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BONE FORMATION AND THE OSTEOBLAST.
489 lessened degree of acidosis, and a lessened depressing inefficient supply of these elements, or of some effect of phosphorus on calcium and of the resulting activating body in the tissue fluids ; that this body need to call on the calcium reservoirs. is probably vitamin D, which in its turn is derived I would also draw attention to the fact that any- from the alimentary canal, or synthesised by the thing which increases phosphorus absorption from action of ultra-violet rays on sterols in the skin ; the alimentary tract may make the condition worse. but that occasionally the faulty metabolism may be Definite evidence has, I think, been produced by entirely endogenous in origin, as occurs in renal Teall and myself showing that ultra-violet irradia- rickets ; and finally, that growth is an essential for tion, far from ameliorating, actually increases the the development of rickets. rachitic manifestations. Let me add in passing that Although rickets existed before Glisson’s time it in renal rickets we have another illustration of the certainly increased markedly after his day, and effect of growth in the development of rickets, because became almost universal in some grades of urban in those rare cases which survive until the later society, especially in districts like our own Black ’teens, when the growth period has ceased and the Country and Glasgow. We must, however, remember epiphyses joined up, rickets does not occur, although that except for the empirical discovery of the curative the bone is still osteoporotic to some degree and the effects of cod-liver oil some hundred years ago, our calcium phosphorus ratio is abnormal. knowledge of the disease advanced very little until From what has been said it will be gathered that the last few years. Although there are still many I regard renal rickets as belonging, like coeliac rickets, gaps in our complete knowledge of the disorder, recent to the low calcium category. The occurrence of renal researches have put us in possession of information rickets also proves the importance of the calcium- that should allow us completely to eradicate all phosphorus ratio, since if the calcium-phosphorus ordinary rickets. Already its incidence and severity product were a correct guide it would put these are declining, and we can look forward with sure and deformities far outside the rachitic range. It may certain hope to the day, perhaps no further distant well be asked, therefore, what is the proof that the than the tercentenary of Glisson’s work, when rickets condition is rickets ? I think no one will question will have become one of that small but increasing the fact that some of the cases show a radiographic number of diseases which possess a great interest for appearance absolutely indistinguishable from rickets the historian but happily present no terrors of ill(the " rachitic type "), but, on the other hand, there health for the patient and no cause for anxiety on are radiographic manifestations which we have the part of the doctor. called the "woolly,""honeycomb," or " stippled type," which are totally unlike that seen in ordinary rickets. There is another type, which we have called BONE FORMATION AND THE the " atrophic type," which resembles coeliac rickets, and although I have never seen the rachitic change OSTEOBLAST. into the atrophic type I think they can do so, just BY H. A. HARRIS, B.Sc. CARDIFF, M.B.LOND., as at times we see in uncomplicated rickets a radioASSISTANT PROFESSOR OF ANATOMY, UNIVERSITY COLLEGE, identical with the picture logical absolutely atrophi( LONDON ; ASSISTANT TO THE MEDICAL UNIT, type and with coeliac rickets. In the " woolly UNIVERSITY COLLEGE HOSPITAL. stippled, or honeycomb type " osteoporosis is present the diaphysis is straight but there is a long metaphysis, "Quid dicam de ossibusquae subjecta corpori, mirabiles and it is in the latter that the severe deformities so commissuras habent, et ad stabilitatem aptas, et ad artus characteristic of the condition occur. The meta- finiendos accommodatas, et ad motum, et ad omnem corporis actionem." -Cicero, De Natura Deorum. physis shows irregular ossification, giving the appearScrape a bone, and its vessels bleed; cut or bore a bone, ance of honeycombing, stippling, or woolliness, and and its granulations sprout up ; break a bone, and it will heal ; under the periosteum the bone may appear to be or cut a piece away, and more bone will readily be produoed ; -Charles Bell, Anaiom1/. eroded. The changes do not appear to the same burn it, and it dies." degree in all the long bones. As the change advances Cicero and Charles Bell have given pithy descripthe absence of subperiosteal bone becomes so marked tions of the marvels of bone, the tissue which, in that the end of the bone collapses, and since this common with bone-marrow, displays the highest absence of bone is usually more marked on one side powers of regeneration and repair in the whole than the other the collapse usually occurs sideways, human economy. Sir Arthur Keithhas recently with the result that the most extreme deformities asked " Quid dicam de ossificatione ? " The answer The skull in some cases of this type to the problem of ossification has not yet been found, are produced. shows most extraordinary changes, marked stippling and to review the search for the mode of ossification being present. In the severest case that I have is to review the history of morbid anatomy. No observed all trace of inner and outer tables of the subject has been attacked more vigorously, no subject cranial bones had disappeared and the bone was has been- deserted more frequently. When Monro much thickened, the whole presenting an appearance Secundus and William Hewson were pleading a indistinguishable from Paget’s disease. Post-mortem priority suit, in relation to their discoveries in the examination of the long bones shows that the woolli- lymphatic system, with Benjamin Franklin as ness or stippling is due to the -presence of islets of assessor, Abernethy said: "All our knowledge of cartilage deep down in the long metaphysis, and that the absorbing vessels has been obtained by fragments, the appearance of subperiosteal erosion is also due and our future acquisitions must be made in the same to unossified cartilage. The metaphysis itself, manner." This is equally true of bone development. although long, is not broad and splayed out as in Our knowledge of the histological structure of bone the rachitic type. Although this type cannot be is a memorial to three Englishmen: Clopton Havers recognised radiographically as due to rickets, and (1650-1702), John Howship (d. 1841), and William microscopical examination shows that the changes Sharpey (1802-1880), who are familiarised in the present differ from those ordinarily seen in rickets, canals, lacunae, and fibres which bear their names. The the proliferative cartilage being much more irregular bone corpuscles were first described by Purkinje and and broken, yet Prof. Haswell Wilson, who has Deutsch in 1834. The specific terms " osteoblast " examined the sections for me, pronounces them as and " osteoclast " as applied to cells actively engaged definitely rachitic in nature-a view also held by in depositing or absorbing bone respectively were Shipley. introduced by Gegenbaur and Kö1liker and cam& CONCLUSION. into general use 60 years ago. It is of interest to. I hope that in these lectures I have made clear note that as early as 1689, just after the invention that recent advances in our knowledge have shown of the Huyghens eye-piece, Gagliardi, a professor of that rickets is a disorder of calcium and phosphorus medicine in Rome, had described certain " claviculi’-’ salt metabolism, usually the result of defective or " small nails," which are identical with the fibres absorption of these elements’from the bowel; further of Sharpey. Moreover, as Sharpey maintains, the that this defective absorption is due either to arossification in, membrane without the intervening "
