British Journal of Rheumatology 1990,29:142-144
VIEWPOINT
VENOUS LEG ULCERS AND ARTHROPATHY BY P. M. GAYLARDE, H. J. DODD AND I. SARKANY Department of Dermatology, Royal Free Hospital, London NW3 2QG
SUMMARY Reduced ankle mobility impairs the venous muscle pump and this leads to an increase in mean venous pressure in the lower leg. We have previously shown that pressure-induced venous distension leads to cutaneous hypoxia which is caused by arteriolar vasoconstriction in response to a spinal reflex. The prolonged cutaneous hypoxia which is thus a consequence of sustained elevation of venous pressure is an important factor in the development of gravitational ulcers. It is postulated that the increased incidence of leg ulcers in patients with rheumatoid arthritis is the result of impairment of the efficiency of the venous muscle pump by reduced ankle mobility. Conversely, the elevation of venous blood pressure in patients with venous insufficiency may lead to arthropathy in the ankle. The hypothesis is presented that prolonged elevation of venous blood pressure causes injury to both the ankle joint and veins leading to chronic reciprocal damage to both. This explains the frequent association between arthropathy of the ankle and venous leg ulcers. Ankle joint, Venous insufficiency, Ulcer.
IN normal subjects, skin oxygen tension measured at an electrode temperature of 37°C falls on standing to levels close to zero [1, 2]. It rises during exercise to values similar to those seen when the subject is recumbent [1]. The fall in skin oxygen tension seen on standing is the result of a decrease in skin blood flow caused by arteriolar vasoconstriction [3]. This vasoconstrictor reaction is mediated by the release of noradrenaline in response to a spinal reflex activated by stimulation of venous stretch receptors by increased venous pressure [3]. The threshold pressure required to activate this reflex is approximately 25 mmHg [3]. In normal subjects, exercise reduces venous hydrostatic pressure to below this level [4]. When venous pressure falls during exercise [4], the reflex is not activated [5] and skin oxygen tension rises as skin blood flow increases [1]. In patients with venous leg ulcers, venous pressure remains high during exercise [6] when venous abnormalities impair the normal unidirectional blood flow in the veins. The fall in venous pressure below the threshold which activates the vasoconstrictor reflex therefore fails to take place and the normal increase in skin oxygen tension in response to exercise whilst standing is absent [1]. As a result of these observations, we have put forward the hypothesis that venous ulcers are the result of prolonged cutaneous hypoxia when patients with defective venous return are either standing or walking about [1]. This hypothesis accounts for the role of posture in the development of venous ulcers and explains the clinical value of bed rest and elastic compression stockings in the treatment of venous ulcers. The standardized exercise test adopted in our studies was alternate plantar and dorsiflexion at a rate of 60 times per minute [1]. It was noted that a high proportion of patients with venous ulcers were unable to carry out this manoeuvre, either as a result of old injury or arthritic changes in the ankle. This association between ulcers of the lower leg and loss of mobility of the ankle joint has been previously noted [7,8]. Ruckley etal. [8] Correspondence to Dr P. Gaylarde.
