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Epidemiological research and Substance Abuse Warning Systems point to a sharp increase in the use of "Ecstasy" (MDMA), as well as to structural changes in the drug scene in and outside Europe. For some consumers, "Ecstasy" opens the door to the abuse of other illegal substances. Since the mid-eighties psychiatric complications and consequences of the abuse of MDMA have been reported in at least 48 cases. It is necessary to differentiate between acute psychiatric complications, which subside completely when the level of intoxication comes down, toxic psychoses and long-term psychiatric diseases as a consequence of substance abuse. The latter involve atypical and paranoid psychoses, depressions, panic disorders, depersonalisation and behavioural disorders. Convulsive seizures are among the most common problems involving the central nervous system. Furthermore, there have been reports on cerebrovascular accidents and intracranial haemorrhages. Literature reports on at least 53 cases of medical complications in abusers of MDMA, 14 of which came to a lethal end. Research still blatantly lacks prospective epidemiological and clinical studies on a sufficiently large scale to identify different developments of dependency and predictors of harmful and unhealthy consumption.

The distribution pattern of renal organic osmolytes in surgically explanted human kidneys was investigated and compared with that of untreated Sprague-Dawley rats (Uosmo = 1186 mosmol/kg H2O). Sorbitol, myo-inositol, glycerophosphorylcholine and betaine were measured by liquid chromatography (HPLC) in homogenates of five different kidney zones from the cortex towards the papillary tip. All four organic osmolytes were detected as in human as in rat kidney. The expected increase from the inner medulla to the papillary tip for sorbitol and betaine, and from the outer medulla to the papilla for glycerophosphorylcholine, was observed in rats, but not in explanted human kidney. An inverse distribution pattern was observed with decreasing tissue contents from the inner and outer medulla to the papillary tip for all organic osmolytes and urea. This intrarenal osmolyte profile is in accordance with that observed during water and lithium diuresis in rats. Therefore it can be assumed that a loss of renal medullary osmolytes during the intra-operative treatment of patients led to the observed osmolyte pattern. We conclude that organic osmolytes are involved in renal medullary osmoadaptation of humans.

A radioenzymatic microassay was developed to quantitate choline dehydrogenase activity in single microdissected nephron segments. This enzyme is the rate limiting step in the biosynthesis of betaine, which serves as an intracellular osmoregulatory organic solute in mammalian kidney. The enzyme localized in renal mitochondrial inner membrane forms betaine aldehyde, which in the assay is converted to betaine by oxidative treatment. A histochemical procedure based on the formazan detection of tetranitroblue tetrazolium chloride was applied in parallel. The results show that activities in proximal convoluted and straight tubules are more than 5 times higher (21 to 25 pmol h-1 mm tubule-1) compared to distal nephron segments with no significant differences along the proximal tubule. Along the osmotic gradient from the outer medullary towards the papillary structures enzyme activities increased in ascending limbs of Henle's loop and collecting tubules. Collecting ducts showed two times higher activities than ascending loop segments when corrected for tubular cell volumes. The quantitative data were confirmed by the histochemical procedure. The results allow for the conclusion that betaine synthesis is sufficient to build up renal betaine, but cannot explain the distribution pattern of betaine along the corticopapillary axis. Additional mechanisms like intrarenal and tubular transport have to be postulated.

The polyols, sorbitol and myo-inositol, seem to be involved in the development of diabetic complications of different organs. High concentrations of both polyols were found in kidney medulla in addition to trimethylamines. To investigate the influence of diabetes mellitus on the regulation of both polyols and glycerophosphorylcholine in kidney, these osmolytes were quantitated enzymatically along the corticopapillary axis in untreated, streptozotocin-diabetic and insulin-treated streptozotocin-diabetic rats. In control animals three individual osmolyte patterns were found: a steep gradient of sorbitol in the papilla, increasing amounts of glycerophosphorylcholine from the outer medulla to the papilla, and nearly equal amounts of myo-inositol in the renal medulla, decreasing towards the cortex. Diabetic rats exhibit an up to fourfold increase of inner medullary sorbitol, whereas myo-inositol was only elevated in the outer medulla. Glycerophosphorylcholine was lowered in the papillary tip and elevated in the outer medulla and cortex. Insulin treatment reduced sorbitol to a concentration between those of diabetic and control rats, caused a restoration of glycerophosphorylcholine in the papillary tip and outer medulla to control values, and increased cortical myo-inositol. These data confirm previous in vitro data, which show that papillary sorbitol specifically increases in hyperglycaemic states, thereby counteracting the increased extracellular tonicity due to elevated tissue glucose concentrations. Imbalance of extra- vs intracellular osmolality during insulin treatment may be involved in the pathomechanism of renal papillary necrosis.

