[Retroperitoneal fibrosis: development of a biomarker profile for diagnosis and therapy monitoring]. / Retroperitoneale Fibrose : Entwicklung eines Biomarkerprofils zur Diagnostik und Verlaufskontrolle.

INTRODUCTION: Retroperitoneal fibrosis (RPF) is a rare chronic inflammatory disease which is characterized by fibrotic tissue in the retroperitoneal space. There have only been a few studies on serum markers of this disease. The main goal of the current investigation was to identify biological markers which are increased in the serum of patients suffering from RPF and which may correlate with the extent of fibrosis. MATERIAL AND METHODS: The serum of 42 patients with primary and yet untreated retroperitoneal fibrosis was examined for biomarkers known to be specific for fibrotic diseases and compared to a control group. In addition, patients were stratified according to the extent and volume of the retroperitoneal mass using cross-sectional imaging. To estimate the discriminatory power of the evaluated biomarkers, receiver operating characteristic (ROC) curves were created. RESULTS: Independent of the extent of fibrosis, calprotectin, fibrinogen, osteopontin, matrix metallopeptidase 9 (MMP-9), tenascin C and TIMP metallopeptidase inhibitor 1 (TIMP-1) were significantly increased (p<0.01) in patients suffering from RPF compared to the control group. Connective tissue growth factor (CTGF) was significantly elevated (p<0.01) in patients with high RPF burden only but monocyte chemoattractant protein 1 (MCP-1) and heart-type fatty acid binding protein (H-FABP) showed no increase in serum levels. The discriminatory power of these parameters was ranked by the ROC analysis which demonstrated an area under the curve (AUC) >0.87 for MMP-9, TIMP-1, osteopontin, tenascin C, asymmetric dimethylarginine (ADMA), fibrinogen and calprotectin and an AUC <0.64 for MMP-2, CTGF, H-FABP and MCP-1. CONCLUSION: Several biomarkers of fibrogenesis were significantly elevated in patients suffering from RPF as compared to a control group. These biomarker candidates will be further evaluated for their potential to allow a differentiation between other diseases or if they could be used for disease monitoring.

[Renal denervation: current state and future perspectives]. / Renale Denervierung: Atueller Stand und Perspektiven.

Hypertension is a well-known risk factor for major cardiovascular events. Despite advances in medical therapy, sufficient treatment of hypertension remains unsatisfying in a substantial number of patients and is therefore one of the main challenges in modern medicine. In Germany 5-15 % of patients with hypertension suffer from resistant hypertension with elevated blood pressure despite the use of at least three antihypertensive drugs. Additionally patients often suffer from side effects. In patients with resistant hypertension the important role of the sympathetic nervous system with increased sympathetic activity is well known. In the past surgical sympathectomy with extended removal of sympathetic ganglia was performed to reduce blood pressure in patients with malignant hypertension. The positive effect of this highly invasive procedure on blood pressure led to the development of new strategies for the treatment of uncontrolled hypertension. One of the novel procedures includes catheter-based renal sympathetic denervation. The most common system is the radiofrequency ablation catheter (Symplicity®, Medtronic, Minneapolis, USA) which ablates the nerve fibers in the adventitia of the renal arteries by using high-frequency energy. As the results of the Symplicity trials (HTN-1 and HTN-2) showed significant reduction of systolic and diastolic blood pressure after renal denervation there is growing interest in this novel procedure. Moreover, by reducing the sympathetic activity after renal denervation early results indicate a positive impact on glucose metabolism, sleep apnea syndrome, as well as heart and renal failure. These effects led to the development of many different devices for renal denervation; however, trials with a higher number of patients and longer follow-up need to confirm these initially promising results and the value of newer devices. Until then renal denervation should not be regarded as standard therapy for arterial hypertension or an alternative to medical antihypertensive treatment and should be reserved for selected patients with resistant hypertension and specialized medical centres.

[Expert consensus statement on interventional renal sympathetic denervation for hypertension treatment]. / Interventionelle renale Sympathikusdenervation zur Behandlung der therapieresistenten Hypertonie.