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stage of cartilage formation had been described by Nesbitt in 1736. Coincidently with the slow unfolding of the microscopic structure of bone, the experimental method was pursued by Stephen Hales, Nehemiah Grew, John Belchier, and John Hunter in this country, by Duhamel in Paris, and by Haller in Gottingen. Their methods consisted largely of actual measurements of growing bones and of the feeding of madder to experimental animals. Hales and Grew were activated by the search for vegetable processes in the development of the animal world. The madder experiments of Belchier and Hunter
have been repeated on innumerable occasions, the most recent being the work of Prof. Brash,2 of Birmingham, on the growth of the mandible. It is interesting to note how most modern investigators have failed to appreciate Hunter’s description of the sites of deposition of the dye. Hunter3 insisted on the fact that the whole of the bone was stained by madder, and that the depth of the staining was medullated and non-medullated nerve-fibres. Numerous investigators have found that trophic changes in proportional to the rate of deposition and absorption bone follow nerve-section, such as loss of size and of the earthy salts. diminution of inorganic material, and, in But in the full-grown state, it would appear from the weight, animals, defective development. Numerous growing circumstances of reddening a whole bone by feeding the animal with madder, that a bone, although completely observations have been recorded upon the influence formed, yet is changing its earth, and probably every other in bone of nerve lesions and diseases in man. Here part. This effect, however, is much slower than in the again, especially in leprosy, regressive changes seem growing bone. This would show that the madder does not to be the rule. In general, lesions of mixed nerves act as a dye upon the earth which is already deposited in produce more bony changes than those of purely the bone, but only upon that matter which is every day motor nerves, and irritative lesions of sensory nerves deposited ; and as there is a great deal more deposited in seem to be the most potent, as in leprosy. Goering a young bone than in an old one in a given time, in the same proportion must it dye sooner than an old one. The concludes, on clinical grounds, that there are special trophic fibres of sympathetic origin passing to bones, new matter that is deposited in an old bone is to make up for the waste that is daily going on in it; but in a very with corresponding spinal centres. A general conold bone the waste is more than the repair." trolling centre, so it is claimed, is situated in the brain in the region of the floor of the third ventricle. It is This is the first clear expression of the fact that the obvious that there is much room for anatomical calcium of the bones is not permanently fixed as a and clinical research in this field, and that the bony but can be into the circulation brought deposit account of anterior poliomyelitis and tabes dorsalis as a current account. The recent brilliant work of changes offer abundant material. indicates the 4 with extract ease Collip parathyroid with which the extract can raise the blood calcium Problem of Calcium Metabolism. to abnormally high values by calling upon the calcium The vast literature relating to bone formation in the bones and muscles. was admirably summarised by Gideon Wells 1" in Grew, Duhamel, and the other botanists regarded the Harvey lecture of 1911. Since that date biobone as the product of the deeper layers of the chemistry and the intensive study of the vitamins " " periosteum, which they regarded as a cambium have revealed the complexity of the whole problem layer, by analogy with the actively proliferating of calcium metabolism. Wells stated that the zone of plants. Haller regarded bone as a product questions to be answered are :of the arteries, which could lay down bone anywhere. 1. Why is calcium deposited in the tissues at all ? 1 Hunter favoured this view, and Sir Arthur Keith 2. Why is it deposited in some tissues and not in others ? has recently attributed to the perithelial cells of the 3. How is the calcium carried in the blood ? 4. How is it held in the tissues where deposited ? capillaries the power of conversion into osteoblasts. 5. Why is the composition of calcified deposits so conGoodsir, differing from Hunter, believed that the qualitatively and quantitatively ? cartilage cells gave rise to " bone-forming corpuscles." stant, 6. What are the causes of rickets and osteomalacia ? The present-day teaching of the formation of bone in membrane, in cartilage, and in the deep layer of These questions still await concise answers. The the periosteum represents a consolidation of the views first question involves the whole problem of senescence of Sharpey, Kölliker, and Virchow. The source of and death. Calcification occurs not only in certain the osteoblast is, however, still a problem. Stump5 cartilages but also in tumours, such as fibroids and traces the cartilage cell, the subperiosteal osteoblast, granulomata, in the meninges, and in tendons, the endochondral osteoblast, the osteoclast, the ligaments, and arteries. The second question brings endothelial cells of the growing capillaries, the to mind the fact that the tissues which undergo primitive blood cells and the " haemoblasts " to the calcification in senescence are the tissues which same young connective tissue cells. This is an afford examples of vegetative reproduction, with or extreme statement of the monophyletic origin. Fell,6 without mitotic division of nuclei, in relatively bloodin a study of osteogenesis in the domestic fowl, claims, less areas. Cartilage, which most readily undergoes on the other hand, that the chondroblasts suffer a calcification, is a tissue in which the cells live by the triple fate. They may give rise to osteoblasts, as imbibition of tissue juice, removed from an active described by Ranvier, Retterer, Macewen, and Van blood-supply. There is undoubtedly a limit to the der Stricht, or they may give rise to the reticulum size of the mass of cartilage which any animal can of the bone-marrow, or they may degenerate and grow, just as there is a limit to the size of a granuloma. disappear. Experiments on animals, such as those When the limit of growth is reached certain of the of Bast, Sullivan, and Geiston the repair of frac- cells degenerate and the matrix calcifies or caseates. tured bones, show that the " cambium " layer of Thus in cartilage proliferation, degeneration and the periosteum, the osteogenetic cells lining the calcification are closely related to the vegetative Haversian canals, and the cells of the endosteum are processes of proliferation without specialisation of all active in the production of new bone. They found function and without differentiation of structure, that the only site of formation of cartilage in the leading to old age and death of the tissue. On the repair of bones was at the cut edge of the fibrous other hand, bone formation is an active process, part of the periosteum. They saw fibrous tissue8 distinct from calcification. It occurs in the presence cells giving rise to cartilage cells. Carey and Zeit, of a rich blood-supply and is accompanied by differenas a result of the study of the ossifying patella in the tiation of the primitive cells for function, as distinct "
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dog, emphasise the dual origin of the osteoblast, and depict both osteoblasts arising from the subendothelial mesenchyme cells accompanying the invading blood-vessels, and osteoblasts formed directly from the embryonic chondroblasts in the neighbourhood of the capillaries. Nerve-supply of Bone. The problem of the nerve-supply of bone has remained in abeyance. The innervation of the two tissues of the body which exhibit the greatest power of regeneration and repair, bone and its marrow, still awaits adequate description. Sir G. Thane, in Quain’s Anatomy (tenth edition), mentions the fact that distinct nerves can be seen entering the nutrient foramina of the long bones. D. Goering9 has studied the influence of the nervous system on bones and joints. She concludes that bone has a somatic and a sympathetic innervation by means of
