Effect of cryopreservation on DNA damage and DNA repair activity in human blood samples in the comet assay.

The comet assay is a commonly used method to determine DNA damage and repair activity in many types of samples. In recent years, the use of the comet assay in human biomonitoring became highly attractive due to its various modified versions, which may be useful to determine individual susceptibility in blood samples. However, in human biomonitoring studies, working with large sample numbers that are acquired over an extended time period requires some additional considerations. One of the most important issues is the storage of samples and its effect on the outcome of the comet assay. Another important question is the suitability of different blood preparations. In this study, we analysed the effect of cryopreservation on DNA damage and repair activity in human blood samples. In addition, we investigated the suitability of different blood preparations. The alkaline and FPG as well as two different types of repair comet assay and an in vitro hydrogen peroxide challenge were applied. Our results confirmed that cryopreserved blood preparations are suitable for investigating DNA damage in the alkaline and FPG comet assay in whole blood, buffy coat and PBMCs. Ex vivo hydrogen peroxide challenge yielded its optimal effect in isolated PBMCs. The utilised repair comet assay with either UVC or hydrogen peroxide-induced lesions and an aphidicolin block worked well in fresh PBMCs. Cryopreserved PBMCs could not be used immediately after thawing. However, a 16-h recovery with or without mitotic stimulation enabled the application of the repair comet assay, albeit only in a surviving cell fraction.

25-hydroxyvitamin d and advanced glycation endproducts in healthy and hypertensive subjects: are there interactions?

Advanced glycation endproducts (AGEs) accumulate during aging. Skin is the single organ of vitamin D synthesis, induced by ultraviolet B light. Accumulation of AGEs in the skin could interfere with synthesis of the vitamin, whereas the microinflammation and oxidative stress (associated with hypovitaminosis D) could amplify both the toxic effects of AGEs and their production. Clinical data on potential interactions between vitamin D3 deficiency and AGE accumulation are sparse. Here we investigated potential associations between levels of circulating vitamin D3 and those of AGEs in blood and skin with regard to markers of inflammation and oxidative stress in nondiabetic subjects. In a cross-sectional study, 146 subjects (119 healthy persons and 27 hypertensive patients; 73 male and 73 female; mean age, 57.0 ± 15.5 years) were included. Skin autofluorescence (SAF) and plasma levels of vitamin D3, AGE-associated fluorescence, high-sensitivity C-reactive protein level, and advanced oxidation protein products as well as renal function (estimated glomerular filtration rate) were determined. In a subgroup of 61 patients, N(ε)-carboxymethyllysine, soluble receptor of AGEs, and soluble vascular adhesion protein-1 were additionally analyzed. Vitamin D3 level averaged 22.5 ± 8.9 ng/mL. Prevalence of vitamin D insufficiency (20-29 ng/mL) was 43%, and that of deficiency (<20 ng/mL) 37%. The age-dependent rise in SAF was steeper in smokers and in subjects presenting arterial hypertension. No association between SAF and hypovitaminosis D was revealed. Among smokers, an inverse relationship manifested between vitamin D3 and plasma AGE-associated fluorescence as well as soluble vascular adhesion protein-1. Our data suggest that in nondiabetic adults, hypovitaminosis D does not enhance toxicity and accumulation of AGEs. Only in smokers interactions are conceivable.

Neuromuscular electrostimulation techniques: historical aspects and current possibilities in treatment of pain and muscle waisting.