This commentary summarizes the expert consensus and recommendations of the working group 'Herz und Niere' of the German Society of Cardiology (DGK), the German Society of Nephrology (DGfN) and the German Hypertension League (DHL) on renal denervation for antihypertensive treatment. Renal denervation is a new, interventional approach to selectively denervate renal afferent and efferent sympathetic fibers. Renal denervation has been demonstrated to reduce office systolic and diastolic blood pressure in patients with resistant hypertension, defined as systolic office blood pressure ≥ 160 mm Hg and ≥ 150 mm Hg in patients with diabetes type 2, which should currently be used as blood pressure thresholds for undergoing the procedure. Exclusion of secondary hypertension causes and optimized antihypertensive drug treatment is mandatory in every patient with resistant hypertension. In order to exclude pseudoresistance, 24-hour blood pressure measurements should be performed. Preserved renal function was an inclusion criterion in the Symplicity studies, therefore, renal denervation should be only considered in patients with a glomerular filtration rate > 45 ml/min. Adequate centre qualification in both, treatment of hypertension and interventional expertise are essential to ensure correct patient selection and procedural safety. Long-term follow-up after renal denervation and participation in the German Renal Denervation (GREAT) Registry are recommended to assess safety and efficacy after renal denervation over time.

Presynaptic alpha-2C adrenoceptor-mediated control of noradrenaline release in humans: genotype- or age-dependent?

In vitro alpha-2CDel322-325 adrenoceptor (AR) polymorphism exhibits reduced functional responsiveness. We studied whether this is true also in vivo in humans. We assessed in nine young wild-type (WT) alpha-2C AR subjects (aged 23 years), 10 elder WT alpha-2C AR subjects (aged 63 years), and nine alpha-2CDel AR subjects (aged 28 years) clonidine (1 microg/kg intravenous (i.v.) bolus)-evoked plasma noradrenaline (pNA), heart rate (HR), and blood pressure (BP) changes. Clonidine-evoked pNA decreases were comparable in young WT alpha-2C and in alpha-2CDel AR subjects, but significantly lower (P=0.033) in elder subjects. Similarly, clonidine-evoked HR decreases were significantly larger in young WT alpha-2C and in alpha-2CDel AR subjects than in elder subjects, whereas clonidine-evoked BP decreases were larger in elder subjects. In conclusion, alpha-2CDel AR appears to play only a minor role in presynaptic regulation of NA release and/or to be not hypofunctional in vivo in humans, but functional responsiveness of presynaptic alpha-2 AR declines with ageing.

Beta-adrenoceptor polymorphisms.

There can be no doubt that beta(1)-, beta(2)- and beta(3)-adrenoceptor genes have genetic polymorphisms. Two single nucleotide polymorphisms have been described for the beta(1)- (Ser49Gly; Gly389Arg), three for the beta(2)- (Arg16Gly; Gln27Glu; Thr164Ile) and one for the beta(3)-adrenoceptor subtype (Trp64Arg) that might be of functional importance. The possibility that changes in expression or properties of the beta-adrenoceptors due to single nucleotide polymorphisms might have phenotypic consequences influencing their cardiovascular or metabolic function or may contribute to the pathophysiology of several disorders like hypertension, congestive heart failure, asthma or obesity is an idea that has attracted much interest during the last 10 years. At present, it appears that these beta-adrenoceptor polymorphisms are very likely not disease-causing genes, but might be risk factors, might modify disease and/or might influence progression of disease. The aim of this review is to provide an overview of the functional consequences of such beta-adrenoceptor polymorphisms in vitro, ex vivo and in vivo.

Enhanced vasoconstriction to endothelin-1, angiotensin II and noradrenaline in carriers of the GNB3 825T allele in the skin microcirculation.