491 cation of the cartilage cells in vitro, with typical mitoses. Policard and Boucharlat 20 implanted periosteum and perichondrium of chicks, but in vitro they gave rise to connective tissue cells without the formation of cartilage or bone. A. O. Wjerinski 21 relatively poor in blood-supply. The question of the carriage of calcium in the reports the same results in vitro, though a homoplastic blood has been attacked with great vigour by the transplant in vivo led to strong mitotic multiplication chemist. Howland, Shipley, and Marriott and of the cells of the periosteum and actual conversion Kramer 11 have stated that bone normally contains into osteoblasts. Thus, so far, osteoblasts have bicalcium phosphate, that different bones of the same not been grown or propagated in vitro by the technique individual have the same inorganic percentage, that of tissue culture. This suggests that the osteoblast the ratio of calcium phosphate to calcium carbonate is a purposively differentiated cell which may is greater in normal than in rachitic bones, and, easily regress into a fibroblast, but will only redifferfurther, that the bone contains the phosphate and entiate in the presence of the blood-borne exudate carbonate of calcium in the same proportion as the of a living capillary. The nerve cell of the young embryo has been grown R. Robison 12 has disagreed with these views serum. and has emphasised the significance of the hexose in tissue culture, but the growth has been localised phosphoric esters. He states that the osteoblastsI almost entirely in the axone-i.e., in the part of the and the hypertrophic cartilage cells of the growing cell which was shown capable of growth in the adult animal secrete an active phosphatase which, by by Waller’s classical experiments on nerve regenerahydrolysing the phosphoric esters of the blood, tion. The osteoblast, as Burrows.22 has pointed out brings about a local increase of the tricalcium phos- for the fully matured lymphocyte, polymorphonuclear phate concentration. This concentration exceeds the leucocy-te, and many other mononuclear cells, will not solubility product of the salt and leads to its deposition grow in a tissue culture. Neither the nerve cell nor in the ossifying zone. Howland and his co-workers the osteoblast can be propagated. Thus these cells do not favour simple precipitation as the explanation, seem to exhibit an extreme degree of differentiation. but regard the process as a chemico-physical one, R. G. Harrison,23 in 1914, pointed out that cells depending on the activity of the living tissue in a will not grow in tissue cultures in clotted plasma medium in which the concentration of calcium andI unless some form of support is afforded, such as the phosphate in the serum and tissue juice exceed a surface of the cover-glass, the surface of the fluid film, certain minimum value. J. B. Collip4 in Canada, or a framework of spider-web, silk gauze, or cottonand C. P. Stewart and J. H. Percival 13 in this country, thread. In cultures in which the tissue floats free have dealt in particular with the changes in serum in a fluid medium no outgrowth occurs and the cell calcium under administration of Collip’s parathyroid succumbs. This phenomenon whereby a cell in hormone. The diffusible calcium is markedly increased the free rounded stage, devoid of support, is unable thereby. These experiments indicate the ease with to grow was described by Leo Loeb and Fleischer 24 which calcium passes into the blood from bone and under the name of stereotropism. It involves a other tissues, and this is a brilliant confirmation of most fundamental conception of a skeletal support Hunter’s precocious statement about the continuous for the cell, and may account for the failure to grow absorption and deposition of alkaline earths in old osteoblasts and fully differentiated blood cells such bone as well as in young bone. as Kidney and liver are grown with Several attempts have been made to imitate in ease because of their associated connective tissue colloidal solutions the actual deposition of tricalcium stroma. Cartilage cells die when they round up phosphate and calcium carbonate. Barille 14 in near the epiphysis. Osteoblasts apparently require France and J. C. Watt 15 in Canada have come to the the support of a connective tissue stroma and the conclusion that the salts in bone are deposited by adequate supply of blood-borne substances such as the activity of the osteoblasts as a secretory pheno- vitamin A and ergusia. Only those animals which menon. Orétin,16 in particular, has contributed much have ablood vascular system and a coelom are able to our knowledge of the staining reaction of bone to producean active osteoblast. and of the possible conditions of deposition of the Bone Pathology. calcium salts. He regards the actual areas of muscular attachment to be of great significance in determining The pathology of bone, like the pathology of the cartilage formation and ossification. The sterno- blood-vessels, has been so obscured by diverse mastoid and trapezius muscles in relation to the classifications and a multitude of strange names that clavicle and the occinital bone are differentiated certain simple facts escape observation. Chondrobefore the cartilage or bone appears. The point dystrophies, osteochondrites, and osteites have been of cartilage formation and of bone formation is subdivided without end, and dysostoses, aclasias, always related to the muscular. attachment. The and dysclasias have been added thereto. Vrolik’s transportation of phosphorus in combination with term of " osteogenesis inperfecta " is one of the few alkali metals converts the primitive tissue into safe terms in the pathology of growing bone. H. A. cartilage by producing a modification in the Harris’s 25 tentative scheme, as a simple working basis albumenoids of the matrix. Whereas cartilage is for the analysis of bone growth, serves also as a basis rich in sodium, growth ceases when calcium disturbs for the interpretation of bone pathology. He states the equilibrium between phosphate on the one hand that cartilage grows vegetatively by the imbibition and sodium and potassium on the other. Calcium of tissue juice in much the same way as bacteria, carbonate is now precipitated, redissolved in the yeasts, tumour cells, and granulomata. This vegepresence of alkalies, and then reprecipitated by tative proliferation of the cell is largely under the phosphate in the form of basic phosphate or phospho- control ofthe water-soluble vitamins and of those carbonate. substances which workers in the realm of tissue T-issue Culture Experiments. culture have designed as archusia " (M. T. " The results of tissue culture experiments have so far Burrows)26 The or Ca.rell).2’ (A. trephones been disappointing. A. Carrel and M. T. Burrows 17 process of proliferation of the undifferentiated cartilage cultivated conjugal cartilage as early as 1910, but cell is limited by the size of the mass and by the the first detailed experiments were those of adequacy of nutrition. When the mass of cartilage A. Fischer 18 in 1922. He cultivated the cartilage reaches a certain limit, as in the case of a granuloma, cells from the sclera of the chick embryoa’in vitro," the cells within the mass become senescent, degenerate, and found that the cells would not grow in the sub- and gradually pass into a resting stage which in many stance but would grow on the surface of a clot of cases leads to death. This process of degeneration plasma. In the implant the hyaline substance is accompanied by calcification of the matrix, and is liquefies, the cells migrate, increase in size, and comparable to the phenomenon of caseation and continue to live. No division of the cells was seen. calcification in a tubercle, gumma, or fibroid, or to T. S. Strangeways 19 succeeded in producing multipli- hyalinisation and the formation of cell nests in a
In short, bone is a live mere proliferation. tissue, actively growing or functioning in an area richly endowed with blood. Calcined cartilage is so senescent as to be virtually a dead tissue in an area
from
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lymphocytes.
