[Unusual cause of Staphylococcus aureus septicemia in a 79-year-old male patient]. / Ungewöhnliche Ursache einer Staphylococcus-aureus-Septikämie bei einem 79-jährigen Patienten.

High grade fever in the context of Staphylococcus aureus bacteremia led to hospital admission of a 79 year old male patient. A covered perforation of the ascending aorta resulted in the formation of a pseudoaneurysm which was complicated by superinfection caused by hematogenic spread of Staphylococcus aureus. The infected pseudoaneurysm found per continuitatem contact to the pericardium and resulted in bacterial pericarditis. Antibiotic pretreatment was followed by operation with a complex procedure including resection of pseudoaneurysm and suture closure of the perforation site.

Chemotactic activity of serum obtained from patients with idiopathic dilated cardiomyopathy.

Elevated circulating levels of alpha- and beta-chemokines in heart failure have been reported. The objective of this study was to investigate the interrelation of chemotactic activity of serum and circulating chemokine levels in patients suffering from idiopathic dilated cardiomyopathy (IDCM). Chemokine serum levels (MCP-1, MIP1-alpha, RANTES, IL-8 and TNF-alpha) were determined in patients with IDCM (n = 10), patients with coronary artery disease with normal (CAD-1; n = 10) or depressed (CAD-2; n = 10) left ventricular function and healthy controls (n = 10). The chemotactic effect of sera obtained from these groups was measured using an in vitro chemotaxis assay. Sera obtained from IDCM (5475 +/- 681 cells) showed the highest chemotactic activity when compared to controls (1850 +/- 215 cells), CAD-1 (3325 +/- 275 cells) and CAD-2 (2800 +/- 275 cells, P < 0.05) associated with significantly higher circulating MCP-1 levels. Sera obtained from IDCM patients show a high chemotactic activity associated with significantly elevated circulating MCP-1.

Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin.

OBJECTIVE: Chronic elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. This is followed by the appearance of macrophages and type I collagen-producing, fibroblast-like cells that precede the accumulation of fibrous tissue at these sites. Whether this perivascular and interstitial fibrosis is a direct effect of AngII on collagen turnover of these cells or an indirect response mediated by nitric oxide, prostaglandins and/or bradykinin released in response to AngII, is uncertain. METHODS: We measured perivascular and interstitial fibrosis (picrosirius-stained tissue) in response to 14-day infusion of AngII (150 ng/kg/min, s.c.) in male Sprague-Dawley rats. Treated animals were compared to untreated controls and to groups receiving AngII together with either an NO-synthase inhibitor [NG-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg/day in drinking water], a cyclo-oxygenase inhibitor (indomethacin, 2 mg/kg/day in drinking water), or a bradykinin B2 receptor antagonist (Hoe140, 115 ng/kg/min, s.c.). RESULTS: When left and right ventricles of treated rats were compared to untreated controls, AngII led to a respective 68 and 48% increase in perivascular collagen volume fraction (PCVF) and a 54 and 22% increase in interstitial collagen volume fraction (ICVF). Co-administration of AngII + L-NAME did not attenuate either PCVF or ICVF while indomethacin significantly attenuated PCVF by 37 and 33% of left and right ventricle, respectively, but did not alter ICVF in either ventricle when compared to AngII-treated animals. Co-administration of AngII + Hoe140 completely prevented perivascular and interstitial collagen accumulation with the extent of perivascular fibrosis comparable to untreated controls. CONCLUSION: The perivascular and interstitial fibrosis of the rat right and left ventricles seen in association with the exogenous administration of AngII is mediated by the release of bradykinin and prostaglandins, and therefore is an indirect response to elevated circulating AngII.

Angiotensin-II-induced increase in transcoronary protein clearance: role of hypertension vs. nitric oxide or cyclo-oxygenase products.

Elevations in plasma angiotensin II (AngII) are associated with an efflux of plasma macromolecules into the perivascular and contiguous interstitial space. Whether this exudative response is related to associated hypertension or another effect of AngII is uncertain. We therefore monitored plasma and cardiac lymph total protein, albumin and fibronectin and calculated transvascular clearances for total protein (TVPC) and albumin (TVAC) and lymph fibronectin transport (LFT) every 30 min in open-chested, instrumented dogs. After baseline observations were obtained over 30 min, pressor (250 ng.kg.min-1) or nonpressor (11 ng.kg.min-1) doses of AngII were given intravenously for 90 min. Saline-treated, instrumented dogs served as controls. To address a potential secondary effect of AngII on vascular protein clearance, we monitored lymph prostaglandin E2 and cGMP (a marker of released nitric oxide, NO). At > or = 30 min, each dose of AngII was associated with a significant (P < or = 0.05) and comparable increase in TVPC, TVAC and LFT over baseline, indicating that increase in protein clearance was not related to elevated arterial pressure. Lymph cGMP rose significantly (P < or = 0.05) at 30 min for each dose of AngII and remained elevated thereafter. Lymph PGE2 was increased at > or = 60 min (P < or = 0.05) but only with the pressor dose. To determine the contribution of NO and PGE2 on AngII-induced transcoronary protein clearance, each dose of AngII was accompanied by co-administration of either the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), or the cyclo-oxygenase inhibitor, indomethacin. L-NAME completely inhibited the release of cGMP and the increase in protein clearance was not seen. Indomethacin suppressed the release of PGE2, but did not prevent the increase in protein clearance. Thus, AngII-induced increase in transcoronary protein clearance is not related to arterial hypertension or the release of PGE2, but instead appears to be mediated by NO release.

