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BACKGROUND: Blockage of tumour necrosis factor alpha (TNFalpha) is highly effective in rheumatic diseases, especially in rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. Furthermore, TNFalpha antagonists have also been shown to significantly reduce psoriatic skin lesions. CASE REPORTS: A series of nine patients with RA who were treated with different types of TNFalpha antagonists and who unexpectedly developed either a new onset or an exacerbation of psoriatic skin lesions are reported.

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Using isolated amyloplasts from cauliflower buds, we have characterized the interaction and transport of various carbohydrates across the envelope membrane of a heterotrophic plastid. According to our results, glucose 6-phosphate (Glc6P) and glucose 1-phosphate (Glc1P) do not share the same transport protein for uptake into cauliflower-bud amyloplasts. Glc6P-dependent starch synthesis is strongly inhibited in the presence of dihydroxyacetone phosphate (DHAP) or 4,4'-di-isothiocyano-2,2'- stilbenedisulphonic acid (DIDS), whereas Glc1P-dependent starch synthesis is hardly affected by these compounds. Analysis of the Glc6P uptake into proteoliposomes reconstituted from the envelope proteins of cauliflower-bud amyloplasts indicate that Glc6P is taken up in a counter-exchange mode with Pi, DHAP or Glc6P, whereas Glc1P does not act as a counter-exchange substrate. Pi is a strong competitive inhibitor of Glc6P uptake (Ki 0.8 mM) into proteoliposomes, whereas Glc1P does not significantly inhibit Glc6P transport. Beside a hexose-phosphate translocator, these amyloplasts possess an envelope protein mediating the transport of glucose across the membrane. This translocator exhibits an apparent Km for glucose of 2.2 mM and is inhibited by low concentrations of phloretin, known to be a specific inhibitor of glucose-transport proteins. Maltose inhibits the uptake of glucose (Ki 2.3 mM), indicating that both carbohydrates share the same translocator.

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In order to assess the metabolic effects of walking-through phenomenon during treadmill exercise the fluctuations of lactate and pyruvate concentration in arterial and popliteal venous blood and the changes in the lactate pyruvate ratio were studied in seven patients with arterial occlusive disease. During exercise, significant differences in venous lactate, lactate pyruvate ratio and arterial venous differences in lactate were found in patients with walking-through phenomenon. It is concluded that the rate of anaerobic glycolysis is reduced in patients with walking-through phenomenon.

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During intermittent exercise lasting six minutes with two minutes' rest the fluctuations in arterial and venous blood of lactate, pyruvate and blood gases as well as changes in the lactate pyruvate ratio were studied in eleven patients with intermittent claudication. There were significant differences of O2-extraction during intermittent exercise. The level of arterial lactate did not vary significantly. The highest venous lactate was found during the rest period. Significant differences in venous lactate, pyruvate and lactate pyruvate ratio were found between the first and second exercise periods. It is assumed that the rate of glycolysis is reduced during intermittent exercise.

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Recently, we have demonstrated that isolated cauliflower-bud amyloplasts incorporate glucose 6-phosphate at high rates into newly synthesized starch (Neuhaus et al. (1993) Plant Physiol. 101, 573-578). Here we have analyzed the incorporation of radioactively labeled glucose and ADPglucose into newly synthesized starch. It could be shown that glucose incorporation into starch exhibits a typical substrate saturation behaviour and is linear with time for at least 40 min. The incorporation of glucose is strongly dependent upon the intactness of the plastids and upon the presence of both, ATP and 3-phosphoglyceric acid. Using 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) we showed that glucose is taken up into isolated cauliflower-bud amyloplasts as the free glucose molecule, rather than as glucose 6-phosphate. Glucose incorporation into newly synthesized starch is strongly inhibited in the presence of low concentrations of glucose 6-phosphate. The radioactively labeled glucose moiety of ADPglucose is also incorporated into starch. This incorporation can be saturated at increased concentrations of ADPglucose. ATP significantly inhibits the incorporation of the glucose moiety of ADPglucose into starch. This inhibition can be reinforced by the additional presence of glucose 6-phosphate. Glucose 6-phosphate-dependent starch synthesis is not strongly inhibited in the presence of glucose or ADPglucose indicating that glucose 6-phosphate is the precursor for starch synthesis in isolated cauliflower-bud amyloplasts.

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8 patients with arterial occlusive disease were examined for the quantity of their lactate acidose during two treadmill tests. Test I was interrupted after 6 minutes. 20 minutes later test II followed. Lactate, pyruvate and blood gases were determined. There are significant differences between these two exercise tests in term of lactate differences between rest and exercise. It is assumed that the rate of glycolysis is reduced during exercise in test II.

