), daily home exercise periods (20 min/d), and low-fat, low-cholesterol diet (American Heart Association recommendation, phase 3). No lipid-lowering agents were prescribed. After 12 months of participation, repeat coronary angiography was performed; relative and minimal diameter reductions of coronary lesions were measured by digital image processing. Change in myocardial perfusion was assessed by 201Tl scintigraphy. In patients participating in the intervention group, body weight decreased by 5% (p less than 0.001), total cholesterol by 10% (p less than 0.001), and triglycerides by 24% (p less than 0.001); high density lipoproteins increased by 3% (p = NS). Physical work capacity improved by 23% (p less than 0.0001), and myocardial oxygen consumption, as estimated from maximal rate-pressure product, by 10% (p less than 0.05). Stress-induced myocardial ischemia decreased concurrently, indicating improvement of myocardial perfusion. Based on minimal lesion diameter, progression of coronary lesions was noted in nine patients (23%), no change in 18 patients (45%), and regression in 13 patients (32%). In the control group, metabolic and hemodynamic variables remained essentially unchanged, whereas progression of coronary lesions was noted in 25 patients (48%), no change in 18 patients (35%), and regression in nine patients (17%). These changes were significantly different from the intervention group (p less than 0.05). CONCLUSIONS: In patients participating in regular physical exercise and low-fat diet, coronary artery disease progresses at a slower pace compared with a control group on usual care.

Adult↗

PubMed1992

Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts.

The effects of enoximone (MDL 17043, Perfan, CAS 77671-31-9) on the activities of the phosphodiesterase (PDE) isoenzymes I-IV and on force of contraction were investigated in ventricular preparations isolated from failing (end-stage myocardial failure, NYHA IV) and non-failing human hearts. In both tissues four PDE isoenzymes (PDE I-IV) with similar properties were separated by DEAE-sepharose chromatography. The effects of enoximone on PDE I-IV activities did not differ between non-failing and failing human hearts. As compared to PDE I (IC50 2100 mumol/l) and II (IC50 2900 mumol/l) enoximone is a selective PDE III (cGMP-inhibited PDE, IC50 5.9 mumol/l) and PDE IV (cGMP-insensitive PDE, IC50 21.1 mumol/l) inhibitor. Milrinone, 3-isobutyl-1-methylxanthine (IBMX) and UD-CG 212 Cl, a derivative of pimobendan, were studied in the failing heart for comparison. Milrinone inhibited PDE I-IV activities similar to enoximone, revealing IC50 values for inhibition of PDE III and IV (1.2 and 3.3 mumol/l) which were about two orders of magnitude lower than that of PDE I and II (173 and 306 mumol/l). UD-CG 212 Cl was the most potent (IC50 0.05 mumol/l) and most selective PDE III inhibitor tested (IC50 for PDE I, II and IV were 175, 181 and 40.8 mumol/l, resp.), whereas IBMX inhibited PDE I-IV nonselectively (IC50 15.3, 26.2, 5.6, 5.8 mumol/l, respectively). In trabeculae carneae from nonfailing and failing human hearts enoximone increased force of contraction only marginally by 18.0 +/- 9.1% (n = 8) and 24.5 +/- 8.7% (n = 9) of the predrug value.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