Application of electricity for pain treatment dates back to thousands of years BC. The Ancient Egyptians and later the Greeks and Romans recognized that electrical fishes are capable of generating electric shocks for relief of pain. In the 18th and 19th centuries these natural producers of electricity were replaced by man-made electrical devices. This happened in following phases. The first was the application of static electrical currents (called Franklinism), which was produced by a friction generator. Christian Kratzenstein was the first to apply it medically, followed shortly by Benjamin Franklin. The second phase was Galvanism. This method applied a direct electrical current to the skin by chemical means, applied a direct and pulsed electrical current to the skin. In the third phase the electrical current was induced intermittently and in alternate directions (called Faradism). The fourth stage was the use of high frequency currents (called d'Arsonvalisation). The 19th century was the "golden age" of electrotherapy. It was used for countless dental, neurological, psychiatric and gynecological disturbances. However, at beginning of the 20th century electrotherapy fell from grace. It was dismissed as lacking a scientific basis and being used also by quacks and charlatans for unserious aims. Furthermore, the development of effective analgesic drugs decreased the interest in electricity. In the second half of the 20th century electrotherapy underwent a revival. Based on animal experiments and clinical investigations, its neurophysiological mechanisms were elucidated in more details. The pain relieving action of electricity was explained in particular by two main mechanisms: first, segmental inhibition of pain signals to the brain in the dorsal horn of the spinal cord and second, activation of the descending inhibitory pathway with enhanced release of endogenous opioids and other neurochemical compounds (serotonin, noradrenaline, gamma aminobutyric acid (GABA), acetylcholine and adenosine). The modern electrotherapy of neuromusculo- skeletal pain is based in particular on the following types: transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS or electro-acupuncture) and spinal cord stimulation (SCS). In mild to moderate pain, TENS and PENS are effective methods, whereas SCS is very useful for therapy of refractory neuropathic or ischemic pain. In 2005, high tone external muscle stimulation (HTEMS) was introduced. In diabetic peripheral neuropathy, its analgesic action was more pronounced than TENS application. HTEMS appeared also to have value in the therapy of symptomatic peripheral neuropathy in end-stage renal disease (ESRD). Besides its pain-relieving effect, electrical stimulation is of major importance for prevention or treatment of muscle dysfunction and sarcopenia. In controlled clinical studies electrical myostimulation (EMS) has been shown to be effective against the sarcopenia of patients with chronic congestive heart disease, diabetes, chronic obstructive pulmonary disease and ESRD.

High-tone external muscle stimulation in endstage renal disease: effects on quality of life in patients with peripheral neuropathy.

OBJECTIVE: High-tone external muscle stimulation (HTEMS) has been shown to ameliorate painful peripheral neuropathy of dialysis patients. We hypothesized that HTEMS could also lead to improved parameters of health-related quality of life (HRQOL). METHODS: 25 end-stage renal disease (ESRD) patients (17 men/8 women, mean age 62.2 ± 14.2 years) were enrolled for the study. For evaluation of HRQOL the short form SF-36 was used. In addition, the Hospital Anxiety and Depression Scale (HADS) and the pain severity score were investigated. HTEMS was applied intradialytically for 1 hour, 3 times a week. Its effect was evaluated just before the beginning and both 6 and 12 weeks after onset of this study. RESULTS: SF-36 showed a significant effect of time for the subscales of physical role functioning and social functioning. A marginal significant positive trend could be observed for physical functioning. The pain symptom questionnaire sum scores improved significantly after 12 weeks. The HADS did not change significantly. CONCLUSION: The data indicate that intradialytic HTEMS treatment of ESRD patients with peripheral neuropathy ameliorates various components of physical health.

AT1 receptor antagonist candesartan attenuates genomic damage in peripheral blood lymphocytes of patients on maintenance hemodialysis treatment.

BACKGROUND: Angiotensin II (ANG II) and advanced glycation end products (AGEs) exert genotoxic effects in vitro which were prevented by the ANG II type 1 (AT1) receptor blocker, candesartan. In end-stage renal disease (ESRD) the incidence of genomic damage is increased. A stimulation of the renin-angiotensin system and accumulation of AGEs could be involved. METHODS: We tested whether oral co-administration of candesartan modulates enhanced DNA damage in ESRD patients. Fifteen maintenance hemodialysis (MHD) patients with mild hypertension were treated with candesartan for 4.5 months. Fourteen MHD patients served as conventionally treated uremic controls. DNA damage was measured as micronucleus frequency (MNF) in peripheral blood lymphocytes and evaluated three times before candesartan therapy and afterwards every 6 weeks. RESULTS: Compared to 14 healthy controls, MNF at baseline was significantly elevated in MHD patients. While in the conventionally treated MHD patients the enhanced DNA damage persisted, the co-administration of candesartan ameliorated the genomic damage significantly and independently of blood pressure changes. CONCLUSION: Blockade of AT1 receptors with candesartan can reduce DNA damage in MHD patients. Long-term studies in larger patient groups are needed to investigate whether the improved genomic damage lowers atherosclerotic complications and cancer development.