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Lastly, the propinquity of a rapidly and Weed ’30 in their experimental studies on the growing capillary system in the bone-marrow brings cerebro-spinal fluid of cats, observed numerous into the region a new set of factors which lead to instances of calcification and ossification of the tissue differentiation as distinct from cell proliferation. arachnoid membrane. Calcification occurred in nonThe capillaries of the bone-marrow proceed to remove vascular areas, for the nutrition of the arachnoid the dead calcified cartilage as they would proceed to is obtained through the cerebro-spinal fluid rather On the other hand, remove any other foreign dead body, such as a than through the blood stream. caseated granuloma or a ligature. The cells of the every case of true bone formation was vascularised calcified cartilage that are not quite dead, but rather and could be attributed to the proliferation of in a resting or spore " stage, respond to the approach mesothelial cells in a vascularised area, as distinct of the blood capillaries by active amitotic division from the calcification of aged cells in an avascular to form osteoblasts. Any primitive connective area. In the aged cadaver of the dissecting-room, tissue cell in the vicinity of the actively proliferating calcification of the membranes, both dura and capillary can give rise to osteoblasts, whether this arachnoid, is common. True bone formation, on cell be periosteal, perivascular, or reticular. This the other hand, is rare. For a considerable time it was thought that theprocess of cell differentiation for function is in part carcinoma.
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attributable to the arrival in the area, via the blood
secret of calcification would be found in the formation of calcium soaps with fatty acids, for the early pathologists had described calcification by soap formation in degenerating lipomata as early as 1850. The absence of any appreciable amount of calcium soaps from areas of normal calcification has negatived proliferation, and a failure of ergusia or vitamin A this idea, and the presence of large quantities of leads to the formation of imperfectly differentiated calcium soaps in certain stages of the digestion of osteoblasts. The degree of differentiation may be fat without associated calcification is also against so low that the osteoblast is little more than a fibrothe theory. We seem to be confronted with the blast ; it may be more" advanced, so that the cells need for a new chemical concept. The hydrogen-ion deserve the name of osteoidoblast," but only in concentration and the salt content must be known, the presence of an adequate supply of the blood- not only for the arterial and venous streams but also borne vitamin A does one see the fully differentiated for the contents of the lymphatics, for the tissue osteoblast with deeply staining nucleus and numerous juice, and for the interior of the cell. The high basophilic granules in the cytoplasm. This con- percentage of calcium which can be absorbed in a ception of the vegetative proliferative process in cartilage designed for later calcification was shown cartilage, in contradistinction to the differentiating by Wells.1.0 He showed that pieces of epiphysial and functional process in bone, is not entirely new. cartilage, tracheal cartilage, and costal cartilageIts formulation in terms of archusia and ergusia absorb decreasing amounts of calcium salts, irreon the one hand, or in terms of water-soluble and spective of whether the cells in the transplant be fat-soluble vitamins on the other hand, is but an alive or dead. Moreover, decalcified bone-grafts. experimental and clinical statement of a long- are known to be less efficient than normal bone-grafts, established teleological fact. Richard Owen,28 when so that a preliminary calcification or power of calcium Curator of the.Royal College of Surgeons of England, absorption in the tissue seems to be advantageous for said, as far back as 1843 :subsequent ossification. Pathological ossification, no less. " Organic forms result from the antagonistic working than normal ossification, seems to require preliminary of two principles, of which one brings about a vegetative calcification of the cartilage or of the necrosed tissue. repetition of structure, while the other, a teleological Since no chemical ion or soap in cartilage can be principle, shapes the living thing to its functions.... proved to be an adequate agent in producing the In every species these two forces are at work, and the extent to which the general polarising orvegetative deposition of calcium phosphate and carbonate, it repetition force ’ is subdued by the teleological is an index is interesting to note that Jan Wolf 31 has returned to the problem of chondroitin-sulphuric acid. This of the grade of the species." Evolution is measured by the extent of the triumph substance is a normal constituent of cartilage; it is of ergusia and the fat-soluble vitamins over archusia increased in calcifying cartilage ; it occurs in theamyloid deposits of the spleen, liver, and arteries-, and the water-soluble vitamins. The term metastatic calcification was applied its calcium salt is very soluble. Jan Wolf has shown the small veins draining the costal cartilage by Virchow to the occurrence of deposits of calcium that salts in abnormal sites. There is hardly a tissue in contain a measurable amount of chondroitin-sulphuric the body which does not present numerous examples acid, and that this can be stained in situ by mucicarmin of abnormal calcification, from ganglion cells and or basophilic stains. The acid is not found in the skin on the one hand, to kidney, liver, lungs, and arteries. This suggests that the continuous removal gastric mucosa on the other. Most of the cases of of chondroitin-sulphuric acid from the matrix of a calcification occur in an area of senile or necrosed cartilage is necessary to preserve it from calcification. tissue, with a poor blood-supply and a slow lymph As yet no one has studied the effects on the solubility stream. There are, however, three marked exceptions, product of this acid or its calcium salt in the presence for calcification has been repeatedly reported in the of other ions. Even as long ago as 1891, Schmiedelungs, kidneys, and gastric mucous membrane. These berg 32 suggested that one of the functions of cartilage three areas are the sites of excretion or secretion was the production of chondroitin-sulphuric acid of acid substances, and the tendency to calcification and that this acid served as a mordant and possibly in these areas may be an expression of this fact. as a regulator of the processes of nutrition in other Cartilage, when calcifying, stains deeply with tissues. A chemical study of cartilage from this basophilic dyes, and has an acid reaction. Wells 29 point of view may throw some light upon the metahas stated that the well-known tendency of muscle- bolism of mucin, which hitherto has been unsolved. fibres to calcify in the vicinity of recent wounds, Dentine and the Odontoblast. including laparotomy wounds, may be due to the with the problem of the osteoblast salts lactic associated of calcium set free acid, Closely by precipitation by the injury to the muscle-fibres during the process and bone is the problem of the odontoblast and of degeneration. The question whether a site of dentine. The metabolic processes involved are calcification shall also become a site of bone formation closely related, and the pathological processes are is apparently a question of blood-supply. Tendons, parallel in craniotabes, in dysostosis cleidocranialis.. ligaments, the media of arteries and caseating in osteomalacia, and in experimental rickets. The granulomata rarely produce true bone, but muscle, problem has been discussed recently by Mrs. kidney, lung, suprarenal, and tonsil frequently do, Mellanby,33 W. Fish,34 and D. Stewart,35and attention by reason of the association of primitive connective must be drawn to the disturbing evidence adduced tissue cells with a rich capillary network. Cusbing by Donaldson and French,36 who claim that growth