Hypertension is associated with enhanced peripheral vascular resistance, which may be mediated by enhanced vasoconstriction. The impact of the recently detected G-protein beta3-subunit gene C825T polymorphism on the response to the major pressor mediators has been studied in vivo in the human microcirculation. We assessed the effects of endothelin-1 (ET-1), angiotensin II (AT), endothelin-antagonists (BQ-123 and BQ-788) and noradrenaline (NA, each 10-16-10-8 mol) on vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers (13 with CC genotype, 12 TC/TT genotype) using laser Doppler flowmetry. The effects of endothelium-derived vasodilation on NA-induced effects were studied using the NO-synthase inhibitor l-nitro-monomethyl-arginine (L-NMMA) and the alpha2-adrenoceptor-antagonist yohimbine (YO). ET-1, AT and NA caused a dose-dependent vasoconstriction (P < 0.001). In carriers of the 825T allele the response to ET-1, AT and NA was significantly enhanced leading to a shift to the left of the dose-response curve of up to two log units (ET-1: P < 0.001 vs. CC; AT: P < 0.01 vs. CC; NA: P < 0.05 vs. CC). After pretreatment with L-NMMA or YO, NA induced vasoconstriction was no longer different between subjects with the CC- and CT/TT genotypes. However, following combined pretreatment with both L-NMMA and YO, vasoconstriction to NA was significantly potentiated in carriers of the T-allele. Vasodilatation to an ETA-antagonist (BQ-123) was more pronounced in the CT/TT genotype, while ETB-antagonism (BQ-788) led to a more pronounced vasoconstriction in the CT/TT genotype (not significant vs. CC). Healthy, normotensive carriers of the 825T-allele have enhanced vasoconstriction to ET-1, AT and NA in the skin microcirculation. This enhanced vasoconstriction appears to be partially antagonized by an enhanced release of endothelium derived vasodilators mediated by the stimulation of endothelial alpha2-adrenoceptors. The GNB3 C825T polymorphism is potentially an attractive pharmacogenetic marker to predict hormone-mediated responses in humans.

Endothelin-A receptor antagonist inhibits angiotensin II and noradrenaline in man.

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear. METHODS: We studied the effects of the ETA-selective antagonist BQ-123 and the ETB-selective antagonist BQ-788 (both 10(-10)-10(-8) M) on ET-1 (10(-16)-10(-10) M), angiotensin II (AT, 10(-16)-10(-10) M) and noradrenaline (NA, 10(-16)-10(-10) M) induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler flowmetry and double injection technique. RESULTS: BQ-123 caused a dose-dependent vasodilatation (maximum effect: + 949 +/- 84 AUC-PU, P < 0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: -388 +/- 96 AUC-PU, P < 0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10(-14) M: + 814 +/- 93 AUC-PU vs ET alone, P < 0.001), followed by noradrenaline (maximum effect at 10(-16) M: +580 +/- 107 AUC-PU vs NA alone, P < 0.01) and angiotensin II (maximum effect at 10(-14) M: + 493 +/- 111 AUC-PU vs AT alone, P < 0.001). CONCLUSIONS: ETA-selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.

The nitric oxide synthase inhibitor L-NMMA potentiates noradrenaline-induced vasoconstriction: effects of the alpha2-receptor antagonist yohimbine.

