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.

Karl Peter's fundamental contribution to the structural organization of the kidney.

Karl Peter provided the first detailed description of the structure and morphology of the human kidney and defined at least 9 major segments of the tubules. He showed that the nephrons were heterogeneous in their structure and could be divided in 2 categories: the short-looped and the long-looped ones. Peter's scheme of the human nephrons was published in many journals and textbooks. Another contribution was the demonstration of a relationship between the relative occurrence of long thin loops (versus short loops) and the maximal urinary concentration capacity. Peter was also the first to describe the cells of the macula densa, which are of fundamental importance in the tubuloglomerular feedback mechanism. Furthermore, Peter gave a detailed description of the principal zones of the human kidney: the cortex, the outer medulla with outer and inner stripes, and the inner medulla.

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.

Mechanisms of acute uremic encephalopathy: early activation of Fos and Fra-2 gene products in different nuclei/areas of the rat brain.

High levels of various uremic toxins such as guanidino compounds and advanced glycation endproducts, as well as an excess of parathyroid hormones, are involved in the pathogenesis of acute uremic encephalopathy. Moreover, distant effects of the damaged kidney with enhanced production of inflammatory mediators are implicated. Data on the pump activity of an abnormal Na-K-ATPase and inhibition of the organic anion transporter system in the brain have been published previously. Recently, the effect of an experimentally induced acute renal failure (ARF) on the neuronal cell activation of Fos and Fra-2 in the rat brain was investigated by immunohistochemistry. ARF was induced by using the following 3 rat models: bilateral nephrectomy, bilateral ureter ligation, and uranyl acetate injection with corresponding controls. The Fos and the Fra-2 immunoreactive neurons of the brain were determined in a total of 120 brain areas over a period of 3 days post bilateral nephrectomy and bilateral ureter ligation and 12 days after uranyl acetate. An activation response was observed in 73 of 120 areas of the brain. The responses were classified into 4 groups: (1) biogenic amines (noradrenaline, adrenaline, histamine, and 5-hydroxytryptamine), (2) stress-sensitive forebrain areas, (3) neuronal cell groups involved in the regulation of water and electrolyte homeostasis, and (4) central autonomic cell groups. In the uranyl acetate-induced ARF, activation of Fos and Fra-2 immunoreactivity took place at the earliest time-point (3 hours) which persisted even after improvement of ARF. This suggests the involvement of the toxic effects of uranium as a result of its accumulation in the brain.

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.

Renal effects of S18886 (Terutroban), a TP receptor antagonist, in an experimental model of type 2 diabetes.

Thromboxane A(2) (TxA(2)) is assumed to contribute to the development of diabetes complications, including nephropathy. We investigated whether the selective thromboxane-prostanoid endoperoxide receptor antagonist, S18886, ameliorates renal damage in uninephrectomized (UNX) obese Zucker rats (OZR). S18886, at doses of 10 (S18886-10) and 30 (S18886-30) mg x kg(-1) x day(-1), was administered to UNX-OZR by gavage over 8 weeks (n = 8 each group). UNX lean rats (n = 12) and OZR rats that received placebo (OZR-PLAC, n = 8) served as controls. As compared with the OZR-PLAC, S18886 had no significant effect on the elevated blood pressure and the enhanced creatinine clearance, while augmented proteinuria was partially prevented (-12 and -37%, low and high dose, respectively; NS). The increased excretion of transforming growth factor beta(1) (TGF-beta(1)) and of the thromboxane metabolite 2,3-dinor thromboxane B(2) (TxB(2)) was lowered (P < 0.05). S18886 prevented both the enhanced mesangiolysis (P < 0.01) in the OZR-PLAC as well as enlargement and degeneration of podocytes. In the blood, S18886-30 augmented the antioxidant enzymes (P < 0.01) and lessened the increase of plasma advanced oxidation protein products (-25%, NS). Body weight, hyperglycemia, and dyslipidemia remained uninfluenced under both doses of treatment. S18886 has renoprotective properties in the model of UNX-OZR. It prevents mesangiolysis, reduces urinary TGF-beta(1) and 2,3-dinor-TxB(2) excretion, and enhances the antioxidative defense.