Acute phase reaction to gadolinium-DTPA in dialysis patients.

BACKGROUND: Several late sequelae of the administration of gadolinium (Gd)-containing MRI contrast agents have been described in patients with advanced renal failure. In an observational series, we found a remarkable frequency of peracute reactions after administration of Gd-DTPA used for cardiovascular evaluation before renal transplantation. METHODS: In a 26-month observational period, 13 of 136 haemodialyzed or CAPD patients exhibited onset of fever, chills and nausea within hours after administration of Gd-DTPA peracute. A minority showed persistent cessation of residual diuresis. We performed blood cultures in most patients and evaluated white blood cell (WBC) counts, eosinophils, CRP, heart rate and blood pressure. RESULTS: Within an average of 12 h (range 12-36 h) after Gd administration, the 13 patients (9 males, 4 females; median age 61 years, range 47-79) developed consistent symptomatology with fever (median 39.0 degrees C, range 37.5-39.5), chills, malaise, hypotension, vomiting, dyspnoea-initially raising suspicion of septicaemia. Subsequent blood cultures on bacterial contamination of the injected product remained negative throughout; bacterial or endotoxin contamination of the reagent was excluded. Steroids were tried in the first two patients without a noticeable effect. In all subsequent patients, symptoms were attenuated during the first 5 h dialysis (F60HPS with 280 ml/min blood flow) and disappeared within 72 h. CRP levels remained markedly elevated up to 14 days. Lymphopenia was seen in all patients, and polymorphic neutrophils (PMN) remained normal. Two polyuric patients developed persistent anuria. After a median of 16 months, none of these patients developed nephrogenic systemic fibrosis. CONCLUSION: This series with unusually severe acute phase reactions was caused by one specific preparation. Such peracute reactions may be relevant for the so-far largely unresolved pathogenesis of the skin reaction to some Gd products in end-stage renal disease (ESRD) patients. It remains unresolved whether the reaction observed with Gd-DTPA do in principle also occur with other Gd reagents.

Beginning of modern concept of inflammation: the work of Friedrich Daniel von Recklinghausen and Julius Friedrich Cohnheim.

In Rudolf Virchow's concept of inflammation, the basic alterations were derived from connective tissue cells, which underwent a marked metamorphosis. This cell-based and static conception was fundamentally broadened and, in part, refuted in the ensuing decade by 2 of his scholars. Friedrich Daniel von Recklinghausen characterized the pus cells in acute inflammation and made the seminal observation of their contractility and mobility. He was the first who described the wandering leukocytes which were demonstrated in particular in experimental keratitis. He also showed that pus cells could migrate from the places of their origin in the interstitium to other tissues and epithelial cells. Von Recklinghausen in addition contributed to the concept of phagocytosis. The work of Julius Friedrich Cohnheim was focused on the mechanisms involved in the extravasation of leukocytes from the blood vessels in the inflamed mesentery of the frog and carefully described the time-dependent alterations: dilatation of the arteries and veins, adhesion of colorless cells to the endothelial cells, and the subsequent transmigration from the capillaries and venules into the interstitial space. In the last few decades, experimental and clinical studies using modern techniques have fully confirmed and extended these basic observations made by von Recklinghausen and Cohnheim more than 100 years ago.

Mass-screening for early detection of renal disease: benefits and limitations of self-testing for proteinuria.