OBJECTIVE: Alpha2-adrenoceptors can be found both on vascular smooth muscle cells and on the endothelium, where they exert opposing effects on vascular tone. In vitro, the stimulation of alpha2-adrenoceptors on endothelial cells leads to the release of vasodilating substances like nitric oxide (NO) and prostanoids. Little is known of this mechanism in vivo. DESIGN AND METHODS: We investigated the effects of the NO-synthase inhibitor L-NMMA (10(-6) mol) and the alpha2-adrenoceptor antagonist yohimbine (YO, 10(-10)-10(-6) mol) on noradrenaline (NA, 10(-12)-10(-8) mol)-induced vasoconstriction in the forearm skin microcirculation of 16 healthy volunteers using double injection technique and laser Doppler flowmetry. Results are expressed in perfusion units (PU) as differences from baseline and control in mean +/- SEM; the area under the time-response-curve was calculated (AUC). RESULTS: NA (10(-8)- 10(-12) mol) caused a marked, dose-dependent reduction in blood flow (mean effect -745 +/- 84 AUC PU; P< 0.001 versus saline). NA-induced vasoconstriction was enhanced by L-NMMA (mean effect -916 +/- 72 AUC PU; P< 0.001 versus NA). YO (10(-6)-10(-10) mol) induced a significant, dose-dependent vasodilation (mean effect +/- 446 +/- 110 AUC PU; P < 0.05 versus control); high doses of YO (10(-6) mol) inhibited NA constriction (P < 0.001 versus NA), whereas lower doses of YO (10(-8)/10(-10) mol) had no effect or even increased NA-induced constriction. In the presence of L-NMMA, YO (10(-8) and 10(-10) mol) further potentiated NA-induced vasoconstriction (mean effect -1165 +/- 108 AUC PU; NS versus NA). CONCLUSION: These data demonstrate, that in humans in vivo, endogenous NO attenuates noradrenergic constriction. The effects of YO suggest that endothelial alpha2-adrenoceptors are involved in the release of NO and other vasodilating substances. Furthermore, there is an additive NO-independent vasodilation, which can be unmasked by L-NMMA.

Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart.

The sympathetic and parasympathetic nervous system play a powerful role in controlling cardiac function by activating adrenergic and muscarinic receptors. In the human heart there exist alpha1-, beta1- and beta2-adrenoceptors and M2-muscarinic receptors and possibly also (prejunctional) alpha2-adrenoceptors. Beta1- and beta2-adrenoceptors are quite evenly distributed in the human heart while M2-receptors are heterogeneously distributed (more receptors in atria than in ventricles). Stimulation of beta1- and beta2-adrenoceptors causes increases in heart rate and force of contraction while stimulation of M2-receptors decreases heart rate (directly in atria) and force of contraction (indirectly in ventricles). Pathological situations (such as heart failure) or pharmacological interventions (for example, beta-blocker treatment) can alter the distribution of beta1- and beta2-adrenoceptors in the human heart, while M2-receptors are only marginally affected. On the other hand, relatively little is known on distribution and functional role of alpha1- and alpha2-adrenoceptor subtypes in the human heart.

Antihypertensive drugs and the sympathetic nervous system.

The sympathetic nervous system (SNS) plays an important role in the regulation of blood pressure homeostasis and cardiac function. Furthermore, the increased SNS activity is a predictor of mortality in patients with hypertension, coronary artery disease and congestive heart failure. Experimental data and a few clinical trials suggest that there are important interactions between the main pressor systems, i.e. the SNS, the renin-angiotensin system and the vascular endothelium with the strongest vasoconstrictor, endothelin. The main methods for the assessment of SNS activity are described. Cardiovascular drugs of different classes interfere differently with the SNS and the other pressor systems. Pure vasodilators including nitrates, alpha-blockers and dihydropyridine (DHP)-calcium channel blockers increase SNS activity. Finally, central sympatholytics and possibly phenylalkylamine-type calcium channel blockers reduce SNS activity. The effects of angiotensin-II receptor antagonists on SNS activity in humans is not clear; experimental data are discussed in this review. There are important interactions between the pressor systems under experimental conditions. Recent studies in humans suggest that an activation of the SNS with pure vasodilators in parallel increases plasma endothelin. It can be assumed that, in cardiovascular diseases with already enhanced SNS activity, drugs which do not increase SNS activity or even lower it are preferable. Whether this reflects in lower mortality needs to be investigated in intervention trials.

Skin microcirculation in healthy subjects and patients with arteriosclerosis.

