[Evidence-based rehabilitation of mobility after stroke]. / Evidenzbasierte Rehabilitation der Mobilität nach Schlaganfall.

BACKGROUND: Approximately two thirds of stroke patients initially suffer from at least impaired mobility. Various rehabilitation concepts have been proposed. OBJECTIVE: Based on the current literature, which rehabilitation methods can be recommended for improvement of gait, gait velocity, gait distance and balance? METHODS: A systematic literature search was carried out for randomized clinical studies and reviews with clinically relevant outcome variables. Formulation of recommendations, separated for target variables and time after stroke. RESULTS: Restoration and improvement of gait function relies on a high number of repetitions of gait movements, which for more severely affected patients is preferentially machine-based. For improvement of gait velocity for less severely affected patients intensive gait training does not necessarily rely on mechanical support. Gait distance can be improved by aerobic endurance exercises with a cardiovascular effect, which have to be performed in a functional context. Improvement of balance should be achieved by intensive functional gait training. Additional stimulation techniques are only effective when included in a functionally relevant training program. DISCUSSION: These guidelines not only provide recommendations for action but also provide pathophysiological insights into functional restoration of stance and gait after stroke.

Groundwater intrusion into leaky sewer systems.

Vast volumes of groundwater are drained by urban sewer systems. This unwanted flow component intrudes into sewer systems through leaky joints or connected house drains. However, unlike urban storm drainage, it has a high seasonal variation corresponding to groundwater storage and long slow recessions similar to baseflow in rivers also fed by shallow groundwater exfiltrating into the surface waters. By applying the nonlinear reservoir algorithm as used for baseflow separation from total flow in a river, groundwater flow is separated from daily measured influents to treatment plants in Lower Saxony and Baden-Württemberg, Germany and in the Terkos Lake watershed near Istanbul, Turkey. While waste water flows vary only moderately within a year, separated intruded groundwater flows show recessions and seasonal variations correlated to baseflow in neighbouring rivers. It is possible to conclude that recession characteristics of treatment plant influents allow quantification and prediction of groundwater intrusion into sewer systems.

Effect of inhibition of synthesis and receptor antagonism of SRS-A in cardiac anaphylaxis.

The effects of infusions of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 1.1 X 10(-7) mol min-1) and the antagonist of slow-reacting substance of anaphylaxis (SRS-A) FPL 55712 (1.2 X 10(-7) mol min-1) on the coronary constriction and the release of SRS-A, leukotreine C4-like immunoreactivity, thromboxane B2 and 6-keto-prostaglandin F1 alpha from perfused anaphylactic guinea-pig hearts were investigated. Both NDGA and FPL 55712 in the concentrations used induced an increase in basal coronary flow, but did not prevent the coronary flow reduction in the early phase (0-4 min) after antigen injection. On the other hand, NDGA and FPL 55712 inhibited the less pronounced long-lasting coronary flow reduction in the later phase of cardiac anaphylaxis. NDGA decreased the release of SRS-A from the anaphylactic guinea-pig hearts below or close to the detection limit of the bioassay and simultaneously diminished the release of leukotriene C4-like immunoreactivity. On the other hand, FPL 55712 did not influence the amounts of leukotriene C4-like immunoreactivity released in cardiac anaphylaxis. Neither NDGA nor FPL 55712 affected the release of immunoreactive thromboxane B2 (TXB2) from anaphylactic guinea-pig hearts. Release of 6-keto-prostaglandin F1 alpha after challenge, however, was decreased by NDGA, while FPL 55712 had no significant effect. These results suggest, that SRS-A may be a relatively more important mediator in the late phase of coronary constriction occurring during cardiac anaphylaxis, while the effects of other mediators, particularly vasoconstrictor cyclo-oxygenase products, seem to prevail in the early phase.

[Effect of sulfasalazine and its metabolites on prostaglandin and leukotriene liberation from human synovial tissue]. / Der Effekt von Sulfasalazin und seiner Metabolite auf die Prostaglandin- und Leukotrien-Freisetzung aus menschlichem Synovialgewebe.