found 268 of 827 patients with chronic leg ulcers (32%) had severe limitation of ankle joint movement, but only 9% of the patients had rheumatoid arthritis (RA). A survey of ulcer incidence in patients attending a rheumatology clinic [9] found 20 of 207 patients with RA had leg ulcers compared to an incidence of only 9 of 192 patients with osteoarthritis or spondylosis. The difference in ulcer incidence in the two groups may be attributed to the increased incidence of ankle joint changes in patients with RA and is not accounted for by the occasional occurrence of ulcers due to vasculitis. In contrast, Hach et al. [10] observed that the fall in venous pressure on exercise in patients with venous disease and limited ankle mobility was smaller than in patients with normal mobility and that the incidence of venous leg ulcers was very much greater in the group affected by the loss of normal movement. These workers together with others cited in their paper have postulated that the loss of ankle mobility associated with venous disease may indeed be the result of an arthropathy primarily induced by venous hypertension. Loss of ankle joint mobility will impair the action of the venous muscle pump and will tend to be accompanied by prolonged periods of venous distension in the absence of defective venous valves. Muscle atrophy in the lower leg associated with joint deformity will also impair venous return. Prolonged elevation of venous pressure resulting from the impaired action of the venous muscle pump caused by loss of ankle mobility may directly damage the veins leading to venous reflux; reduced mobility may also increase the incidence of deep vein thrombosis, whilst inflammatory changes in the large vessels associated with RA may lead to direct damage to the veins. On the basis of the hypothesis that venous leg ulcers result from prolonged hypoxia associated with prolonged elevation of venous pressure, it is reasonable to predict that RA will lead to an increased incidence of venous leg ulcers. However, rheumatoid arthritis accounted for less than 30% of those patients with leg ulcers in whom severe limitation of ankle movement was observed [8]. Trauma may result in the 142
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 18, 2015
KEY WORDS:
GAYLARDE ETAL.: VENOUS LEG ULCERS AND ARTHROPATHY
Reduced muscle pump activity
I i
Venous damage
Prolonged venous distension
Arthropathy Inflammation
Venous incompetence Venous reflux
Obstruction of venous return
FIG. 1.—Diagram to show the reciprocal relationship between arthropathy and venous incompetence.
tendency to adhere to vessel walls, especially under conditions of low flow velocity. This adhesion causes the cells to roll slowly along the vessel walls and is inhibited by EDTA [22] and is most prominent in venules. The prolonged diminution of blood flow in standing patients with venous incompetence and the distension of the venules by elevated venous pressure will ensure optimal conditions for granulocyte concentration and adhesion in these vessels; the production of chemoattractants in response to hypoxia [18] will enhance the emigration of granulocytes into the tissues. The inhibition of leucocyte adhesion by deformation in capillaries [23] and the physical factors that tend to exclude leucocytes from the smallest capillaries suggest that the capillary occlusion model which claims that leucocytes plug the vessel lumen, as proposed by Coleridge Smith et al. [24], is incorrect. However, the changes in leucocyte number on which their hypothesis is based [25] are consistent with the altered haemodynamics in the dependent leg which we have described. The reduction in plasma volume induced by posture [26] in accord with Starling's hypothesis will further diminish flow in the lower leg by increasing blood viscosity, especially at low flow rates. These observations support the idea that the alterations in blood flow in the lower leg which result from impairment of venous return may lead directly to the emigration of leucocytes into the tissues and the subsequent initiation of an inflammatory process by a mechanism independent of the posturally induced hypoxia. We therefore propose that the association between venous leg ulcers and arthropathy in the lower leg is the result of two reciprocal processes, impairment of venous return by arthropathy and the induction of an inflammatory arthropathy when venous return is compromised (Fig. 1). REFERENCES
1. Dodd HJ, Gaylarde PM, Sarkany I. Skin oxygen tension in venous insufficiency of the lower leg. J Roy SocMed 1985 ;78:373-6. 2. Caspary L, Creutzig A, Alexander K. Comparison of laser-Doppler-flux and tcPO2 in healthy probands and patients with arterial ischemia. Adv Exp Med Biol 1987;220:235^0. 3. Henriksen O. Local sympathetic reflex mechanism in regulation of blood flow in human subcutaneous adipose tissue. Ada Physiol Scand 1977; Suppl 450. 4. Hojensgaard IC, Stiirup H. Static and dynamic pressure in superficial and deep veins of the lower extremity in man. Ada Physiol Scand 1952;27:49-67. 5. Nielsen HV. Effect of vein pump activation upon muscle blood flow and venous pressure in the human leg. Ada Physiol Scand 1982;114:481-5. 6. Pollack AA, Taylor BE, Myers MT, Wood EH. The effect of exercise and body position on the venous pressure at the ankle in patients having venous valvular defects. J Clin Invest 1949;28:559-63. 7. Dickson Wright A. The treatment of indolent ulcer of the leg. Lancet 1931;i:457-60. 8. Ruckley CV, Dale JJ, Callam MJ, Harper DR. Causes of chronic leg ulcer. Lancet 1982;ii:615-16.