INTRODUCTION: Chronic kidney diseases are of growing importance for our health system. With regard to the high number of undetected cases, screening programs provide opportunities for an early to detect and treat patients. METHODS: With the support of local newspapers, we performed a mass screening of the citizens of Würzburg, Germany. One hundred thousand dipsticks for proteinuria were distributed. Citizens were invited to self-test their urine and to report the results to the organizing centre. RESULTS: We received information for approximately 22% of the distributed dipsticks. Positive tests results numbered 2,458 after removal of 309 positive results for pre-diagnosed renal diseases. From family doctors, we obtained data for control investigations of 856 dipstick-positive subjects. In 104 of them, chronic proteinuria could be confirmed, due to essential hypertension (n=47), pyelo/interstitial nephritis (n=26), diabetic nephropathy (n=20), glomerulonephritis (n=4), nephrolithiasis (n=4), hypernephroma (n=2) and polycystic kidney disease (n=1). DISCUSSION: The benefit of self-testing was an unexpectedly high compliance, even in males. However, a great number of abnormal tests could not be confirmed by family doctors, possibly owing to the time variation in urine testing (early-morning urine in the self-test vs. daytime testing by the physician), the high variability of urinary protein excretion and a large number of false-positive tests in the inexperienced participants. CONCLUSION: Mass screening for proteinuria with self-testing enhances the awareness of renal diseases and improves the chances for an early diagnosis and therapy. Limitations are the frequent overdiagnosis of proteinuria due to minimal colour changes in the dipsticks.

Reduction of the genomic damage level in haemodialysis patients by folic acid and vitamin B12 supplementation.

BACKGROUND: Cancer incidence and genomic damage of peripheral lymphocytes are elevated in patients with end-stage renal failure. Among other uraemic toxins, homocysteine (Hcy) levels are increased in most of these patients. In healthy individuals, plasma Hcy correlates with the degree of genomic damage observed in peripheral blood lymphocytes (PBL). The accumulation of Hcy can be reduced by supplementation with folic acid and vitamin B12. The aim of this study was to analyse whether this supplementation can also lower the genomic damage in PBL of haemodialysis patients. This may ultimately help to reduce cancer incidence in renal patients. METHODS: In a prospective study with 27 patients, we analysed the genomic damage in dialysis patients before and at different time points after the initiation of folate/vitamin B12 supplementation. Genomic damage was measured by the frequency of micronuclei, a subset of chromosomal aberrations, in PBL. RESULTS: Supplementation with folic acid and vitamin B12 (more markedly with both) reduced the micronucleus frequency in PBL of dialysis patients. This was not mediated by altered lymphocyte proliferation capacity or changes in DNA cytosine-methylation. Plasma-Hcy was lowered more efficiently by the combined folic acid/vitamin B12 supplementation, and lymphocyte DNA of this group exhibited a nonsignificant trend for a reduction of 1,N(6)-etheno-2'-deoxyadenosine, a marker for oxidative stress. CONCLUSIONS: A reduction of the genomic damage in PBL can be achieved in dialysis patients by supplementation with folic acid and vitamin B12. This may be mediated by Hcy reduction.

Benfotiamine reduces genomic damage in peripheral lymphocytes of hemodialysis patients.

Hemodialysis patients have an elevated genomic damage in peripheral blood lymphocytes (PBLs) and an increased cancer incidence, possibly due to accumulation of uremic toxins like advanced glycation end products (AGEs). Because the vitamin B1 prodrug benfotiamine reduces AGE levels in experimental diabetes, and dialysis patients often suffer from vitamin B1 deficiency, we conducted two consecutive studies supplementing hemodialysis patients with benfotiamine. In both studies, genomic damage was measured as micronucleus frequency of PBLs before and at three time-points after initiation of benfotiamine supplementation. AGE-associated fluorescence in plasma, and in the second study additionally, the antioxidative capacity of plasma was analyzed. Benfotiamine significantly lowered the genomic damage of PBLs in hemodialysis patients of both studies independent of changes in plasma AGE levels. The second study gave a hint to the mechanism, as the antioxidative capacity of the plasma of the treated patients clearly increased, which might ameliorate the DNA damage.