Differential inhibition of coumarin 7-hydroxylase activity in mouse and human liver microsomes.

Coumarin is 7-hydroxylated by the P450 isoform Cyp2a-5 in mice and CYP2A6 in humans. Various drugs, endogenous substances, plant substances and carcinogens, altogether about 90 chemicals, were evaluated as possible inhibitors of coumarin 7-hydroxylase (COH) activity in mouse microsomes. The effects of selected compounds on COH activity in human liver microsomes were also tested. The furanocoumarin derivatives methoxsalen (8-methoxypsoralen) and psoralen proved to be the most potent inhibitors of mouse COH activity (IC50 values 1.0 and 3.1 microM, respectively). The furanocoumarins bergapten (5-methoxypsoralen), isopimpinellin (5,8-dimethoxypsoralen), imperatorin and sphondin also effectively inhibited mouse COH activity (IC50 values 19-40 microM). Methoxsalen, isopimpinellin and metyrapone were also inhibitors in mice in vivo. Methoxsalen was a potent inhibitor of COH activity also in human liver microsomes, (IC50 value 5.4 microM), whereas bergapten, isopimpinellin and imperatorin had no effect. The imidazole antimycotic miconazole was a potent but non-specific inhibitor of COH activity. Several known substrates and inhibitors of members in the CYP1A, CYP2B, CYP2C, CYP2D and CYP3A subfamilies were poor inhibitors of COH activity. These results suggest that (i) the coumarin-type compounds in particular interact with the active sites of Cyp2a-5 and CYP2A6, and (ii) the active sites of Cyp2a-5 and CYP2A6 are structurally different, since a number of compounds inhibited mouse, but not human COH activity.

Immunohistochemical properties of dipyrone-induced cytochromes P450 in rats.

1. Rat hepatic cytochrome P450s induced by dipyrone were studied enzymatically, immunochemically and immunohistochemically. 2. Dipyrone administered to male Wistar rats increased pentoxyresorufin O-depentylation (PROD), ethoxyresorufin O-deethylation (EROD) and 7-ethoxycoumarin O-deethylation (ECOD) activities up to 44-, 1.9-, and 2.6-fold, respectively. Aryl hydrocarbon hydroxylase (AHH) activity was not affected. 3. Immunoinhibition with the monoclonal antibody (Mab) 2-66-3 (to CYP2B1/2) markedly decreased PROD and EROD activities, but not AHH activity. The Mab 1-7-1 (to CYP1A1/2) was without effect. 4. Histochemically, the Mab 2-66-3 gave a strong and uniform staining in livers from dipyrone-treated rats, whereas the Mab 1-7-1 gave a positive reaction in a narrow perivenous strip. 5. The induction pattern as well as inhibition by the Mabs convincingly demonstrate the predominant production of CYP2B1/2 in the induction spectrum of dipyrone. The increase in enzyme activities other than PROD may be due to the overlapping substrate specificity of CYP2B1/2 enzymes. The immunohistochemical analysis also indicated the participation of CYP1A1/2.

Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation.

The objective of this study was to investigate in a twoway randomized crossover whether repeated uptake of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h enhances bioavailability of a nifedipine (1) slow release formulation (20 mg) in ten healthy volunteers. Grapefruit juice increased the AUC and cmax of 1 statistically significantly by 103 (SD 73, range 48 to 265)% and 94 (SD 83, range -23 to 259)%, respectively. AUC of dehydronifedipine (2) was also higher during grapefruit phase, but to a lesser extent (mean increase 66, SD 106, range -30 to 236)%. Half lives of neither 1 nor 2 were altered by grapefruit juice. Because 2/1-ratio was not lowered by grapefruit juice in comparison to control, a selective inhibition of cytochrome P450 3A based on the presented in vivo data is not very likely. In the light of other reports concerning grapefruit juice induced increase in bioavailability our data contradict the assumption of a selective inhibition of only one cytochrome P450 subfamily. The observed effect could be clinically significant, especially if other factors affecting the elimination of 1 occur.

Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects.