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 18, 2015
limitation of ankle movement and this suggests that injury may cause leg ulcers because the muscle pump efficiency is impaired. Persistent prolonged elevation of venous pressure may also damage the ankle joint and such damage would be self-perpetuating because the loss of mobility resulting from such changes may further compromise venous return. It is known that venous insufficiency may be associated with periostitis [7, 11, 12], subcutaneous calcification [13, 14] and muscle changes [15] in addition to the well known cutaneous changes. The high incidence of loss of ankle joint mobility of unknown aetiology observed in patients with leg ulcers suggests that the ankle changes in some patients are secondary to their venous disease. Inflammatory changes in the skin and periosteum of the lower leg are accompanied by elevation of the levels of lysosomal enzymes in the systemic circulation of patients with varicose veins [16]. This suggests that inflammation may be the result of venous insufficiency. Similarly, elevated levels of lysosomal enzymes have been described in other inflammatory conditions such as vasculitis and systemic lupus erythematosus [17], but elevated levels of these enzymes may be observed in conditions such as muscular dystrophy, the result of cellular injury by non-inflammatory mechanisms. The mechanism whereby venous incompetence leads to inflammation is uncertain. Hypoxia can induce the release of physiologically active mediators from endothelial cells in vitro [18] which may initiate inflammation under similar conditions in vivo. Hypoxia may also lead to cell injury as a result of free radical generation when tissue oxygen levels are restored [19]. The effects of the altered haemodynamics in patients with impaired venous return may also be a factor leading to granulocyte adhesion in the vascular bed. The concentration of the formed elements in the blood is dependent on both vessel diameter andflowvelocity. It is widely known that the packed cell volume differs between venous blood and capillary blood samples obtained byfingerpricks. The effect of these factors on leucocytes is more pronounced since their volume is greater than that of the erythrocytes. The formed elements in the blood are found in highest concentrations in distal capillaries and venules [20, 21], whereas the lowest concentrations are found in the smallest capillaries. Although the formed elements in the blood tend to be kept away from the vessel wall in accord with the principles of fluid dynamics, granulocytes exhibit a
143
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXIX NO. 2
144
9. ThurtleOA, CawleyMID. The frequency of leg ulceration in rheumatoid arthritis: a survey. J Rheumatol 1983;10:507-9. 10. Hach W, Langer Ch, Schirmers U. Das arthrogene Stauungssyndrom. VASA 1983;12:109-16. 11. Dannels EG, Nashel DJ. Periostitis. J Am Pediatr Ass
DATES FOR 1990-91 1990 May
3
May May May Aug
18 25 31 28-30
Sept Sept Oct Nov Nov 1991 April Sept
6-7 26-28 12 15-16 23
One day BSR course in rheumatology and medicine for Part 2 MRCP. CHARING CROSS HOSPITAL, LONDON (Dr P. Venables). BSR Basic Rheumatology Course. STOKE (Dr P. T. Dawes). Closing date for 1990 Annual General Meeting abstracts. Closing date for Michael Mason Prize. BSR Advanced Rheumatology Course. 'The Edinburgh Festival of Rheumatology and Science', EDINBURGH (Prof. Nuki). BSR Paediatric Course. BATH (Dr A. Clarke). BSR Annual General Meeting. IMPERIAL COLLEGE, LONDON. BSR Basic Rheumatology Course. CAMBRIDGE (Dr B. Hazleman). BSR Rehabilitation Course. NORTHWICK PARK (Dr A. Frank). French Rheumatology Society Meeting. PARIS.
12 18-20
BSR Spring Meeting and Heberden Round. OXFORD (Dr A. Mowat). BSR Annual General Meeting. IMPERIAL COLLEGE, LONDON.
Further information about these events from Ms L. Johnson, British Society for Rheumatology, 3 St Andrew's Place, Regent's Park, London NW1 4LE.