Use of cinacalcet HCl to achieve the recommended targets of bone metabolism in a patient with therapy-resistant renal hyperparathyroidism.

We report on a patient with end-stage renal disease and severe progressive secondary hyperparathyroidism, whose condition failed to respond to conventional pharmacologic or surgical interventions. Although immunotherapy produced a partial response, it failed to decrease serum parathyroid hormone to the levels recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative clinical practice guidelines. Treatment with a new calcimimetic agent, cinacalcet HCl (Mimpara, Amgen, Munich, Germany), resulted in a rapid decline in elevated parathyroid hormone levels, near normalization of other laboratory markers of bone metabolism, improvement in mobility and skeletal pain caused by renal osteodystrophy, and an increase in body weight.

Central atrial natriuretic peptide in dehydration.

To test the effect of dehydration on brain atrial natriuretic peptide (ANP) concentrations in areas important to salt appetite, water balance and cardiovascular regulation, we subjected rats to dehydration and rehydration and measured ANP concentration in 18 brain areas, as well as all relevant peripheral parameters. Water deprivation decreased body weight, blood pressure, urine volume, and plasma ANP, while it increased urine and plasma osmolality, angiotensin II, and vasopressin. ANP greatly increased in 17 and 18 brain areas (all cut cerebral cortex) by 24 h. Rehydration for 12 h corrected all changes evoked by dehydration, including elevated ANP levels in brain. We conclude that chronic dehydration results in increased ANP in brain areas important to salt appetite and water balance. These results support a role for ANP as a neuroregulatory substance that participates in salt and water balance.

Effect of different hemodialysis regimens on genomic damage in end-stage renal failure.

Patients with end-stage renal disease display enhanced genomic damage that may have pathophysiologic relevance for cancer development and cardiovascular complications. We investigated to what extent the genomic damage in peripheral blood lymphocytes can be modulated #1: by initiation of standard hemodialysis (SHD) in formerly conservatively treated end-stage renal disease patients, #2: by a switch from SHD to hemodiafiltration, and #3: daily dialysis (DHD). Genomic damage was evaluated by the micronuclei (MN) frequency test and the comet assay (CA). In a prospective study we found that initiation of SHD did not induce significant changes of genomic damage in peripheral blood lymphocytes whereas the change to hemodiafiltration improved the percentage of DNA in the tail as measured by CA without modulating the MN frequency. In a cross-sectional investigation the degree of genomic damage as evaluated by MN frequency was significantly lower in a patient group treated by DHD as compared with a group treated by SHD. In the DHD patients there also was a significant decrease of the plasma concentrations of urea and the advanced glycation end products imidazolone A, carboxymethyllysine, and of advanced glycation end product-associated fluorescence.

The contribution of Rudolf Virchow to the concept of inflammation: what is still of importance?

At the beginning of the 19th century, medicine was based largely on speculative and philosophical concepts. The greatest merit of Rudolf Virchow was without doubt a way of thinking based on natural science. In place of the empirical chaos represented by the doctrines of humors and crasis, he created the new paradigm of cellular pathology. In the field of inflammation, he critically analyzed the meaning of the four key symptoms of inflammation (redness, swelling, heat and pain) and postulated that inflammation cannot be represented as a single process but rather constitutes various inflammatory processes. In addition he introduced the functio laesa , denoting the restricted function of inflamed tissues. In the pathogenesis of inflammation, Virchow highlighted the importance of the inflammatory stimulus. The irritatio is the starting point and the conditio sine qua non . Through his pathohistological investigations in experimental animals and in humans, inflammation was widely accepted as the central cause of atherosclerosis, until the end of the 19th century, and has been confirmed in recent decades. It was Virchow who first coined the term endarteriitis deformans . Likewise, he was also the first to hypothesize a link between microinflammation and subsequent cancer development. This hypothesis has recently been corroborated by numerous studies and may have therapeutic consequences. Virchow contributed to nearly all aspects of human pathology and championed the cause of social medicine.

Renal disease in obesity: the need for greater attention.