stream, of fat-soluble blood-borne substances. These fat-soluble, blood-borne substances correspond to the " ergusia " or differentiating, energy-producing substance of Burrows, and to vitamin A proper. The osteoblasts are cells designed for work, not for
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493 the molar teeth of the rat after eruption. CANCER OF THE INTESTINE. The crown continues to increase in both dimensions ; as much as 10 per cent. is added to its length and A CLINICAL STUDY. breadth during the first two years, and the growth takes place in the dentine. This startling observation BY RICHARD WARREN, M.D., M.CH. OXF., compels us to regard dentine, like bone, as a tissue F.R.C.S. ENG., .subject to prolonged growth, peculiarly susceptible SURGEON TO THE ALEXANDRA MEMORIAL HOSPITAL, WESTONto changes in the blood calcium, and revealing the SUPER-MARE; LATE SURGEON TO THE LONDON HOSPITAL. same processes of absorption and deposition as bone. The rapid development of caries and the fragmentation Tiiis account is based on observations of 69 cases of the enamel in pregnant and nursing mothers may of cancer of the bowel (excluding the rectum) verified be due to the inroad made on the calcium of the by operation. In all except two cases the cancer dentine and the resulting shrinkage. was of the large intestine. Although distinctly a Still more numerous are the problems afforded by disease of middle and old age, no stage of life affords comparative anatomy, and it is surprising that so immunity to it. The youngest in this series was a little has been added to the original observations of of 15 (much younger cases are on record) and the John Goodsir (1814-1867), who inaugurated the study boy oldest a man of 78. Cancer of the small gut is rare ; of calcification in sponges and molluscs. Pearl and two cases were noted. In the colon the distribuSurface 37 in 1909 performed a classical experiment. only was as follows : csecum to hepatic flexure, 12 ; They anastomosed the gut to the oviduct of the fowlItion transverse colon, 4 ; splenic flexure and descending and showed that the faeces were covered with a shell.I 20 ; sigmoid, 31. It is, therefore, much more The domestic fowl, with its active metabolism and colon, common at the two ends of the colon, especially the great powers of repair, appears to be an ideal animal lower. for the study of calcification and ossification. ConThe onset is usually insidious, taking the form of sidering the extent to which the costochondral a vague dyspepsia or abdominal discomfort which junction and the costal cartilages have figured in the may be regarded lightly by the patient until the literature of rickets and respiratory diseases, it is crisis arrives with a well-marked attack of intestinal evident that a detailed study of the comparative obstruction. The commonest symptoms and signs of these a structures offers field anatomy promising are : (a) in the earlier quiet period-pain, flatulence, for research. The costal cartilages calcify in old and meteorism or distension with gas, alteration in in in adolescence in and and man, goats, age sheep the motions such as constipation and diarrhoea, and they become really ossified in birds. a local (b) the urgent conIt seems that until the chemist explains the colloidal occasionally of acutetumour; intestinal obstruction and of dition-signs processes which lead to the deposition of the salts local or general peritoneal irritation. Most of the of calcium in two tissues so fundamentally distinct early signs are those of early intestinal obstruction as dying cartilage on the one hand and living bone and must be weighed carefully before being regarded on the other, we must continue to regard the osteoas trivial. blast as a splendid being, endowed with genius, Early Stages. sensibility, and intelligence, ever ready to perform In the a mild degree of obstruction is early stages the work at hand. to be the only significant sign. Rarely a local apt Bibliography. tumour can be felt. A woman of 50 who had suffered 1. Keith, Sir A. : Proc. Roy. Soc. Med., 1927, xxi., 301. from metrorrhagia for some years was brought up 2. Brash, J. C.: Lect. Dental Board of U.K., London, 1925. 3. Hunter, John: Essays and Observations, London, 1861, for examination. In addition to the enlarged nodular i., 377. fibroid uterus there was a small mobile lump on the 4. Collip, J. B. : Harvey Lectures (New York), 1926-27. left of, and not definitely attached to, the uterus, but 5. Stump, W. C. : Jour. Anat., 1923, lix., 136. 6. Fell, H. B. : Jour. Morph. and Phys., 1925, xl., 417. sufficiently close to lead to the conclusion that it was 7. Bast, T. H., Sullivan, W. E., and Geist, F. D.: Anat. a very mobile subperitoneal fibroid. At operation Record, 1925, xxxi., 255. the small lump proved to be a cancer of the sigmoid. 8. Carey, E. J., and Zeit, W.: Ibid., 1927, xxxvi., 51. 9. Goering, D. : Zeitschr. f. d. ges. Neur. and Psych., 1924, The caecum is the part where a cancerous tumour is most commonly noted early. xlii., 1. 10. Wells, Gideon : Harvey Lectures (New York), 1910-11. 1. The pain tends to be intermittent and varies from W. B.: 11. Howland, J., Marriott, Jour. M., and Kramer, Biol. Chem., 1926, lxviii., 721. abdominal discomfort to fairly severe colic as the 12. Robison, R. : Biochem. Jour., 1926, xx., 388. obstruction becomes more advanced. It may have 13. Stewart, C. P., and Percival, G. H.: Ibid., 1927, xxi., 301. a relation to meals and is, in fact, one of the forms 14. Barillé : Jour. de Pharm. et Chim., 1910, i., 342. 15. Watt, J. C. : Biol. Bull., 1923, xliv., 280. of dyspepsia. The time relation is not, however, 16. Crétin, A. : Recherches sur l’ossification et sur la réparation constant, like that of peptic ulcer, and the associated des os fracturés, Le Mans, 1925. 17. Carrel, A., and Burrows, M. T.: Jour. Amer. Med. Assoc., flatulence renders it more likely to be confused with 1910, lv., 1379. gall-bladder dyspepsia. In a great many instances 18. Fischer, A. : Jour. Exp. Med., 1922, xxxvi., 379. is not enough to make the patient seek 19. Strangeways, T. S. P. : Proc. Roy. Soc. B., 1922-23, the pain advice before acute obstruction. supervenes. More xciv., 137. 20. Policard, A., and Boucharlat, M.: Arch. f. Exper. Zellforsch., rarely there is pain of a different type in the vicinity 1925, ii., 223. of the growth, as in one case where there was a large 21. Wjerinski, A. O. : Virchows Arch., 1924, ccli., 268. 22. Burrows, M. T.: Proc. Soc. Exp. Biol. and Med., 1927, growth of the caecum simulating a renal tumour, but not reducible into the loin. In other patients xxiv., 899. 