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 18, 2015
12. Daumont A, Queneau P, Deplante JP, Bouvier M. Hypertrophic periostitis and varicose veins in the lower limbs. Lyon Med 1975 ;233:1261-6. 13. Lippmann HI, Goldin RR. Subcutaneous ossification of the legs in chronic venous insufficiency. Radiology 1960;74:279-288. 14. Sarkany I, Kreel L. Subcutaneous ossification of the legs in chronic venous stasis. Br Med J 1966; 2:27-8. 15.Taheri SA, Heffner R, Lazar L, Elias S. Muscle changes in venous insufficiency. Arch Surg 1984;119:929-31. 16. Niebes P. Determination of enzymes and degradation products of glycosaminoglycan metabolism in the serum of healthy and varicose subjects. Clin Chim Ada 1972;42:399-408. 17. Kar NC, Pearson CM. Serum G-acetylglucosaminidase and arylsulphatase A in inflammatory disorders of muscle and connective tissue. Proc Soc Exp Biol Med 1972; 140:1480-5. 18. FarberHW, Center DM, Rounds S. Effect of ambient oxygen on cultured endothelial cells from different vascular beds. Am J Physiol 1987;253:878-83. 19. Zweier JL, Kuppusamy P, Lutty GA. Measurement of
endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues. Proc Natl Acad Sci USA 1988;85:4046-50. 20. Blixt A, Braide M, Myrhage R, Bagge U. Vital microscopic studies on the capillary distribution of leukocytes in rat cremaster muscle. Int J Microcirc Clin Exp 1987;6:273-86. 21. Ley K, Pries AR, Gaehtgens P. Preferential distribution of leukocytes in rat mesentery microvessel networks. Pflugers Arch 1988;412:93-100. 22. Atherton A, Born GVR. Quantitative investigations of the adhesiveness of circulating polymorphonuclear leucocytes to blood vessels walls. J Physiol 1972;222:447-74. 23. Gaehtgens P. Deformation and activation of leukocytes—two contradictory phenomena? In: Meiselman HJ, Lichtman MA, LaCelle PL, eds. White cell mechanics: basic science and clinical aspects. New York: Liss, 1984: 159-65. 24. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J 1988;296:1726-7. 25. Thomas PRS, Nash GB, Dormandy JA. White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J 1988;296:1693-5. 26. Hilsted J, Parving HH, Christensen NJ, Benn J, Galbo H. Hemodynamics in diabetic orthostatic hypotension. / Clin Invest 1981 ;68:1427-34.
VIEWPOINT
VENOUS LEG ULCERS AND ARTHROPATHY BY P. M. GAYLARDE, H. J. DODD AND I. SARKANY Department of Dermatology, Royal Free Hospital, London NW3 2QG
SUMMARY Reduced ankle mobility impairs the venous muscle pump and this leads to an increase in mean venous pressure in the lower leg. We have previously shown that pressure-induced venous distension leads to cutaneous hypoxia which is caused by arteriolar vasoconstriction in response to a spinal reflex. The prolonged cutaneous hypoxia which is thus a consequence of sustained elevation of venous pressure is an important factor in the development of gravitational ulcers. It is postulated that the increased incidence of leg ulcers in patients with rheumatoid arthritis is the result of impairment of the efficiency of the venous muscle pump by reduced ankle mobility. Conversely, the elevation of venous blood pressure in patients with venous insufficiency may lead to arthropathy in the ankle. The hypothesis is presented that prolonged elevation of venous blood pressure causes injury to both the ankle joint and veins leading to chronic reciprocal damage to both. This explains the frequent association between arthropathy of the ankle and venous leg ulcers. Ankle joint, Venous insufficiency, Ulcer.