Excess body weight may be associated with various functional/structural lesions of the kidney. The spectrum ranges from glomerulomegaly with or without focal or segmental glomerulosclerosis, to diabetic nephropathy, to carcinoma of the kidney and nephrolithiasis. The first sign of renal injury is microalbuminuria or frank proteinuria, in particular in the presence of hypertension. The occurrence of microalbuminuria and/or chronic kidney insufficiency (glomerular filtration rate < 60 mL/min/1.73 m2) is related to the increasing number of components of the metabolic syndrome, ie, central obesity, elevated fasting blood glucose level, hypertriglycerides, low high-density lipoprotein cholesterol, and hypertension. In the long run, end-stage renal failure may develop. An increased body mass index is particularly harmful in patients with reduced renal functional mass (unilateral renal agenesis or nephrectomy) and other renal diseases (immunoglobulin A nephritis and chronic graft dysfunction after kidney transplantation). In the pathogenesis of obesity-associated glomerulopathy, hyperfiltration is of fundamental importance. The factors involved are energy intake (high protein and salt), hyperinsulinemia, and enhanced tubuloglomerular feedback because of increased sodium reabsorption. The adrenergic and renin-angiotensin-aldosterone systems as well as glucocorticoids are stimulated. In addition, several active proteins generated in the central adipose tissue, such as leptin, proinflammatory cytokines, plasminogen activator inhibitor-1, angiotensinogen, and growth factors (transforming growth factor-beta1), as well as low levels of the protective adiponectin, may contribute to renal injury. Of greatest importance is the development of hypertension and of diabetes, which are directly related to the severity of central obesity. Obesity-associated renal disease should be prevented or retarded by weight reduction following lifestyle modification (salt restriction, hypocaloric diet, aerobic exercise), or eventually by antiobesity medication or bariatric surgery. In the presence of glomerulopathy and/or hypertension, angiotensin converting enzyme inhibitors or angiotensin II type I receptor blockers are the drugs of choice to improve glomerular hyperfiltration.

Efficacy and safety of a 7.5% icodextrin peritoneal dialysis solution in patients treated with automated peritoneal dialysis.

In a randomized, prospective, multicenter study, we compared the safety, efficacy, and metabolic effects of a 7.5% icodextrin solution (Extraneal) with a 2.27% glucose solution for long dwell exchanges in patients undergoing automated peritoneal dialysis. Thirty-nine stable patients on automated peritoneal dialysis were randomized to receive either icodextrin (n = 20) or glucose 2.27% solution (n = 19). The study included a 2-week baseline period followed by a 12-week icodextrin treatment phase and a 2-week follow-up period when switching back to glucose. The average net ultrafiltration during the long dwell period was 278 +/- 43 mL/d for the icodextrin group and -138 +/- 81 mL/d for the control group (P < 0.001). The higher ultrafiltration volume with icodextrin was associated with higher creatinine (2.59 +/- 0.09 mL/min versus 2.16 +/- 0.11 mL/min) and urea (2.67 +/- 0.09 mL/min versus 2.28 +/- 0.12 mL/min) peritoneal clearances for the long dwell (both P < 0.001). Ultrafiltration rate per mass of carbohydrate absorbed was +5.2 +/- 1.2 microL/min/g in the icodextrin group and -5.5 +/- 2.8 microL/min/g in the glucose group (P < 0.001). In the icodextrin group, there was a decrease in serum sodium and chloride compared with baseline (P < 0.01). Total dialysate sodium removal increased in the icodextrin group from 226.7 mEq to 269.6 mEq (week 12, P < 0.001). Serum alpha-amylase activity decreased from 103 U/L to 16 U/L (P < 0.001). The total icodextrin plasma levels reached a steady-state concentration of 6,187 +/- 399 mg/L after 1 week of treatment. Urine volume and residual renal function were not specifically affected by icodextrin compared with glucose. None of the laboratory changes resulted in any reported clinically meaningful side effect. Icodextrin produced increased, sustained ultrafiltration during the long dwell period, increasing (convective) peritoneal clearance and sodium removal in automated peritoneal dialysis patients.