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In a controlled multicenter study 70 patients with chronic arterial occlusive disease stage IV according to Fontaine's classification were randomised to treatment with prostaglandin E1 (PGE1) or pentoxifylline (PX), administered over 4 weeks. Parameters of effectiveness were the reduction of analgesics, the relief of rest pain according to an analogue scale, the improvement of the ulceration according to an ulcer score and the healing of necrotic area. The results show that both forms of treatment produced a significant reduction in analgesic consumption and rest pain. Moreover in both groups a significant reduction of the ulcer score and healing of the necrotic area were observed. Side effects occurred in six patients of the PGE1-group and in ten patients of the PX-group, which required premature discontinuation of treatment in four patients of the PX-group. The study also demonstrated that PGE1 is more effective in the treatment of severe arterial occlusive disease than PX. With respect to the analgesic consumption, the reduction of ulcer score and the healing of necrotic area a significant difference was found in favour of PGE1. In accordance the six months follow-up examinations showed a marked deterioration in the PX-group opposed to the PGE1-group. The intravenous application of PGE1 over a period of 4 weeks in patients with severe arterial occlusive disease seems to be an effective therapeutical principle.

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Lactate and pyruvate movements in arterial and venous blood during recovery following treadmill exercise in 8 patients with arterial occlusive disease were studied by means of a two-compartment model. Blood lactate and pyruvate concentration curves over the recovery period were found to fit a two-exponential time function including a rapidly increasing and a slowly decreasing component. The velocity constants gamma 2 were dependent on the exercise load. The time of lactate disappearance during recovery decreased with the work load in patients with intermittent claudication. The velocity constant of the arterial blood pyruvate decrease was similar to that of the simultaneously measured lactate indicating that the rate of lactate removal is closely related to that of pyruvate. In conclusion, the use of the model allows to study factors likely to modify the coefficients, such as physical training, therapeutic effects and active recovery.

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During intermittent exercise with periods of six minutes with two minutes pause the fluctuations in arterial and popliteal venous blood of lactate and pyruvate as well as changes in the lactate pyruvate ratio were studied in eleven patients with claudicatio intermittens. Oxygen uptake stabilizes itself within 4-6 min during exercise and VO2 at the end of an exercise period is higher than in the beginning of recovery. The level of arterial lactate does not vary significantly. The highest venous lactate was found in the pause. Significant differences in venous lactate, pyruvate and lactate pyruvate ratio were found between the first and second exercise. It is concluded that during intermittent exercise less glycogen was used and that this glycogen saving effect seems to have been accomplished both by a shift towards more oxidative metabolism and by a greater contribution from other substrates than glycogen.

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Parameters characterizing the hemoglobin oxygen affinity were determined in blood of 12 male patients suffering from arterial occlusive disease (AOD) of the legs and compared with data obtained earlier from healthy human subjects (controls). Due to a COHb content of 4.8% +/- 2.2% in the cigarette-smoking AOD patients, the standard oxygen dissociation curve (ODC) was left-shifted, the half-saturation pressure (P50) amounted to 24.8 +/- 1.7 mmHg (3.30 +/- 0.23 kPa), although the 2,3-diphosphoglycerate concentration was increased to 15.3 +/- 1.7 mumol/g Hb. Correcting the effects of elevated COHb shifts the P50 to 26.3 mmHg (3.5 kPa) and increases the steepness of the ODC (Hill's "n") from 2.79 +/- 0.27 to about 2.99, which is significantly different from controls. The Bohr coefficients after acidification of blood with lactic acid (BCLac) show high values at low oxygen saturations of hemoglobin (-0.50 +/- 0.04 in AOD patients, -0.32 +/- 0.04 in controls; P less than 0.05 at 10% SO2). The cause of the alterations in hemoglobin oxygen affinity may be a reduced mean erythrocyte age, but also the influence of unknown factors generated, e.g., from anaerobic muscle metabolism in AOD.

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In a double blind, randomized multicenter study naftidrofuryl, a vasoactive substance, was compared with placebo in the treatment of 104 patients with chronic arterial occlusive disease. After a run-in period of four weeks the patients received either naftidrofuryl (600 mg daily) or placebo over 12 weeks. The pain-free and the total walking distances improved significantly in both groups. However, the difference in the improvement of the pain-free walking distance was significant (p less than 0.02) in favour of naftidrofuryl. There also was a difference in the improvement of the total walking distance in favour of naftidrofuryl which was not significant. The results indicate that naftidrofuryl has a beneficial effect on the symptoms and lengthens the painfree walking distance in patients with arterial occlusive disease.