IN normal subjects, skin oxygen tension measured at an electrode temperature of 37°C falls on standing to levels close to zero [1, 2]. It rises during exercise to values similar to those seen when the subject is recumbent [1]. The fall in skin oxygen tension seen on standing is the result of a decrease in skin blood flow caused by arteriolar vasoconstriction [3]. This vasoconstrictor reaction is mediated by the release of noradrenaline in response to a spinal reflex activated by stimulation of venous stretch receptors by increased venous pressure [3]. The threshold pressure required to activate this reflex is approximately 25 mmHg [3]. In normal subjects, exercise reduces venous hydrostatic pressure to below this level [4]. When venous pressure falls during exercise [4], the reflex is not activated [5] and skin oxygen tension rises as skin blood flow increases [1]. In patients with venous leg ulcers, venous pressure remains high during exercise [6] when venous abnormalities impair the normal unidirectional blood flow in the veins. The fall in venous pressure below the threshold which activates the vasoconstrictor reflex therefore fails to take place and the normal increase in skin oxygen tension in response to exercise whilst standing is absent [1]. As a result of these observations, we have put forward the hypothesis that venous ulcers are the result of prolonged cutaneous hypoxia when patients with defective venous return are either standing or walking about [1]. This hypothesis accounts for the role of posture in the development of venous ulcers and explains the clinical value of bed rest and elastic compression stockings in the treatment of venous ulcers. The standardized exercise test adopted in our studies was alternate plantar and dorsiflexion at a rate of 60 times per minute [1]. It was noted that a high proportion of patients with venous ulcers were unable to carry out this manoeuvre, either as a result of old injury or arthritic changes in the ankle. This association between ulcers of the lower leg and loss of mobility of the ankle joint has been previously noted [7,8]. Ruckley etal. [8] Correspondence to Dr P. Gaylarde.
found 268 of 827 patients with chronic leg ulcers (32%) had severe limitation of ankle joint movement, but only 9% of the patients had rheumatoid arthritis (RA). A survey of ulcer incidence in patients attending a rheumatology clinic [9] found 20 of 207 patients with RA had leg ulcers compared to an incidence of only 9 of 192 patients with osteoarthritis or spondylosis. The difference in ulcer incidence in the two groups may be attributed to the increased incidence of ankle joint changes in patients with RA and is not accounted for by the occasional occurrence of ulcers due to vasculitis. In contrast, Hach et al. [10] observed that the fall in venous pressure on exercise in patients with venous disease and limited ankle mobility was smaller than in patients with normal mobility and that the incidence of venous leg ulcers was very much greater in the group affected by the loss of normal movement. These workers together with others cited in their paper have postulated that the loss of ankle mobility associated with venous disease may indeed be the result of an arthropathy primarily induced by venous hypertension. Loss of ankle joint mobility will impair the action of the venous muscle pump and will tend to be accompanied by prolonged periods of venous distension in the absence of defective venous valves. Muscle atrophy in the lower leg associated with joint deformity will also impair venous return. Prolonged elevation of venous pressure resulting from the impaired action of the venous muscle pump caused by loss of ankle mobility may directly damage the veins leading to venous reflux; reduced mobility may also increase the incidence of deep vein thrombosis, whilst inflammatory changes in the large vessels associated with RA may lead to direct damage to the veins. On the basis of the hypothesis that venous leg ulcers result from prolonged hypoxia associated with prolonged elevation of venous pressure, it is reasonable to predict that RA will lead to an increased incidence of venous leg ulcers. However, rheumatoid arthritis accounted for less than 30% of those patients with leg ulcers in whom severe limitation of ankle movement was observed [8]. Trauma may result in the 142
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 18, 2015
KEY WORDS:
GAYLARDE ETAL.: VENOUS LEG ULCERS AND ARTHROPATHY
Reduced muscle pump activity
I i
Venous damage
Prolonged venous distension
Arthropathy Inflammation
Venous incompetence Venous reflux
Obstruction of venous return
FIG. 1.—Diagram to show the reciprocal relationship between arthropathy and venous incompetence.