The concept to use the human skin microcirculation as a pharmacological in-vivo test system is old; however, methods developed in the 50s have been abandoned because of side effects and/or use of radioactive substances. We describe a newly developed minimally invasive method that allows in-vivo pharmacology in the human skin microcirculation injecting very low doses of a substance of drug without any systemic effects. The double injection technique (DIT) bears the potential to predict the effects of a drug and/or the vascular reactivity or dysfunction of other less accessible areas of the circulation (e.g. the myocardium). The DIT has been applied for studies in healthy volunteers and patients with atherosclerosis; the focus of interest was endothelial (dys-)function and the effect of exogenous vasoactive drugs. Using endothelin antagonists, we investigated the role of endogenous endothelin under physiological conditions and in atherosclerosis. The NO-synthase inhibitor L-NMMA has been applied to study the L-arginine-NO-pathway and the role of endothelial adrenoceptors. Ongoing studies with the DIT comparing coronary and skin microcirculation may help to develop minimally invasive methods to predict the effects of drugs and vascular function in the heart.

Hypoplasia of the lower medial quadrant of the breast.

A corrective surgical technique is described for a newly defined deformity: hypoplasia of the lower medial quadrant of the breast. It involves reducing the usually enlarged nipple-areola complex and reshaping the breast by turning a glandular pedicled flap from the fairly large upper two quadrants on a medial base into the underdeveloped site of the medial lower quadrant. The method proved uniformly successful in 11 cases and 17 breasts involved.

[Long-term results following implantation of breast prosthesis with a polyurethane coating]. / Langzeitergebnisse nach Implantation von Brustprothesen mit einem Polyurethanüberzug.

42 of 63 cases of bilateral augmentation mammaplasty using polyurethane-covered prostheses, so-called Ashley "Natural-Y" prostheses were seen 15 to 17 years after the primary operation. Two implants had previously been replaced by Cronin gel type prostheses for various reasons. The 84 breasts which were examined in follow-up compared well with breasts augmented with other devices as far as capsular contracture was concerned. The extreme difficulty of removing these implants because of the deterioration of the polyurethane cover makes any further use of these implants unjustifiable.

Long-term results of polyurethane-covered prostheses.

Forty two of 63 cases of bilateral augmentation mammaplasty are surveyed in which the so-called Ashley "Natural-Y" polyurethane-covered prosthesis was used. The cases were evaluated 15-17 years after the primary operation. These cases were compared with breasts augmented with other devices with respect to capsular contracture. The extreme difficulty of removing these implants because of the deterioration of the polyurethane cover leads the author to conclude that any further use of these implants is unjustifiable.

Dados clínicos mundiais sobre a eficácia e a segurança da ciprofloxacina / World wide clinical data on efficacy and safety of ciprofloxacin

Em ensaios clínicos 8.861 pacientes foram tratados com ciprofloxacina a nível mundial. Dos tratamentos realizados,03.822 foram válidos para análise da eficácia, de acordo cocm os padröes do FDA. Em geral foram administradas as seguintes doses: infecçöes do trato urinário: 100 a 50 mg duas vezes por dia, por via oral ou 100 mg duas vezes por dia, por via intravenosa; infecçöes do trato respiratório: 250 a 1.000 mg, duas vezes ao dia, por via oral ou 200 mg duas vezes por dia, por via intravenosa; septicemia: 200 mg duas vezes por dia, por via intravenosa; gonorréia: 250 a 500 mg, por via oral, em dose única; todas as outras infecçöes: 500 a 1000 mg duas vezes por dia, por via oral ou 200 mg, duas vezes por dia, por via intravenosa. A ciprofloxacina foi administrada em 762 tratamentos de infecçöes respiratórias baixas, 88 infecçöes respiratórias altas, 108 bacteremias, 766 infecçöes de pele e anexos, 142 infecçöes dos ossos e articulaçöes, 149 infecçöes intra-abdominais, 33 infecçöes gastrintestinais, 1.633 infecçöes do trato urinário, 49 infecçöes pélvicas, 279 doenças transmitidas sexualmente, principalmente gonorréia, e em três meningites. A resposta clínica foi cura em 76%, melhora em 18% e falha em apenas 6%. A resposta bacteriológica em relaçäo a todos os locais avaliáveis foi: patógenos erradicados em 74%, acentuadamente reduzidos em 2% e persistentes em 10%. Ocorrem recidivas em 4% e reinfecçöes em outros 6%. A resposta global foi favorável em 90% dos pacientes. A segurança da droga foi estabelecida com base nos dados de 8.861 tratamentos a nível mundial. De acordo com a terminologia de COSTART, foram observadas as seguintes reaçöes adversas: digestivas 5%, metabólico-nutricionais 4,6% sistema nervoso central 1,6%, pele 1,4%, hematológicas e linfáticas 1%, cardiovasculares 0,4%, urogenitais 0,3%, órgäos dos sentidos 0,3%, músculo-esqueléticas 0,1%, respiratórias 0,08%...