Diabetic nephropathy not only involves vascular and glomerular changes but also affects tubular metabolism, structure and function. Under acute insulin withdrawal the tubular size increases with glomerular hyperfiltration. Insulin like growth factor 1 (IGF1) has been found to be a candidate mediator involved under these conditions. Tubular carbohydrate metabolism is characterized by gluconeogenesis in the proximal tubule, glycolytic enzymes in the distal segments and high aldose reductase activity in the structures of the renal papilla. In the diabetic state, gluconeogenesis is stimulated by changes of the acid base status. Mitochondrial glucose oxidation is decreased by inhibition of pyruvate dehydrogenase activity through preferential oxidation of fatty acids and ketone bodies. The increase in glycogen in distal tubule cells and sorbitol accumulated in papillary structures can be explained by the high extracellular glucose supply under diabetic conditions. Fatty acids taken up in excess of tubular energy needs accumulate in the nephron as triacylglycerols, mainly in the proximal convoluted tubule. Fatty acid oxidation is inhibited by ketone bodies in proximal and outer medullary tubules, leading to preferential oxidation of the latter under ketotic conditions. Ammonia formed during tubular metabolism of glutamine increases in metabolic acidosis but is suppressed by ketone bodies, leading to a nitrogen sparing effect of ketone bodies. All acute metabolic derangements are abolished, and normal metabolism reestablished by adequate insulin treatment in vivo.

The polyols sorbitol and inositol were determined in single freshly microdissected tubule segments of rat kidney. Twenty different structures were separated from six different kidney zones reaching from cortex to papillary tip. Picomol amounts of sorbitol and inositol were quantitated by use of an enzymatic bioluminescence procedure. Experimental conditions (700 mosmol/kg, 4 degrees C) were chosen to assure constant polyol concentrations over 3 h dissection period. Sorbitol exhibited a concentration gradient in the collecting duct system from the outer/inner medullary border (3.9 +/- 0.5 pmol/mm) to the papillary tip (78.8 +/- 6.9 pmol/mm). In the same region descending and ascending limbs of Henle's loop contained 1.5 +/- 0.5 to 5.3 +/- 1.6 pmol/mm and 2.5 +/- 0.8 to 8.35 +/- 1.5 pmol/mm, respectively. In contrast, all outer medullary and cortical structures had lower sorbitol concentrations. Inositol amounts increased continuously in the collecting duct from cortex (5.3 +/- 0.5 pmol/mm) to inner medulla (30.7 +/- 3.8 pmol/mm). This polyol was also found in thick ascending limb of Henle's loop (6.2 +/- 1.1 pmol/mm in cortex to 11.2 +/- 1.4 pmol/mm in outer medulla) and in proximal tubules (5.6 +/- 1.2 pmol/mm in S1 and 4.5 +/- 1.5 pmol/mm in S3). When related to cellular volume measured by planimetry, intracellular sorbitol concentration was calculated to be 51 mmol/l in papillary collecting duct and inositol 28 mmol/l in outer medullary thick ascending limb cells. These data confirm the role of sorbitol in the renal concentrating process in papilla. Inositol seems to have additional function in thick ascending limb of Henle's loop and the proximal tubule.

Glycerophosphorylcholine (GPC), sorbitol and inositol were quantitated in renal tubule suspensions from inner and outer medulla of untreated Sprague-Dawley rats to study the regulation of organic osmolyte concentrations under different metabolic conditions and varying extracellular osmolalities in vitro. Inner medullary tubules prepared in hypertonic saline (550 mosm/kg) contained osmolyte concentrations comparable to those found in the kidney in vivo. Incubation for up to 8 h at 5 mmol/l glucose increased sorbitol in the inner medullary tubules and medium in an osmolality-dependent fashion, whereas GPC and inositol remained constant. At a given glucose concentration the rate of sorbitol formation decreased linearly with increasing tubular sorbitol concentration, which was regulated by an osmolality-dependent export mechanism. Perturbation of tubular mechanisms by inhibition of glycolysis or oxidative phosphorylation did not change the tubular osmolyte content. In contrast to papilla outer medullary tubules contained only inositol. Lactate added as a metabolic substrate to the outer medullary tubules did not change the cellular inositol levels. In outer medullary tubules osmolality changes (320-710 mosm/kg) had no effect on tubular inositol. Addition of furosemide was without effect, when added in vitro. The results indicate that tubular sorbitol formation is regulated by glucose concentration, the level of tubular sorbitol, and an osmolality-dependent export mechanism. In contrast, cellular inositol and GPC levels seem to be independent of acute changes in tubular metabolism.