tendency to adhere to vessel walls, especially under conditions of low flow velocity. This adhesion causes the cells to roll slowly along the vessel walls and is inhibited by EDTA [22] and is most prominent in venules. The prolonged diminution of blood flow in standing patients with venous incompetence and the distension of the venules by elevated venous pressure will ensure optimal conditions for granulocyte concentration and adhesion in these vessels; the production of chemoattractants in response to hypoxia [18] will enhance the emigration of granulocytes into the tissues. The inhibition of leucocyte adhesion by deformation in capillaries [23] and the physical factors that tend to exclude leucocytes from the smallest capillaries suggest that the capillary occlusion model which claims that leucocytes plug the vessel lumen, as proposed by Coleridge Smith et al. [24], is incorrect. However, the changes in leucocyte number on which their hypothesis is based [25] are consistent with the altered haemodynamics in the dependent leg which we have described. The reduction in plasma volume induced by posture [26] in accord with Starling's hypothesis will further diminish flow in the lower leg by increasing blood viscosity, especially at low flow rates. These observations support the idea that the alterations in blood flow in the lower leg which result from impairment of venous return may lead directly to the emigration of leucocytes into the tissues and the subsequent initiation of an inflammatory process by a mechanism independent of the posturally induced hypoxia. We therefore propose that the association between venous leg ulcers and arthropathy in the lower leg is the result of two reciprocal processes, impairment of venous return by arthropathy and the induction of an inflammatory arthropathy when venous return is compromised (Fig. 1). REFERENCES
1. Dodd HJ, Gaylarde PM, Sarkany I. Skin oxygen tension in venous insufficiency of the lower leg. J Roy SocMed 1985 ;78:373-6. 2. Caspary L, Creutzig A, Alexander K. Comparison of laser-Doppler-flux and tcPO2 in healthy probands and patients with arterial ischemia. Adv Exp Med Biol 1987;220:235^0. 3. Henriksen O. Local sympathetic reflex mechanism in regulation of blood flow in human subcutaneous adipose tissue. Ada Physiol Scand 1977; Suppl 450. 4. Hojensgaard IC, Stiirup H. Static and dynamic pressure in superficial and deep veins of the lower extremity in man. Ada Physiol Scand 1952;27:49-67. 5. Nielsen HV. Effect of vein pump activation upon muscle blood flow and venous pressure in the human leg. Ada Physiol Scand 1982;114:481-5. 6. Pollack AA, Taylor BE, Myers MT, Wood EH. The effect of exercise and body position on the venous pressure at the ankle in patients having venous valvular defects. J Clin Invest 1949;28:559-63. 7. Dickson Wright A. The treatment of indolent ulcer of the leg. Lancet 1931;i:457-60. 8. Ruckley CV, Dale JJ, Callam MJ, Harper DR. Causes of chronic leg ulcer. Lancet 1982;ii:615-16.
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 18, 2015
limitation of ankle movement and this suggests that injury may cause leg ulcers because the muscle pump efficiency is impaired. Persistent prolonged elevation of venous pressure may also damage the ankle joint and such damage would be self-perpetuating because the loss of mobility resulting from such changes may further compromise venous return. It is known that venous insufficiency may be associated with periostitis [7, 11, 12], subcutaneous calcification [13, 14] and muscle changes [15] in addition to the well known cutaneous changes. The high incidence of loss of ankle joint mobility of unknown aetiology observed in patients with leg ulcers suggests that the ankle changes in some patients are secondary to their venous disease. Inflammatory changes in the skin and periosteum of the lower leg are accompanied by elevation of the levels of lysosomal enzymes in the systemic circulation of patients with varicose veins [16]. This suggests that inflammation may be the result of venous insufficiency. Similarly, elevated levels of lysosomal enzymes have been described in other inflammatory conditions such as vasculitis and systemic lupus erythematosus [17], but elevated levels of these enzymes may be observed in conditions such as muscular dystrophy, the result of cellular injury by non-inflammatory mechanisms. The mechanism whereby venous incompetence leads to inflammation is uncertain. Hypoxia can induce the release of physiologically active mediators from endothelial cells in vitro [18] which may initiate inflammation under similar conditions in vivo. Hypoxia may also lead to cell injury as a result of free radical generation when tissue oxygen levels are restored [19]. The effects of the altered haemodynamics in patients with impaired venous return may also be a factor leading to granulocyte adhesion in the vascular bed. The concentration of the formed elements in the blood is dependent on both vessel diameter andflowvelocity. It is widely known that the packed cell volume differs between venous blood and capillary blood samples obtained byfingerpricks. The effect of these factors on leucocytes is more pronounced since their volume is greater than that of the erythrocytes. The formed elements in the blood are found in highest concentrations in distal capillaries and venules [20, 21], whereas the lowest concentrations are found in the smallest capillaries. Although the formed elements in the blood tend to be kept away from the vessel wall in accord with the principles of fluid dynamics, granulocytes exhibit a
143
BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXIX NO. 2
144
9. ThurtleOA, CawleyMID. The frequency of leg ulceration in rheumatoid arthritis: a survey. J Rheumatol 1983;10:507-9. 10. Hach W, Langer Ch, Schirmers U. Das arthrogene Stauungssyndrom. VASA 1983;12:109-16. 11. Dannels EG, Nashel DJ. Periostitis. J Am Pediatr Ass
DATES FOR 1990-91 1990 May
3
May May May Aug
18 25 31 28-30
Sept Sept Oct Nov Nov 1991 April Sept
6-7 26-28 12 15-16 23
One day BSR course in rheumatology and medicine for Part 2 MRCP. CHARING CROSS HOSPITAL, LONDON (Dr P. Venables). BSR Basic Rheumatology Course. STOKE (Dr P. T. Dawes). Closing date for 1990 Annual General Meeting abstracts. Closing date for Michael Mason Prize. BSR Advanced Rheumatology Course. 'The Edinburgh Festival of Rheumatology and Science', EDINBURGH (Prof. Nuki). BSR Paediatric Course. BATH (Dr A. Clarke). BSR Annual General Meeting. IMPERIAL COLLEGE, LONDON. BSR Basic Rheumatology Course. CAMBRIDGE (Dr B. Hazleman). BSR Rehabilitation Course. NORTHWICK PARK (Dr A. Frank). French Rheumatology Society Meeting. PARIS.