[Pigmented neurofibroma]. / Pigmentiertes Neurofibrom.

In a 24-year-old male melanin synthesis was demonstrated in a neurofibroma by light and electron microscopy. Although it is unclear whether the tumor cells are pigment-synthesizing Schwann cells or whether they originate from a coexisting melanocytic tumor, this tumor again demonstrates the close relationship between peripheral nerve sheath tumors and melanocytic malformations, as for example cellular blue nevi.

[Vaginal closure with resorbable clip in total abdominal hysterectomy]. / Vaginalverschluss mit resorbierbaren Klammern bei der abdominalen totalen Hysterektomie.

The latest type of clip stapler with resorbable clips for closure of the vaginal stump in abdominal hysterectomies was used by nineteen different surgeons on 80 patients at two university clinics, employing the same surgical procedure. Perioperative handling and the complication-free postoperative course were considered satisfactory. There was no dyspareunia, previously described in association with metal clips. Granular tissue requiring therapy and serosanguinous discharge were clearly reduced. On the basis of measurements of vaginal cuffs removed at the same time it can be said that there is no shortening of the vagina. The question of costs is discussed.

Worldwide clinical data on efficacy and safety of ciprofloxacin.

During the clinical trials 8,861 patients have been treated with ciprofloxacin worldwide. 3,822 of the therapeutic courses were valid for analysis of efficacy according to FDA standards. The following dosages were usually administered: UTI: 100 to 500 mg twice daily orally or 100 mg twice daily intravenously; RTI: 250 to 1000 mg twice daily orally or 200 mg twice daily intravenously; septicemia: 200 mg intravenously twice daily; gonorrhea: 250 to 500 mg single tablet orally; all other infections: 500 to 1000 mg twice daily orally or 200 mg twice daily intravenously. Ciprofloxacin was administered to 762 courses of lower RTI, 88 courses of upper RTI, 108 courses of bacteremia, 766 courses of skin structure infection, 142 courses of bone and joint infections, 149 courses of intra-abdominal infections, 33 courses of gastrointestinal infections, 1,633 courses of UTI, 49 courses of pelvic infections, 279 courses of STD, mainly gonorrhea, and three courses of meningitis. The clinical response was resolution in 76%, improvement in 18% and failure in only 6%. Bacteriologic response by all sites evaluable: pathogens were eradicated from 74%, markedly reduced in 2%, persisted in 10%. Relapse occurred in 4% and reinfection was observed in another 6%. The overall response was favourable for 90% of the patients. Drug safety was established on a data base of 8,861 courses worldwide. The following side-effects according to COSTART terminology were observed: digestive 5%, metabolic nutritional 4.6%, central nervous 1.6%, skin 1.4%, hemic and lymphatic 1%, cardiovascular 0.4%, body as a whole 0.4%, urogenital 0.3%, special senses 0.3%, musculo-skeletal 0.1%, respiratory 0.08%. Several courses had more than one reaction. Thus the total incidence of side-effects for the treated patient population was 10.2%. Ciprofloxacin is a highly effective drug and a breakthrough in several areas of medical interest. It is relatively safe and side-effects are usually mild or moderate in intensity and transient.

[Secondary rhinoplasty]. / Die sekundäre Nasenplastik.

A personal experience of 1199 cases of secondary rhinoplasty with an analysis of possible mistakes is attempted. Avoidable and partly avoidable complications are listed. The surgical and psychological aspects are discussed and the therapeutic consequences outlined. Typical cases to illustrate these principles are presented.