5,6-Benzo-[alpha]-pyrone results in slow but safe reduction of lymphedema of the extremities.
The structure of the lymphatic capillaries and lacunes as seen by electron microscopy was similar to that of the blood capillaries of, for instance, skeletal muscle. All the lymphatic endothelial cells contained many vesicles and caveolke intercellulares. No fenestrations in the endothelium were seen, but some intercellular junctions were patent, especially in diaphragmatic lacunes. The basement membrane was less regular than that of blood capillaries or of mesothelium and in many places, especially in diaphragmatic lacunes, it appeared to be absent.Carbon and ferritin were injected into the peritoneal cavity and could be seen in the lumen of diaphragmatic lacunes, in vesicles in mesothelium and endothelium, and in patent junctions between endothelial cells. Deposits of ferritin without an encircling membrane were also seen in the cytoplasm.LYMPHATICS are composed of, or lined by, endothelium which when viewed by light microscopy bears a strong resemblance to the endothelium of blood vessels [for a review see Yoffey and Courtice, 1956].Although many electron microscopical investigations of blood capillary endothelium have been made [Palade, 1953;Moore and Ruska, 1957;Policard, Collet and Pregermain, 1957; Maynard, Schultz and Pease, 1957;Bennett, Luft and Hampton, 1959;Fawcett, 1959; Longley, Banfield and Brindley, 1960], there are few recorded studies on lymphatic endothelium [Palay and Karlin, 1959 a; French, Florey and Morris, 1960]. This paper records some observations made by electron microscopy on the structure of normal lymphatics. EXPERIMENTAL Lymphatics were examined in the ears of mice and guinea-pigs, the diaphragms of mice and the colons of rats.Lymphatics in the ears of mice and guinea-pigs were identified by injecting them with a mixture of equal parts of 25 per cent Thorium dioxide (" Thorotrast ", Testagar & Co.) and 5 per cent Pontamine blue in physiological saline, using Pullinger and Florey's [1935] modification of Hudack and McMaster's [1932] micro-injection technique. Small blocks of tissue were then cut from the ears and fixed in Caulfield's modification [1957] of Palade's fixative [1952]. Lymphatic lacunes in the diaphragm of rats and mice were filled by intraperitoneal injection of Pelikan India ink (Gunther Wagner) mixed with an equal quantity of 10 per cent gelatin in water. In some experiments an equal part of a 5 per cent solution of ferritin in Tyrode's solution was added to the mixture. At 1-5 min. after the injection the animals were ancesthetized and suspended by their heads. Their pleural cavities were then injected with cold Caulfield's solution which killed them. The carcase was left to fix at 40 C. for 3-4 hr. When the diaphragms were excised and transilluminated, filled lacunes could be located. The large intestines of rats were exposed and a small
Complex Physical Therapy (CPT) is discussed and its principles outlined. CPT involves: 1. skin care, 2. a special lymphatic massage, 3. compression bandaging and (later) garments, 4. special exercises which supplement the massage. CPT was used on 78 patients with postmastectomy lymphoedema (17 with Grade 1 and 61 with Grade 2). There were significant differences between the Grades. In the first four-week course the mean Grade 1 was reduced from 121% of normal to 107% (the mean change in the oedema was 103% of its initial value), and Grade 2 from 153% to 123% (with a mean change in oedema of 60%). All these were very highly significant. Over the next year there was a small, but very significant, decrease in the percentage of oedema. A further four-week course resulted in significant, and similar, reductions in the residual oedema. CPT was used to treat 128 lymphoedematous legs; 22 were Grade 1 lymphoedema, 84 were Grade 2 and 19 were elephantitic (Grade 3). After the first course of CPT the mean losses were: 1.1, 1.3 and 3.7 litres, respectively (all very significant). Over the next 11 months there were significant further reductions for all legs and in the amount of oedema of the unilateral legs. Some patients had a second course of CPT with similar reductions in the remaining oedema to that after the first course.
The electron microscopic appearances of chylomicra and lipoproteins have been investigated. The particles were isolated from rat chyle by differential flotation in an ultracentrifuge. Various fixing and embedding media were used. The two kinds of particles were then identified in thin sections of the jejunum of rats. The chylomicra had diameters of from 1,000 A to 1 ~; the lipoproteins ranged from 100 to 1,000 A. They were identified by their sizes and their similarities to the isolated particles after the various fixing and embedding procedures, In addition, the relative amounts of the two kinds of particle varied greatly under different dietary conditions. The chylomicra had a thin rim, probably of phospholipid. Section B records the passage of the two kinds of particle into the lacteals in the villi of the jejunum. Both chylomicra and lipoproteins were seen passing through many open junctions. From permeability considerations it would seem that this is the most important route. These open junctions appear to act as "inlet valves" which prevent backflow as the contractions of the villi pump material out of the lacteals. Both chylomicra and lipoproreins were also seen entering the endothelial cells and lying inside them. The lipoproteins entered via "normal" caveolae and were seen in "normal" vesicles (~ 500 A); the chylomicra necessarily occupied much larger organelles. Both kinds of particles were also seen in caveolae on the luminal surface of the endothelium, but it was impossible to be certain that these were not just particles entering the cells from the lumen. The chylomicra often seemed to be washed out of these caveolae as many large, empty ones were seen on the luminal sides of the cells. Frequently, these caveolae had dark membranes.
The benzo-pyrones reduce all high-protein oedemas, including lymphoedema and elephantiasis, by increasing the numbers of macrophages and their normal proteolysis. Thus they remove the excess protein, and thereby the oedema which is caused by it. They also remove the stimulus it provides for chronic inflammation and fibrosis, and its action as a culture medium for bacteria. Coumarin (5,6 benzo-[alpha]-pyrone, 56 BaP) and oxerutins (HR, O(beta-hydroxy-ethyl)-rutosides) have been used in many clinical trials on a variety of high-protein oedemas. Four such trials are summarised here: on lymphoedema and elephantiasis (from many causes in Australia, and filaritic in India and China). The drugs reduced these much more slowly than adequate physical therapy, but they did reduce them. About half the excess volume was removed over six months in the Australian trials. In India and China similar rates were achieved with lymphoedema, but elephantiasis reduced at a slower rate. The benzo-pyrones convert a slowly worsening condition into a slowly improving one. No compression garments are necessary. In addition, the drugs considerably reduce the number of attacks of secondary acute infection, reduce the deformities of elephantiasis and considerably improve the patients' comfort and mobility. They may be taken orally, or applied topically, have very low toxicities and only few, minor side-effects. They are useful in many other forms of high-protein oedema, and improve the results of physical therapy for lymphoedema.
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