The objective of the presented two-way randomized crossover study was to investigate whether repeated doses of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h) enhanced bioavailability of diltiazem (120 mg, orally) in nine healthy male subjects. Grapefruit juice did not alter AUC or cmax of diltiazem, whereas the half life experienced a slight, but statistically significant, increase (4.1 +/- = 1.2 vs 5.1 +/- 0.7 h). The N-demethyldiltiazem/diltiazem and deacetyldiltiazem/diltiazem ratios were not affected by grapefruit juice intake, which indicates that these metabolic pathways are not inhibited. Whereas bioavailability of some calcium channel antagonists of the dihydropyridine type metabolized via the same cytochrome P450 has been shown to be dramatically increased by grapefruit juice intake, the bioavailability of the benzothiazepine calcium channel antagonist diltiazem remained unchanged. This suggests that factors other than biotransformation may contribute to the clear effect of grapefruit juice on the bioavailability of those substances.

A common variant of the angiotensinogen gene and the risk of coronary artery disease in a German population.

The thymidine to cytosine transition at position 704 in exon 2 of the angiotensinogen gene leads to the amino acid substitution of threonine for methionine (T235 variant) and is responsible for elevated plasma levels of angiotensinogen. To examine the influence of T235 on the risk of coronary artery disease (CAD) we genotyped 184 CAD patients, 77 controls in whom CAD was excluded angiographically, and 155 healthy controls without signs of CAD by polymerase chain amplification and restriction enzyme digestion. Allele frequencies for A (wildtype) and a (mutant allele) in the total study population were 0.538 and 0.462, 0.536 and 0.464 in the healthy controls, and 0.481 and 0.519 in patients with excluded CAD, respectively. The allele frequencies and the genotype distribution in these groups did not show a significant difference. In conclusion, we did not observe an association between the T235 variant of the angiotensinogen gene and the risk of CAD.

Pharmacokinetic interactions of nifedipine and quinidine.

Several clinical investigations have been published regarding the interaction of nifedipine and quinidine. The results of these studies are contradictory. In vitro studies indicate that the 3-hydroxylation and N-oxigenation of quinidine appear to involve the P4503A4 family, a form of cytochrome that predominantly catalyzes the aromatization of nifedipine, too. The aim of our study was to investigate the effect of oral intake of 200 mg quinidine on the kinetics of 20 mg nifedipine as a retarded formulation and vice versa. Twelve healthy male volunteers between 18 and 40 years were treated. Each subject was studied on three occasions each separated by a one week washout period. Drug administration consisted of one oral dose of nifedipine (Adalat retard 20 mg), one oral dose of quinidine (Chinidin sulfuricum "Buchler" 200 mg) or a combination of both (20 mg nifedipine and 200 mg quinidine) in a randomised 3 way crossover. Administration of the test drugs in combination slightly increased the bioavailability of both--nifedipine [N] to 18% and quinidine [Q] to 16%--and decreased the clearance of both drugs. The results were not statistically significant. Based on our data, the combination of nifedipine and quinidine seems to lack a clinically relevant interaction.

[Clinical picture and differential diagnosis of cardiomyopathy and myocarditis]. / Klinisches Bild und Differentialdiagnose von Kardiomyopathie und Myokarditis.

The main feature of idiopathic dilated cardiomyopathy is the dilation and impaired contractility of the left ventricle or both ventricles. The clinical picture with forward and backward failure is based on the pump impairment of the left ventricle. However, the clinical presentation of patients with dilated cardiomyopathy is indistinguishable from any other secondary form of heart failure. The symptoms of myocarditis are also often determined by the degree of left ventricular dysfunction and--apart from perimyocarditis-associated precordial discomfort--therefore also often indistinguishable from dilated cardiomyopathy. The differentiation of dilated cardiomyopathy from other myocardial diseases by noninvasive methods is insufficient. Without invasive tests about 1/3 of the patients will be diagnosed incorrectly. Therefore, invasive diagnostics including coronary angiography are necessary to differentiate dilated cardiomyopathy from other diseases, especially coronary artery disease. Standard laboratory findings and cytokine serum concentrations (e.g. TNF-alpha) are not suitable to differentiate dilated cardiomyopathy and myocarditis and endomyocardial biopsy is indicated. Endomyocardial biopsies have to undergo evaluation by standard histology and immunohistology, and should be tested for the persistence of infectious agents. According to cardiac catheterization and evaluation of the endomyocardial biopsy idiopathic left ventricular dysfunction can be further stratified using the criterion of a myocardial virus persistence and the presence/absence of inflammatory infiltrates. Idiopathic dilated cardiomyopathy (approximately 70 to 75%), virus-associated dilated cardiomyopathy (approximately 20 to 25%), myocarditis (approximately 7%) and autoimmune myocarditis (approximately 3%) are the 4 possible resulting forms of idiopathic left ventricular dysfunction. Beside conventional medical therapy there are new therapeutic concepts e.g. using interferon for enterovirus-positive patients and immunosuppression for autoimmune, virus-negative patients with a cellular infiltrate.