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.

Genomic damage and circulating AGE levels in patients undergoing daily versus standard haemodialysis.

BACKGROUND: Patients with end-stage renal failure, whether on conservative or haemodialysis therapy, have a high incidence of DNA damage. It is not known if improved control of the uraemic state by daily haemodialysis (DHD) reduces DNA lesions. METHODS: DNA damage in peripheral blood lymphocytes (PBLs) was evaluated in a cross-sectional study of 13 patients on DHD (2-3 h, 6 times/week), 12 patients on standard haemodialysis (SHD) therapy (4-5 h, 3 times/week) and 12 healthy age-matched volunteer controls. The biomarker of DNA damage used was micronucleus frequency. The assessed plasma parameters of microinflammation and oxidative stress were C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, advanced oxidation protein products (AOPP), and homocysteine. We also measured plasma concentrations of the circulating advanced glycation end products (AGEs) MGI (methylglyoxal-derived imidazolinone), CML (carboxymethyllysine), imidazolone A (3-deoxyglucosone-derived imidazolinone) and AGE-associated fluorescence. RESULTS: Compared to SHD, DHD was associated with significantly lower DNA damage, approaching the normal range. Micronuclei (MN) frequency averaged 29.1 MN+/-5.9/1000 binucleated (BN) cells in the SHD group, which is significantly elevated (P<0.01), 14.8 MN+/-4.0/1000 BN cells in the DHD group, and 13.2 MN+/-3.04/1000 BN cells in the controls. CRP and AOPP were in the normal range (and similar between the dialysis groups). In contrast, IL-6 and neopterin were significantly elevated, with lower values associated with DHD as compared with SHD. The increased levels of AGEs tended to be lower in the DHD group, reaching significance for CML and imidazolone A. CONCLUSIONS: Overall, it was found that genomic damage in PBLs is lower in patients on DHD than in those on SHD. Lower plasma concentrations of uraemic toxins, including circulating AGEs, may account for the differences. To confirm these data, prospective clinical trials need to be performed.

Genomic damage in chronic renal failure--potential therapeutic interventions.

In end-stage renal failure, genomic damage is enhanced. This has been shown both in the predialysis and dialysis phase by various biomarkers, such as micronuclei frequency and single cell gel electrophoresis in lymphocytes as well as with 8-hydroxy-2'-deoxyguanosine in leukocytes. There are also data about mitochondrial DNA deletions and chromosomal abnormalities. Genomic damage may be induced by a multitude of toxic factors and mutagens, in particular via enhanced generation of reactive oxygen species. In in vitro studies, incubation of tubular cells with various AGEs (carboxymethyllysine-BSA, AGE-BSA, and methylglyoxal-BSA) and angiotensin II resulted in a marked DNA damage. Coincubation with various antioxidants as well as the angiotensin II receptor blocker, candesartan, suppressed the toxic action. Moreover, an improved uremic state by daily hemodialysis ameliorated the genomic damage in lymphocytes, as compared to patients on conventional hemodialysis.

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.

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.

Effects of opipramol as an evening anaesthesiologic premedication.

To date, opipramol has not been examined within the context of evening premedication in anaesthesiology. A suitable drug for such an application should induce anxiolytic and sleep-favouring effects. Due to its pharmacological properties, one would expect opipramol to lead to these effects. In order to test this possibility, 72 female patients were randomly assigned to 50 mg opipramol, 100 mg opipramol, or placebo (n = 24 patients per group) in the evening prior to surgery in a double-blind trial. Effects were recorded in the morning prior to the operation by means of self-rating questionnaires, regarding the patients' current subjective state and their judgement of the quality of sleep during the night before. The self-rating was done by the Multidimensional Mood Inventory BSKE (EWL), by use of the Multidimensional Somatic Symptom List (MSKL), and by use of the Würzburg Sleep Questionnaire. Further dependent variables were heart rate and blood pressure. Opipramol significantly improved sleep quality. Especially the frequency of awakening at night was reduced. These effects could be observed predominantly after 100 mg opipramol. At this dosage, inner excitement was reduced as well. The autonomic variables remained uninfluenced. There were no adverse events and no hints for interactions with anaesthesiology.