Genomic damage in end-stage renal failure: potential involvement of advanced glycation end products and carbonyl stress.

In patients with chronic renal failure, genomic damage has been shown by numerous biomarkers, such as micronuclei frequency and comet assay (single-cell gel electrophoresis) in peripheral lymphocytes, 8-hydroxy 2'-deoxyguanosine (8-OH-dG) content in leukocytes, mitochondrial DNA deletions in skeletal muscle tissue and hair follicles, as well as in DNA repair mechanisms in freshly isolated lymphocytes after ultraviolet light exposure. In the pathogenesis of DNA damage--besides genetic influences, enhanced reactive oxygen species (ROS), and lipid peroxidation-the genotoxic potential of advanced glycation end products (AGEs) and reactive carbonyl compounds deserve special attention. In fact, reactions of glucose with DNA can lead to mutagenic DNA AGEs. In vitro, incubation of tubulus cells with various AGEs and methylglyoxal induces DNA damage, which is suppressed by antioxidants. This underlines the role played by oxidative stress in DNA damage.

The central vasopressinergic system in experimental left ventricular hypertrophy and dysfunction.

In the course of cardiac diseases, various neuruhomonal systems in the plasma are activated. So far there have been only isolated results of investigations about the functional state of central neuropeptide systems in cardiac diseases and, in particular, in heart failure. We investigated, therefore, the central vasopressinergic system, an important neuropeptide system in cardiocirculatory regulation in a model of myocardial hypertrophy and left ventricular dysfunction, a model of supravalvular aortic stenosis. In addition to increased vasopressin concentrations in plasma, central vasopressin is also altered in this model. A differential stimulation of vasopressin in the hypothalamic areas and in the areas of the brain stem that are involved in central cardiocirculatory regulation was detected. Reduced vasopressin concentrations in the locus coeruleus, an important regulatory area of sympathetic nervous activity, suggest a central regulatory mechanism through which stimulation of the sympathetic nervous activity can be prevented. Our investigations showed that non-osmotic factors like the baroreceptor reflex and angiotensin II, are important stimuli of the vasopressinergic system. We were also able to show that the central vasopressinergic system in rats with experimental heart failure and myocardial hypertrophy is inhibited by treatment with an ACE inhibitor and AT1 receptor antagonist. As seen with autoradiography, this effect is mediated by a central effect of the drugs. Research into central regulatory mechanisms in cardiovascular diseases is, on the one hand, of crucial importance to our understanding of complex pathophysiological processes, and on the other hand, it serves the development of new therapeutic approaches with the goal of influencing these mechanisms directly pharmacologically and for the elucidation of central, currently unknown effects of cardiovascular drugs.

Georg Ganter--a pioneer of peritoneal dialysis and his tragic academic demise at the hand of the Nazi regime.

First reports in German literature on the effective removal of uremic toxins by means of extracorporeal hemodialysis in bi-nephrectomized, acute uremic dogs were given by Heinrich Necheles and Georg Haas. These methods were viewed with great scepticism by Georg Ganter who criticized in particular the extensive operative procedure by use of the femoral artery and vein, the size and fragility of the dialysers, as well as the potential toxic effects of the anticoagulant hirudin. As an alternative approach, he suggested the use of the peritoneum as an especially large endogenous dialysis membrane. In 1923, in experiments on ureter-ligated guinea pigs and rabbits, he demonstrated that the single or repeated instillation (after effective draining) of physiological NaCl solution improves both the symptoms of uremia and the blood urea nitrogen level. In patients this new procedure was implemented only sporadically and in the form of a single fluid instillation after a first observation in a uremic patient where a pleura exudate was substituted: in a female patient with acute uremia as a consequence of a ureter occlusion, due to uterus carcinoma, and in a patient with a diabetic coma. In spite of these limited experiences, Ganter was convinced of the superiority of his method over the troublesome hemodialysis therapy and recommended its broader clinical application.