23. Harrison, R. G.: Jour. Exp. Zool., 1914, xvii., 521. spread of the growth from the splenic flexure along 24. Loeb, L., and Fleischer, M. S. : Med. Res., 1917, xxxvii., 75. the lieno-renal ligament gave severe pain, which in 25. Harris, H. A.: Arch. Int. Med., 1926, xxxviii., 785. 26. Burrows, M. T. : Proc. Soc. Exper. Biol. and Med., 1925, one instance preceded any signs of obstruction by xii., 201. some weeks and drew attention to the kidney rather 27. Carrel, A. : Jour. Amer. Med. Assoc., 1924, lxxxii., 255. Localised pain from ulceration of, 28. Owen, Richard : Lect. on Invertebrate Animals, London, than the bowel. 1843, 171. and peritonitis over, the distended caecum is discussed 29. Wells, Gideon: Jour. Exp. Med., 1909, xi., 1. 30. Cushing, H., and Weed, L. : Johns Hopk. Hos. Bull., 1915, later. 2. Flatulence is a word covering various conditions. xxvi., 297. 31. Wolf, Jan : Bull. d. l’Acad. d. Sci. de Bohême, 1926. may refer to eructation of gas associated with pain 32. Schmiedeberg, O.: Arch. f. exp. Path. u. Pharm., 1891, or discomfort, or to a feeling of fullness and distension, xxviii., 355. 33. Mellanby, May: Brit. Dent. Jour., 1927, xlviii., 737. is by passage of the gas past the obstruc34. Fish, E. W. : Proc. Roy. Soc. Med. (Odontol), 1927, xx., 1. tion with gurgling and tinkling noises known as 35. Stewart, D. : Jour. of Anat., 1927, lxi., 439. Such noises and eructations are so 36. Donaldson, H. H., and French, H. E. : Anat. Record, 1927, borborygmi. xxxiv., 277. commonly due to errors in diet, neurosis, &c., that 37. Pearl, R., and Surface, F. M. : Science, 1909, xxix., 428. unless they are of recent development and recur For further references see Wells, Gideon, The Harvey A. : and Sir Menders of the Keith, Maimed, frequently, accompanied by pain which is relieved Lectures, 1910-11, London, 1919. by the passage of gas, they have little significance.
persists in
-
I It
which relieved
490
stage of cartilage formation had been described by Nesbitt in 1736. Coincidently with the slow unfolding of the microscopic structure of bone, the experimental method was pursued by Stephen Hales, Nehemiah Grew, John Belchier, and John Hunter in this country, by Duhamel in Paris, and by Haller in Gottingen. Their methods consisted largely of actual measurements of growing bones and of the feeding of madder to experimental animals. Hales and Grew were activated by the search for vegetable processes in the development of the animal world. The madder experiments of Belchier and Hunter
have been repeated on innumerable occasions, the most recent being the work of Prof. Brash,2 of Birmingham, on the growth of the mandible. It is interesting to note how most modern investigators have failed to appreciate Hunter’s description of the sites of deposition of the dye. Hunter3 insisted on the fact that the whole of the bone was stained by madder, and that the depth of the staining was medullated and non-medullated nerve-fibres. Numerous investigators have found that trophic changes in proportional to the rate of deposition and absorption bone follow nerve-section, such as loss of size and of the earthy salts. diminution of inorganic material, and, in But in the full-grown state, it would appear from the weight, animals, defective development. Numerous growing circumstances of reddening a whole bone by feeding the animal with madder, that a bone, although completely observations have been recorded upon the influence formed, yet is changing its earth, and probably every other in bone of nerve lesions and diseases in man. Here part. This effect, however, is much slower than in the again, especially in leprosy, regressive changes seem growing bone. This would show that the madder does not to be the rule. In general, lesions of mixed nerves act as a dye upon the earth which is already deposited in produce more bony changes than those of purely the bone, but only upon that matter which is every day motor nerves, and irritative lesions of sensory nerves deposited ; and as there is a great deal more deposited in seem to be the most potent, as in leprosy. Goering a young bone than in an old one in a given time, in the same proportion must it dye sooner than an old one. The concludes, on clinical grounds, that there are special trophic fibres of sympathetic origin passing to bones, new matter that is deposited in an old bone is to make up for the waste that is daily going on in it; but in a very with corresponding spinal centres. A general conold bone the waste is more than the repair." trolling centre, so it is claimed, is situated in the brain in the region of the floor of the third ventricle. It is This is the first clear expression of the fact that the obvious that there is much room for anatomical calcium of the bones is not permanently fixed as a and clinical research in this field, and that the bony but can be into the circulation brought deposit account of anterior poliomyelitis and tabes dorsalis as a current account. The recent brilliant work of changes offer abundant material. indicates the 4 with extract ease Collip parathyroid with which the extract can raise the blood calcium Problem of Calcium Metabolism. to abnormally high values by calling upon the calcium The vast literature relating to bone formation in the bones and muscles. was admirably summarised by Gideon Wells 1" in Grew, Duhamel, and the other botanists regarded the Harvey lecture of 1911. Since that date biobone as the product of the deeper layers of the chemistry and the intensive study of the vitamins " " periosteum, which they regarded as a cambium have revealed the complexity of the whole problem layer, by analogy with the actively proliferating of calcium metabolism. Wells stated that the zone of plants. Haller regarded bone as a product questions to be answered are :of the arteries, which could lay down bone anywhere. 1. Why is calcium deposited in the tissues at all ? 1 Hunter favoured this view, and Sir Arthur Keith 2. Why is it deposited in some tissues and not in others ? has recently attributed to the perithelial cells of the 3. How is the calcium carried in the blood ? 4. How is it held in the tissues where deposited ? capillaries the power of conversion into osteoblasts. 5. Why is the composition of calcified deposits so conGoodsir, differing from Hunter, believed that the qualitatively and quantitatively ? cartilage cells gave rise to " bone-forming corpuscles." stant, 6. What are the causes of rickets and osteomalacia ? The present-day teaching of the formation of bone in membrane, in cartilage, and in the deep layer of These questions still await concise answers. The the periosteum represents a consolidation of the views first question involves the whole problem of senescence of Sharpey, Kölliker, and Virchow. The source of and death. Calcification occurs not only in certain the osteoblast is, however, still a problem. Stump5 cartilages but also in tumours, such as fibroids and traces the cartilage cell, the subperiosteal osteoblast, granulomata, in the meninges, and in tendons, the endochondral osteoblast, the osteoclast, the ligaments, and arteries. The second question brings endothelial cells of the growing capillaries, the to mind the fact that the tissues which undergo primitive blood cells and the " haemoblasts " to the calcification in senescence are the tissues which same young connective tissue cells. This is an afford examples of vegetative reproduction, with or extreme statement of the monophyletic origin. Fell,6 without mitotic division