12 18-20
BSR Spring Meeting and Heberden Round. OXFORD (Dr A. Mowat). BSR Annual General Meeting. IMPERIAL COLLEGE, LONDON.
Further information about these events from Ms L. Johnson, British Society for Rheumatology, 3 St Andrew's Place, Regent's Park, London NW1 4LE.
Downloaded from http://rheumatology.oxfordjournals.org/ at Harvard University on July 18, 2015
12. Daumont A, Queneau P, Deplante JP, Bouvier M. Hypertrophic periostitis and varicose veins in the lower limbs. Lyon Med 1975 ;233:1261-6. 13. Lippmann HI, Goldin RR. Subcutaneous ossification of the legs in chronic venous insufficiency. Radiology 1960;74:279-288. 14. Sarkany I, Kreel L. Subcutaneous ossification of the legs in chronic venous stasis. Br Med J 1966; 2:27-8. 15.Taheri SA, Heffner R, Lazar L, Elias S. Muscle changes in venous insufficiency. Arch Surg 1984;119:929-31. 16. Niebes P. Determination of enzymes and degradation products of glycosaminoglycan metabolism in the serum of healthy and varicose subjects. Clin Chim Ada 1972;42:399-408. 17. Kar NC, Pearson CM. Serum G-acetylglucosaminidase and arylsulphatase A in inflammatory disorders of muscle and connective tissue. Proc Soc Exp Biol Med 1972; 140:1480-5. 18. FarberHW, Center DM, Rounds S. Effect of ambient oxygen on cultured endothelial cells from different vascular beds. Am J Physiol 1987;253:878-83. 19. Zweier JL, Kuppusamy P, Lutty GA. Measurement of
endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissues. Proc Natl Acad Sci USA 1988;85:4046-50. 20. Blixt A, Braide M, Myrhage R, Bagge U. Vital microscopic studies on the capillary distribution of leukocytes in rat cremaster muscle. Int J Microcirc Clin Exp 1987;6:273-86. 21. Ley K, Pries AR, Gaehtgens P. Preferential distribution of leukocytes in rat mesentery microvessel networks. Pflugers Arch 1988;412:93-100. 22. Atherton A, Born GVR. Quantitative investigations of the adhesiveness of circulating polymorphonuclear leucocytes to blood vessels walls. J Physiol 1972;222:447-74. 23. Gaehtgens P. Deformation and activation of leukocytes—two contradictory phenomena? In: Meiselman HJ, Lichtman MA, LaCelle PL, eds. White cell mechanics: basic science and clinical aspects. New York: Liss, 1984: 159-65. 24. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J 1988;296:1726-7. 25. Thomas PRS, Nash GB, Dormandy JA. White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J 1988;296:1693-5. 26. Hilsted J, Parving HH, Christensen NJ, Benn J, Galbo H. Hemodynamics in diabetic orthostatic hypotension. / Clin Invest 1981 ;68:1427-34.