The effects of sulfasalazine (SASP) and its metabolites sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) were investigated on release of prostaglandins (PG) and leukotrienes (LT) from synovial tissue of 37 patients with osteoarthritis, chondrocalcinosis and rheumatoid arthritis. Calcium ionophore A23187 significantly increased the release of PGE2, 6-keto-PGF1 alpha, LTB4, and LTC4 from human synovial tissue irrespective of the underlying joint disease. SASP inhibited release of LTC4 and increased release of PGE2. On the other hand, 5-ASA and SP inhibited the release of all eicosanoids measured. The effective concentrations of SASP and SP were found to be in the range which can be reached during SASP therapy. On the other hand, blood and synovial fluid levels of 5-ASA are considerably lower than those which inhibit eicosanoid synthesis in vitro. While nonsteroidal anti-inflammatory drugs, which are used for symptomatic therapy of rheumatoid arthritis, inhibit cyclooxygenase only, SP, the active metabolite of the second line anti-rheumatic drug SASP, inhibits both PG and LT release. Inhibition of LT synthesis by SASP and SP could contribute to the second line efficacy of SASP therapy in rheumatoid arthritis.

Intracellular free Ca2+ in the course of the Ca2+ paradox and during poisoning. Ca2+-selective microelectrode measurements in the perfused rat heart.

The free intracellular Ca2+ concentration of perfused rat hearts was measured using Ca2+-selective microelectrodes. In Krebs-Ringer bicarbonate buffer + 0.1 mmol/l Ca2+ (controls) the intracellular Ca2+ concentration was 0.87 +/- 0.07 mumol/l and the membrane potential was -51.5 +/- 0.3 mV. Without glucose the membrane potential approached zero after ca. 60 min, whereas the Ca2+ concentration during 110 min increased only slowly to 10.0 mumol/l. During Ca2+-free perfusion (5 min) both parameters did not change significantly. With reintroduction of 2.0 mmol/l Ca2+ the membrane potential rapidly collapsed and the intracellular Ca2+ concentration was elevated above 0.1 mmol/l within two min. Reperfusion with only 0.1 mmol/l Ca2+ decelerated both changes. Poisoning by carbonyl cyanide-p-trifluoromethoxyphenylhydrazone or antimycin A in Ca2+-free Krebs-Ringer bicarbonate buffer increased the intracellular Ca2+ concentration to 30.0 and 25.0 mumol/l, and the membrane potential was collapsed after 16 and 10 min, respectively. In antimycin A- and Ca2+-containing sucrose medium the intracellular Ca2+ during 16 min increased above 1.0 mmol/l, and the membrane potential began to increase only after 10 min. The results are consistent with the postulate of a hypothetical mechanism of cell injury, in which noxious membrane-cytoskeleton interactions are induced by an elevated intracellular Ca2+ concentration. It is concluded that Ca2+ entry via Na/Ca exchange is not fundamentally involved with induction of injury.

In vitro inhibition of phospholipase A2 by gabexate mesilate, camostate, and aprotinine.

Gabexate mesilate (FOY, ethyl-p-(6-guanidino-hexanoyl-oxy)-benzoate-methansulfonate), camostate (N,N-dimethyl-carb-amoylmethyl-4-(guanidinobenzoyloxy)-phenyl-acet ate) methansulfonate and aprotinine (Trasylol) were tested for possible inhibition of phospholipase A2. Gabexate mesilate at a concentration of 5 x 10(-4) mol/l and camostate at a concentration of 10(-3) mol/l caused a 50% reduction in enzyme activity. There was almost no inhibition by aprotinine at clinical doses; 40 million KIU/l were necessary to reduce phospholipase A2 activity by 20%. From the therapeutic dose (4,000 mg/day per i.v. infusion) and the half-life of gabexate mesilate in blood circulation (1 min) it can be calculated that the in vitro concentration of gabexate mesilate is only 10(-6) to 10(-7) mol/l. Under these conditions gabexate mesilate cannot diminish the in vivo enzyme activity of phospholipase A2.

Myocardial cell damage and breakdown of cation homeostasis during conditions of ischaemia and reperfusion, the oxygen paradox, and reduced extracellular calcium.

Enzyme release from perfused rat heart was determined under various conditions of injury. In analogous experiments, intracellular cation concentrations were measured using ion-selective microelectrodes. Under appropriate conditions, the inhibition of mitochondrial and/or glycolytic ATP production led to a decrease in the release of enzymes. During ischaemia or the oxygen paradox, the sarcosolic Ca2+ concentration was highly elevated; reperfusion or reoxygenation was followed by a drastic enzyme release. This was also found to be true under the conditions of an increased permeability brought about by a reduced extracellular Ca2+ concentration of 0.1 mmol/l. The intracellular pH under all conditions of injury was only moderately decreased. The sarcosolic Na+ concentration was markedly increased whereas the K+ concentration was decreased. The critical Ca2+ concentration of the sarcosol beyond which cell damage and enzyme release are inducible was assumed to be in the range between 10 and 32 mumol/l. The driving force of the Na+/Ca2+ exchange reaction of the sarcolemma is discussed in relation to recovery from hypoxic injury and the potential for avoiding cell damage.