of nuclei, in relatively bloodin a study of osteogenesis in the domestic fowl, claims, less areas. Cartilage, which most readily undergoes on the other hand, that the chondroblasts suffer a calcification, is a tissue in which the cells live by the triple fate. They may give rise to osteoblasts, as imbibition of tissue juice, removed from an active described by Ranvier, Retterer, Macewen, and Van blood-supply. There is undoubtedly a limit to the der Stricht, or they may give rise to the reticulum size of the mass of cartilage which any animal can of the bone-marrow, or they may degenerate and grow, just as there is a limit to the size of a granuloma. disappear. Experiments on animals, such as those When the limit of growth is reached certain of the of Bast, Sullivan, and Geiston the repair of frac- cells degenerate and the matrix calcifies or caseates. tured bones, show that the " cambium " layer of Thus in cartilage proliferation, degeneration and the periosteum, the osteogenetic cells lining the calcification are closely related to the vegetative Haversian canals, and the cells of the endosteum are processes of proliferation without specialisation of all active in the production of new bone. They found function and without differentiation of structure, that the only site of formation of cartilage in the leading to old age and death of the tissue. On the repair of bones was at the cut edge of the fibrous other hand, bone formation is an active process, part of the periosteum. They saw fibrous tissue8 distinct from calcification. It occurs in the presence cells giving rise to cartilage cells. Carey and Zeit, of a rich blood-supply and is accompanied by differenas a result of the study of the ossifying patella in the tiation of the primitive cells for function, as distinct "
-
dog, emphasise the dual origin of the osteoblast, and depict both osteoblasts arising from the subendothelial mesenchyme cells accompanying the invading blood-vessels, and osteoblasts formed directly from the embryonic chondroblasts in the neighbourhood of the capillaries. Nerve-supply of Bone. The problem of the nerve-supply of bone has remained in abeyance. The innervation of the two tissues of the body which exhibit the greatest power of regeneration and repair, bone and its marrow, still awaits adequate description. Sir G. Thane, in Quain’s Anatomy (tenth edition), mentions the fact that distinct nerves can be seen entering the nutrient foramina of the long bones. D. Goering9 has studied the influence of the nervous system on bones and joints. She concludes that bone has a somatic and a sympathetic innervation by means of
491 cation of the cartilage cells in vitro, with typical mitoses. Policard and Boucharlat 20 implanted periosteum and perichondrium of chicks, but in vitro they gave rise to connective tissue cells without the formation of cartilage or bone. A. O. Wjerinski 21 relatively poor in blood-supply. The question of the carriage of calcium in the reports the same results in vitro, though a homoplastic blood has been attacked with great vigour by the transplant in vivo led to strong mitotic multiplication chemist. Howland, Shipley, and Marriott and of the cells of the periosteum and actual conversion Kramer 11 have stated that bone normally contains into osteoblasts. Thus, so far, osteoblasts have bicalcium phosphate, that different bones of the same not been grown or propagated in vitro by the technique individual have the same inorganic percentage, that of tissue culture. This suggests that the osteoblast the ratio of calcium phosphate to calcium carbonate is a purposively differentiated cell which may is greater in normal than in rachitic bones, and, easily regress into a fibroblast, but will only redifferfurther, that the bone contains the phosphate and entiate in the presence of the blood-borne exudate carbonate of calcium in the same proportion as the of a living capillary. The nerve cell of the young embryo has been grown R. Robison 12 has disagreed with these views serum. and has emphasised the significance of the hexose in tissue culture, but the growth has been localised phosphoric esters. He states that the osteoblastsI almost entirely in the axone-i.e., in the part of the and the hypertrophic cartilage cells of the growing cell which was shown capable of growth in the adult animal secrete an active phosphatase which, by by Waller’s classical experiments on nerve regenerahydrolysing the phosphoric esters of the blood, tion. The osteoblast, as Burrows.22 has pointed out brings about a local increase of the tricalcium phos- for the fully matured lymphocyte, polymorphonuclear phate concentration. This concentration exceeds the leucocy-te, and many other mononuclear cells, will not solubility product of the salt and leads to its deposition grow in a tissue culture. Neither the nerve cell nor in the ossifying zone. Howland and his co-workers the osteoblast can be propagated. Thus these cells do not favour simple precipitation as the explanation, seem to exhibit an extreme degree of differentiation. but regard the process as a chemico-physical one, R. G. Harrison,23 in 1914, pointed out that cells depending on the activity of the living tissue in a will not grow in tissue cultures in clotted plasma medium in which the concentration of calcium andI unless some form of support is afforded, such as the phosphate in the serum and tissue juice exceed a surface of the cover-glass, the surface of the fluid film, certain minimum value. J. B. Collip4 in Canada, or a framework of spider-web, silk gauze, or cottonand C. P. Stewart and J. H. Percival 13 in this country, thread. In cultures in which the tissue floats free have dealt in particular with the changes in serum in a fluid medium no outgrowth occurs and the cell calcium under administration of Collip’s parathyroid succumbs. This phenomenon whereby a cell in hormone. The diffusible calcium is markedly increased the free rounded stage, devoid of support, is unable thereby. These experiments indicate the ease with to grow was described by Leo Loeb and Fleischer 24 which calcium passes into the blood from bone and under the name of stereotropism. It involves a other tissues, and this is a brilliant confirmation of most fundamental conception of a skeletal support Hunter’s precocious statement about the continuous for the cell, and may account for the failure to grow absorption and deposition of alkaline earths in old osteoblasts and fully differentiated blood cells such bone as well as in young bone. as Kidney and liver are grown with Several attempts have been made to imitate in ease because of their associated connective tissue colloidal solutions the actual deposition of tricalcium stroma. Cartilage cells die when they round up phosphate and calcium carbonate. Barille 14 in near the epiphysis. Osteoblasts apparently require France and J. C. Watt 15 in Canada have come to the the support of a connective tissue stroma and the conclusion that the salts in bone are deposited by adequate supply of blood-borne substances such as the activity of the osteoblasts as a secretory pheno- vitamin A and ergusia. Only those animals which menon. Orétin,16 in particular, has contributed much have ablood vascular system and a coelom are able to our knowledge of the staining reaction of bone to producean active osteoblast. and of the possible conditions of deposition of the Bone Pathology. calcium salts. He regards the