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The efficacy of naftidrofuryl ( Dusodril ) for treatment of stage II arterial occlusive disease was evaluated in a controlled multi-centre study in a total of 104 out-patients with angiographically documented localization of occlusion. The therapeutic effect was assessed over three months by measurements of walking distance using standardized treadmill conditions. Further parameters were venoocclusive plethysmography and Doppler ultrasonography measurement of pressures. The complaint-free walking distance increased significantly during daily application of 600 mg naftidrofuryl orally (n = 54) during the 12-week assessment period when compared to the placebo group (n = 50). Taking the intraindividual variability of 17.2 m in assessment of walking distance into account, the increase of painless walking of 93 m after treatment for 12 weeks in the active-drug group is considered the result of treatment-induced increased performance.

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The objective metabolic evaluation of the insufficiency of the peripheral circulation in patients with arterial occlusive disease has proved to be very intricate. Previously blood specimen were taken more proximally from the femoral vein and not from the draining blood vessel of the exercised muscles. Consequently the analysed blood samples contained a higher degree of blood from non-ischemic muscle. This methodological problem could be overcome by introducing a catheter into the popliteal vein. This new technique permits to study the spontaneous and reactive metabolic changes in the legs during and after treadmill exercise in patients with intermittent claudication. Exercise- and post-exercise metabolism was studied in the legs of 18 individuals without arterial occlusive disease and in 76 patients with intermittent claudication. Change of lactate, pyruvate blood gases and acid-base balance was studied inter- and intraindividually in arterial and popliteal venous blood during and after an exhaustive constant load exercise on a treadmill. The metabolic effect during bicycle- and treadmill exercise was compared intraindividually. During exercise, the difference between the arterio-popliteal venous blood samples in lactate concentrations was significantly higher in patients than in controls. In general, patients had a significantly higher lactate-pyruvate ratio in the popliteal venous blood than in the arterial blood. During treadmill exercise the popliteal venous PO2 did not fall below 16.5 +/- 1.1 mmHg in the controls. Individual values during exercise varied from 6.4 mmHg to 18.1 mmHg in patients. The transition from supine at rest to upright position on the treadmill reduced the popliteal venous oxygen saturation from 49.4% to 26.3% in the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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Blood gases and lactate and pyruvate concentration were measured in arterial and popliteal venous blood in 6 control subjects and 34 patients with intermittent claudication before, during, and after treadmill exercise of 10 min duration. Oxygen saturation, oxygen extraction, base excess, and standard bicarbonate were calculated. The transition from resting supine position to upright position on the treadmill caused the popliteal venous oxygen saturation to fall from 49.4% to 26.3%. In patients, during exercise a further decrease (to 11%) was observed. During treadmill exercise the popliteal venous PO2 did not fall below 16.5 +/- 1.1 mm Hg in the controls. Individual values during exercise varied between 6.4 mm Hg and 17.9 mm Hg in patients. A critical oxygen pressure was reached in 10 patients. Lactate concentration was found to increase to values as high as 14 mmol/l in popliteal venous blood. The lactate-pyruvate ratio varied between 12.9 and 106.3 during exercise, and the corresponding values for venous blood pH were 7.38 and 6.92. Changes in the PCO2, lactate, and pH in arterial and popliteal venous blood showed a significant correlation. The decrease in the base excess was greater than the corresponding increase in the blood lactate concentration. It is concluded that analysis of the acid-base balance in patients with intermittent claudication is best carried out by the regional catheterization technique.

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Exercise and post-exercise metabolism was studied in the legs of 6 healthy individuals without arterial occlusive disease and in 34 patients with intermittent claudication. Venous blood from the popliteal vein was taken intermittently by regional catheterization during and after an exhaustive constant load exercise on a treadmill. Change of lactate and pyruvate was studied in arterial and popliteal venous blood. The mean arterial concentration of pyruvate during exercise was increased less in patients and controls as compared to the lactate concentration in both groups. There was a continuous rise of the arterial pyruvate concentration after exercise in patients in contrast to the controls. During exercise, the difference between the arterio-popliteal venous blood samples in lactate concentrations was significantly higher in patients than in the controls. In general, patients had a significantly higher lactatepyruvate ratio in the popliteal venous blood than in the arterial blood. It is concluded that the onset and degree of anaerobic work is best studied by the regional catheterization technique. This new technique permits to study the spontaneous and reactive metabolic changes in the legs during and after treadmill exercise in patients with intermittent claudication.

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