The decline in catalytic enzyme activity concentration with aging of the rabbit erythrocyte.

Rabbit erythrocytes were separated by centrifugation on a discontinuous Percoll gradient into fractions of progressively increasing cell age to measure the in vivo decline in catalytic activity of eleven enzymes during the erythrocyte life span. Erythrocyte enzymes decline exponentially at different rates. The maximal and minimal catalytic activities (erythrocyte catalytic activity at the beginning and at the end of the erythrocyte life span), the intracellular half-life of enzymes and the daily loss of catalytic activity of total body erythrocytes were estimated.

Enzyme release from the perfused rat heart. The functions of the cytoskeleton under cell-pathological conditions.

The mechanism of enzyme release from Langendorff-perfused rat hearts was studied under the injury conditions of the Ca2+ paradox and 2,4-dinitrophenol poisoning. During perfusion with Krebs-Ringer buffer or in buffered sucrose sarcoplasmic enzymes were massively released when Ca2+ was reintroduced to the perfusion medium (Ca2+ paradox). Mitochondrial matrix enzymes were released to a very small extent. Only the cytoplasmic isoenzyme of the bilocular enzyme malate dehydrogenase was released. The release kinetics of various enzymes with greatly differing molecular weights showed no significant differences. Qualitatively the same results were obtained under 2,4-dinitrophenol poisoned conditions in Ca2+ -free sucrose media. Sarcoplasmic enzymes were massively released, mitochondrial enzymes did not appear in the perfusate. 2,4-Dinitrophenol poisoning alone was not sufficient to cause enzyme release. An additional swelling under these conditions was necessary. ATP from the extracellular space was able to enhance the enzyme release, which was brought about by 2,4-dinitrophenol and cell swelling. A hypothesis is presented that enzyme release is produced by initiating a membrane blebbing process. An elevated intracellular Ca2+ concentration is a necessary prerequisite. In the presence of ATP, active membrane blebbing is caused by contractions of the membrane-anchored cytoskeleton. In the absence of ATP passive membrane blebbing is induced by cell swelling, provided that the cytoskeleton has been crosslinked by Ca2+.

Modulation of eicosanoid release from anaphylactic guinea-pig heart with 5-benzoyl-a-methyl-2-thiophene acetic acid (tiaprofenic acid).

The effects of infusion of the non-steroidal anti-inflammatory drugs (NSAID), tiaprofenic acid (2.2 micrograms/min or 10.0 micrograms/min) and indomethacin (1.0 microgram/min) on the release of leukotriene (LT) C4-like immunoreactivity, thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha from isolated perfused anaphylactic guinea-pig hearts were investigated. Tiaprofenic acid at both concentrations used significantly inhibited anaphylactic release of TXB2 and 6-keto-PGF1 alpha as did indomethacin (1.0 microgram/min) which was, however, about ten times more potent in this respect. Release of immunoreactive LTC4-like material was not influenced by the lower concentration of tiaprofenic acid used (2.2 micrograms/min), but significantly enhanced by the higher concentration (10.0 micrograms/min). Thus, the effect of tiaprofenic acid on eicosanoid release by the anaphylactic heart is very similar to that of indomethacin without any differential inhibition of TXB2 or 6-keto-PGF1 alpha formation.

[Gallstone formation following transmural migration of a surgical clip in the bile ducts. Case report]. / Gallensteinbildung nach transmuraler Einwanderung eines Operationsclips in die Gallenwege. Kasuistik.

Foreign bodies as a nucleus for precipitation of gall-stones are not frequently observed. The combination of primary immigrated foreign bodies into the bile ducts and following encasing by a gall-stone could be even more rarely found. A case report is presented concerning a patient, in whom a hemo-clip was fixed away from the bile-ducts in connection with a cholecystectomy and revision of the common bile-duct. After hospital admission because jaundice in the PTC was found a prepapillary concrement with a central hemo-clip, which has served as a nucleus for precipitation after transmural immigration.

The decline of catalytic enzyme activity concentration of in vivo ageing erythrocytes of the man, the dog and the rat. Approach to a quantitative diagnostic enzymology, IV. Communication.