[Renal manifestations of light chain associated diseases - epidemiology and prognosis]. / Renale Manifestationen von Leichtkettenerkrankungen - Epidemiologie und Prognose.

BACKGROUND: An impaired renal function in light chain associated disorders may be caused by myeloma cast nephropathy (MCN) but also by AL-amyloidosis (AL-A) and monoclonal immundeposition disease (MIDD). PATIENTS AND METHODS: In a monocentric, retrospective analysis, patients suffering from multiple myeloma (MM) (n = 392) requiring medical therapy, AL-A (n = 53) or MIDD (n = 12) diagnosed between 1996 and 2008 were evaluated for renal insufficiency. The different patient cohorts were compared in terms of their clinical course and outcome. RESULTS: Renal insufficiency in MM-, AL-A- or MIDD-patients at the time of diagnosis was found in 45,5 % of the patients. MCN, AL-A and MIDD were found in 68, 25 and 6 %, respectively. Dialysis dependency was seen in 17 % of MCN, in 8 % of AL-A and in 50 % of MIDD patients. Signs of hypervolemia were the leading symptoms in MIDD/AL-A. The time between the occurence of first symptoms and diagnosis was as long as 52 weeks in patients with AL-A. Patients with renal involvement showed a reduced median survival of 17 compared with 77 months in patients with a normal renal function. Median survival was only 12 months in AL-A compared to 21 months in MCN. Stabilization of renal function after chemotherapy occurred only in MCN. Multivariate Cox regression analysis showed impaired renal function as independent risk factor (Hazard-Ratio 2,88 [2,06-4,0]. In terms of survival and kidney function, autologous stem cell transplantation (ASCT) was beneficial for patients with renal involvement. CONCLUSION: Renal insufficiency is an independent risk factor in MM, AL-A and MIDD. Specific therapy, especially ASCT may improve prognosis in patients with renal insufficiency and could stabilize renal function in MCN-patients.

Apoptosis in patients with dilated cardiomyopathy and diabetes: a feature of diabetic cardiomyopathy?

BACKGROUND: Dilated cardiomyopathy (DCM) has been suggested to be a consequence of a prior viral infection leading to a chronic inflammatory and immunological reaction that leads to a structural and functional deterioration of the heart. Nevertheless, the results of present studies are conflicting, regarding the natural course of heart diseases associated with detection of viral genome and inflammation. On the other hand, diabetes mellitus (DM) is the leading endocrine disorder worldwide and sufficient to induce a cardiomyopathy. It is not known whether DM contributes to the clinical picture of cardiomyopathy associated with the presence of viral genome or inflammatory cells in the myocardium. Therefore, the present study was undertaken to compare histological, immunohistochemical, biochemical, and functional data as well as the outcome of patients presenting with DCM and positive for DM with patients negative for DM to evaluate for a diabetic contribution in the course of the disease. METHODS: A total of 216 patients were biopsied between January 1998 and April 2003. From 197 patients diagnosed as having DCM, we were able to complete data set regarding the presence of DM in 108 patients, 20 patients with and 88 patients without DM. RESULTS: There was no significant difference regarding age, gender, body mass index, presence of viral genome and inflammatory cells in the myocardium, left ventricular function and diameter, and the degree of heart insufficiency. There was a significant difference of apoptotic cells in the myocardium of patients with DCM and DM compared to patients with DCM alone (1.7+/-1.9 vs. 0.2+/-0.4, p=0.028). During the follow-up of 16 months, left ventricular function improved in both groups significantly, but not between the groups. Death or transplantation-free survival was not significantly different. CONCLUSION: The different findings regarding the presence of apoptotic cells suggest a contribution of pathobiological pathways in the patients with DM to the underlying heart disease.

[Diplopia and cardiogenic shock]. / Doppelbilder und kardiogener Schock. Eine okuläre Myositis assoziiert mit einer Riesenzellmyokarditis.

Idiopathic giant cell myocarditis is a rare and frequently fatal inflammatory heart disease which leads to congestive heart failure or ventricular arrhythmias. It is often associated with other autoimmune disorders. We report a 39-year-old woman who first presented with diplopia and painful eye movements, the typical clinical picture of orbital myositis. Shortly afterwards, she developed rapidly progressive congestive heart failure due to giant cell myocarditis, which took a fatal course within some weeks. Autopsy confirmed both disorders. This case report underlines the importance of early and repeated monitoring of cardiac function, if orbital myositis is suspected, in order to consider cardiac transplantation, the only efficacious treatment of giant cell myocarditis, in time.