Cultured nephron epithelia offer an advantage as they are available in a completely controlled monolayer environment. Some of the culture systems retain differentiated properties for a time span sufficient to study long term chemical and physical events in epithelia of defined nephronal origin. The characteristics expressed in culture include transepithelial voltage and resistance in cells derived from distal nephron segments, and the hormonal dependence of these parameters. Na-K-ATPase activity and its selective regulation by steroid and thyroid hormones has been evaluated in defined epithelial monolayers. Further, the acute stimulation of adenylate cyclase activity has been demonstrated in human nephron culture, and the Na-coupled glucose transport is present in cortical cell cultures. Transepithelial voltage and Na-K-ATPase activity may be considered complex and highly differentiated expressions of function as they are indicative of several apical and basal transporter systems in cultured polarized nephron cells. The intention of current work is to establish functional lines from defined segments of the nephron, using strategies of passage, cloning, and transfection.

75 patients underwent simultaneous appendectomy, when gall bladder, stomach or large bowel were chiefly operated. Complications of incision marks were observed in six cases, but only one of them being possibly due to appendectomy. Six common complications could not be explained by additional operation. Postoperative treatment was not extended. 5 patients died due to the severity of their main disease. Prophylactic or simultaneous appendectomy were conditionally recommended and subjected to a decision by a fully experienced surgeon.

Long-term effects of nicotine on cultured cells derived from defined segments of the nephron were studied in vitro. Nicotine was added during a 10-day incubation period to a defined nephron culture medium (NCM) which had been supplemented with one of the following: fetal calf serum (FCS), dexamethasone (D), aldosterone (A), or epidermal growth factor (EGF). Thymidine incorporation (10(-15) mmol/10(3) cells) into cultured cells of the cortical thick ascending loop of Henle (TAL) and of the cortical collecting tubule (CT) was inhibited by nicotine (5 X 10(1) ng/ml) when incubated in NCM only; the presence of FCS or of D (10(-8) M) or of D and EGF (25 ng/ml) prevented this inhibitory effect. Nicotine at a concentration of 5 X 10(2) ng/ml was inhibitory in TAL and CT even in the presence of FCS. Na-K-ATPase activity (pmol/10(3) cells X min-1) was stimulated significantly by D when compared with NCM; nicotine (5 X 10(2) ng/ml) prevented this inductive effect. Transepithelial voltage was 27.1 +/- 6 (mV) after incubation with A (10(-9) M), and 7.2 +/- 4.1 when incubated with A and nicotine (5 X 10(2) ng/ml). These data indicate that nicotine may interfere with factors stimulating cell proliferation, sodium pump enzyme activity, and ion flux (voltage). An effect of nicotine on the cellular Na-entry step would be consistent with the data.

Primary monolayer cultures of polarized epithelia were derived from single cortical collecting tubules (CCT) of the mammalian kidney (rabbit). The expression of Na-K-ATPase activity (mol 10(-15)/min.cell) and of the transepithelial voltage (VT) in monolayers on membranes was measured in response to defined hormonal supplements of the nephron culture medium (NCM). Hormones were: triiodothyronine (T3; 10(-11) M), dexamethasone (10(-8) M), and aldosterone (10(-9) M). Control was NCM plus fetal calf serum (FCS; 3% v/v). Data are mean (SEM). Na-K-ATPase activity was 10.4 (6.2) in control (n = 27); 18.8 (5.2) in T3 (n = 35); 21.2 (5.5) in dexamethasone (n = 26), and 30.9 (6.5) in aldosterone (n = 24). VT (mV) was 4.2 (3.2) in control (n = 12); 12.7 (3.7) in T3 (n = 12); 16.8 (2.5) in dexamethasone (n = 12), and 28.4 (3.6) in aldosterone (n = 14). Data are evidence that thyroid and corticosteroid hormones selectively induce the postmitotic expression of the sodium carrier activity and other functions related to vectorial solute transport in this polarized epithelium.

A complete documentation of the clinical and operative findings and a comparison of these with the histologic diagnosis in nearly 900 appendectomy patients from a period of more than two years is presented. In this publication an account of the specific results of nearly 500 women is given. The influences of age, menstruation, and gynecologic illnesses are reported in detail. Sixty-five percent of all women were treated unnecessarily with appendectomy. However, the indications for this operation should not be limited on these grounds.