Human, dog and rat erythrocytes were separated by centrifugation on a discontinuous buffered Percoll gradient into fractions of progressively increasing mean cell age to measure the in vivo decline in catalytic activity of eleven enzymes during the erythrocyte lifespan. Erythrocyte enzymes decline exponentially at different rates and also differ between the species. The maximal and minimal catalytic activities (erythrocyte catalytic activity at the beginning and at the end of the appropriate erythrocyte life-span for a given species) and the intracellular half-life of enzymes estimated. To test the hypothesis that circulating erythrocytes make a significant contribution to the normal catalytic activity in plasma it was assumed as a working hypothesis that the measured loss of catalytic activity in ageing erythrocytes is equivalent to the amount of the enzymes released in catalytically active form into plasma. This contribution was calculated.

Kinetic of adjustment of enzyme catalytic concentrations in the extracellular space of the man, the dog and the rat. Approach to a quantitative diagnostic enzymology, V. Communication.

The high degree of constancy of enzyme catalytic activity in the plasma of a given individual is regulated by a complex system of flux equilibria consisting of eight basic processes. Some of these processes are of primarily theoretic importance. Enzymes from all tissues of the body, including the liver, are released via a continuous physiological process into the interstitial space and get into the intravascular space by way of lymphatic transport. The release of enzymes from tissues directly into the intravascular space is of secondary importance as is the exchange of enzyme molecules across capillary membranes from the intravascular to the interstitial space and vice versa. In contrast, enzymes from circulating blood cells are transported directly into the intravascular space. Enzymes are removed from the intravascular space at rates which vary greatly between both enzymes and species. In a review of the literature, half-lives of diagnostically important enzymes in plasma of man, dogs and rats were given and the striking differences in the results for a given enzyme are discussed from a methodological point of view. In a mathematical analysis, data for lymphatic transport of enzymes from dogs and rats (Lindena et al. (1986) this J. 24, 19-33) and of enzyme efflux from in vivo ageing erythrocytes (Lindena et al. (1986) this J. 24, 49-59) into the plasma are related to the elimination rate constants of enzymes from the plasma. The contribution of lymphatically transported enzymes to the basal catalytic activity in plasma (Lindena & Trautschold (1986) this J. 24, 11-18) amounts to 55-80% for lactate dehydrogenase and malate dehydrogenase, 80-90% for adenylate kinase and phosphohexose isomerase, 90-95% for aspartate aminotransferase and aldolase and 99% for creatine kinase. A model of Ca2+ -mediated vesicular transport of enzymes out of ageing erythrocytes is proposed. The importance of lymphatically transported enzymes to total plasma catalytic activity in dogs and rats argues for a similar contribution of lymph transport in man.

Role of the respiratory system in metabolism of N-nitrosamines after simultaneous application of disulfiram.

Subsequent to modification of N-nitrosamine metabolism by disulfiram, mucus-producing cells and Clara cells in the respiratory tract are involved increasingly in detoxification as well as in bioactivation of N-nitroso-N-methylbenzylamine and N-nitrosodibutylamine. Overtaxing of these cells or local concentration of antigenic metabolites leads to cytolytic defects in tracheal, bronchial and bronchiolar epithelium, in addition to toxic degenerative lesions. The resulting continuous stimulation of proliferation leads to basal-cell hyperplasia, squamous-cell metaplasia and squamous papillomas. In areas with insufficient differentiation, due to cell proliferation, there is an increased probability that focal mutation, subsequent to alkylation of purine bases, will be passed from one cell generation to the next, with subsequent formation of tumours in the bronchiolo-alveolar region.

Effect of disulfiram on N-nitroso-N-methylbenzylamine metabolism. Biochemical aspects.

The present biochemical experiments show that disulfiram inhibits N-nitroso-N-methylbenzylamine metabolism in the rat. More N-nitroso-N-methylbenzylamine may therefore reach extrahepatic tissues. The pathological lesions observed in the lungs in the present system can be explained by the finding that alkylation of lung DNA is increased and repair processes are impaired by enhanced cell proliferation in this organ.

Effect of anti-inflammatory and analgesic pyrazoles on arachidonic acid metabolism in isolated heart and gastric mucosa preparations.

The effects of acidic and nonacidic pyrazoles on the release of arachidonic acid-derived mediators from isolated perfused anaphylactic guinea pig hearts as well as rat and human gastric mucosa were investigated. High concentrations of the acidic drugs phenylbutazone and oxyphenbutazone as well as of the nonacidic metabolites of metamizol, i.e. 4-methylaminoantipyrine and 4-aminoantipyrine, inhibited the release of the cyclo-oxygenase products of arachidonic acid metabolism, TXB2 and 6-keto-PGF1 alpha, and simultaneously increased the release of LTC4-like immunoreactivity in hearts. By contrast, comparatively high concentrations of the metamizol metabolites 4-formylaminoantipyrine and 4-acetylaminoantipyrine were without effect. The comparable effects of acidic and nonacidic pyrazoles on eicosanoid release from anaphylactic hearts support the concept that hypersensitivity reactions to NSAIDs are related to their effect on arachidonic acid metabolism. The anti-inflammatory effects of phenylbutazone and oxyphenbutazone and of high concentrations of metamizol seem to be correlated with the inhibition of cyclo-oxygenase. On the other hand, lower concentrations of metamizol, which have analgesic and anti-pyretic effects, only marginally inhibit cardiac cyclo-oxygenase. It remains to be investigated whether the partial inhibition of the synthesis of PGI2, a major hyperalgesiccyclo-oxygenase product of arachidonic acid metabolism, at lower concentrations of the active metamizol metabolites contributes to the analgesic effect of metamizol. The acidic NSAID mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) had no effect on the cardiac release of arachidonic acid-derived cyclo-oxygenase and lipoxygenase products. The anti-inflammatory effect of these compounds requires further investigation. In isolated gastric mucosa, the active metabolite of metamizol 4-methylaminoantipyrine was found to inhibit fatty acid cyclo-oxygenase dose-dependently. Pharmacokinetic differences due to the nonacidic structure of metamizol and its metabolites as compared to acidic NSAIDs may be responsible for the fact that metamizol is better tolerated than e.g. indomethacin. In rat experiments, phenylbutazone was found to inhibit gastric mucosal cyclo-oxygenase like indomethacin. On the other hand, mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) did not affect gastric mucosal synthesis of 6-keto-PGF1 alpha. This lack of effect on gastric mucosal cyclo-oxygenase seems to be correlated with the considerably lower gastric toxicity of mofebutazone as compared to phenylbutazone.

Treatment of chronic hepatitis B with interferon alfa-2b.

A total of 58 patients with histologically confirmed chronic viral hepatitis B and presence of hepatitis B surface antigen and hepatitis B virus DNA (HBV DNA) in the serum were randomized in a prospectively controlled trial. Thirty patients were treated with 3 megaunits of recombinant interferon alfa-2b (INTRON A, R Schering-Plough, Essex Corporation) subcutaneously thrice weekly for 4 months. Twenty-eight controls received no treatment. The post-treatment follow-up period consisted of 6 months. Twenty-eight treated patients and 27 controls completed the protocol. One female patient of the treatment group showed a complete response, and eight other treated patients (32%) showed a partial response to therapy. Three patients in the control group (11%) lost hepatitis B e antigen and HBV DNA spontaneously. This finding is statistically significant (p less than 0.05). The elimination of hepatitis B virus markers from the serum was associated with a normalization of aminotransferase activities in the serum. Reactivation of hepatitis was not observed after seroconversion.

[Treatment of chronic hepatitis B with interferon alpha-2b]. / Behandlung der chronischen Hepatitis B mit Interferon alpha-2b.

In a prospective randomized trial 58 patients (46 men, 12 women; mean age 41 [18-65] years) with histologically proven chronic hepatitis B and demonstration of HBs antigen and hepatitis B virus DNA in serum were randomly divided into two groups: 30 patients were treated with recombinant alpha 2b interferon. The interferon was administered subcutaneously, 3 x 10(6) IU, three times weekly for four months. 28 patients served as untreated controls. There was a six-month post-treatment follow-up. Two patients in the treatment group and one in the control group had to be excluded later. In the treatment group one patient responded completely (HBs antigen, HBe antigen and HBV-DNA negative) and eight partially (HBe antigen and HBV-DNA negative). In three patients of the control group, HBe antigen and HBV DNA were no longer demonstrated (P less than 0.05). The loss of HBV features was associated with normalization of serum transaminases activity. Reactivation of liver inflammation after seroconversion was not observed.

Low dose alpha interferon treatment in chronic hepatitis B virus infection.

Fifty eight patients with chronic viral hepatitis B (HBV) were randomised in a prospectively controlled trial. Thirty patients were treated with 3 million units (MU) of interferon alfa-2b subcutaneously thrice weekly for four months. Twenty eight controls received no treatment. The follow up period after treatment was six months. Twenty eight treated patients and 27 controls completed the protocol. One woman in the treatment group showed a complete response, and eight other treated patients (32%) showed a partial response. Three patients in the control group (11%) lost hepatitis B e antigen and HBV-DNA spontaneously. This finding is statistically significant (p < 0.05). The elimination of HBV markers from the serum was associated with a return to normal of serum aminotransferase activities. Reactivation of hepatitis was not observed after seroconversion.