actual areas of muscular attachment to be of great significance in determining The pathology of bone, like the pathology of the cartilage formation and ossification. The sterno- blood-vessels, has been so obscured by diverse mastoid and trapezius muscles in relation to the classifications and a multitude of strange names that clavicle and the occinital bone are differentiated certain simple facts escape observation. Chondrobefore the cartilage or bone appears. The point dystrophies, osteochondrites, and osteites have been of cartilage formation and of bone formation is subdivided without end, and dysostoses, aclasias, always related to the muscular. attachment. The and dysclasias have been added thereto. Vrolik’s transportation of phosphorus in combination with term of " osteogenesis inperfecta " is one of the few alkali metals converts the primitive tissue into safe terms in the pathology of growing bone. H. A. cartilage by producing a modification in the Harris’s 25 tentative scheme, as a simple working basis albumenoids of the matrix. Whereas cartilage is for the analysis of bone growth, serves also as a basis rich in sodium, growth ceases when calcium disturbs for the interpretation of bone pathology. He states the equilibrium between phosphate on the one hand that cartilage grows vegetatively by the imbibition and sodium and potassium on the other. Calcium of tissue juice in much the same way as bacteria, carbonate is now precipitated, redissolved in the yeasts, tumour cells, and granulomata. This vegepresence of alkalies, and then reprecipitated by tative proliferation of the cell is largely under the phosphate in the form of basic phosphate or phospho- control ofthe water-soluble vitamins and of those carbonate. substances which workers in the realm of tissue T-issue Culture Experiments. culture have designed as archusia " (M. T. " The results of tissue culture experiments have so far Burrows)26 The or Ca.rell).2’ (A. trephones been disappointing. A. Carrel and M. T. Burrows 17 process of proliferation of the undifferentiated cartilage cultivated conjugal cartilage as early as 1910, but cell is limited by the size of the mass and by the the first detailed experiments were those of adequacy of nutrition. When the mass of cartilage A. Fischer 18 in 1922. He cultivated the cartilage reaches a certain limit, as in the case of a granuloma, cells from the sclera of the chick embryoa’in vitro," the cells within the mass become senescent, degenerate, and found that the cells would not grow in the sub- and gradually pass into a resting stage which in many stance but would grow on the surface of a clot of cases leads to death. This process of degeneration plasma. In the implant the hyaline substance is accompanied by calcification of the matrix, and is liquefies, the cells migrate, increase in size, and comparable to the phenomenon of caseation and continue to live. No division of the cells was seen. calcification in a tubercle, gumma, or fibroid, or to T. S. Strangeways 19 succeeded in producing multipli- hyalinisation and the formation of cell nests in a
In short, bone is a live mere proliferation. tissue, actively growing or functioning in an area richly endowed with blood. Calcined cartilage is so senescent as to be virtually a dead tissue in an area
from
I
lymphocytes.
492
Lastly, the propinquity of a rapidly and Weed ’30 in their experimental studies on the growing capillary system in the bone-marrow brings cerebro-spinal fluid of cats, observed numerous into the region a new set of factors which lead to instances of calcification and ossification of the tissue differentiation as distinct from cell proliferation. arachnoid membrane. Calcification occurred in nonThe capillaries of the bone-marrow proceed to remove vascular areas, for the nutrition of the arachnoid the dead calcified cartilage as they would proceed to is obtained through the cerebro-spinal fluid rather On the other hand, remove any other foreign dead body, such as a than through the blood stream. caseated granuloma or a ligature. The cells of the every case of true bone formation was vascularised calcified cartilage that are not quite dead, but rather and could be attributed to the proliferation of in a resting or spore " stage, respond to the approach mesothelial cells in a vascularised area, as distinct of the blood capillaries by active amitotic division from the calcification of aged cells in an avascular to form osteoblasts. Any primitive connective area. In the aged cadaver of the dissecting-room, tissue cell in the vicinity of the actively proliferating calcification of the membranes, both dura and capillary can give rise to osteoblasts, whether this arachnoid, is common. True bone formation, on cell be periosteal, perivascular, or reticular. This the other hand, is rare. For a considerable time it was thought that theprocess of cell differentiation for function is in part carcinoma.
"
attributable to the arrival in the area, via the blood
secret of calcification would be found in the formation of calcium soaps with fatty acids, for the early pathologists had described calcification by soap formation in degenerating lipomata as early as 1850. The absence of any appreciable amount of calcium soaps from areas of normal calcification has negatived proliferation, and a failure of ergusia or vitamin A this idea, and the presence of large quantities of leads to the formation of imperfectly differentiated calcium soaps in certain stages of the digestion of osteoblasts. The degree of differentiation may be fat without associated calcification is also against so low that the osteoblast is little more than a fibrothe theory. We seem to be confronted with the blast ; it may be more" advanced, so that the cells need for a new chemical concept. The hydrogen-ion deserve the name of osteoidoblast," but only in concentration and the salt content must be known, the presence of an adequate supply of the blood- not only for the arterial and venous streams but also borne vitamin A does one see the fully differentiated for the contents of the lymphatics, for the tissue osteoblast with deeply staining nucleus and numerous juice, and for the interior of the cell. The high basophilic granules in the cytoplasm. This con- percentage of calcium which can be absorbed in a ception of the vegetative proliferative process in cartilage designed for later calcification was shown cartilage, in contradistinction to the differentiating by Wells.1.0 He showed that pieces of epiphysial and functional process in bone, is not entirely new. cartilage, tracheal cartilage, and costal cartilageIts formulation in terms of archusia and ergusia absorb decreasing amounts of calcium salts, irreon the one hand, or in terms of water-soluble and spective of whether the cells in the transplant be fat-soluble vitamins on the other hand, is but an alive or dead. Moreover, decalcified bone-grafts. experimental and clinical statement of a long- are known to be less efficient than normal bone-grafts, established teleological fact. Richard Owen,28 when so that a preliminary calcification or power of calcium Curator of the.Royal College of Surgeons of England, absorption in the tissue seems to be advantageous for said, as far back as 1843 :subsequent ossification. Pathological ossification, no less. " Organic forms result from the antagonistic working than normal ossification, seems to require preliminary of two principles, of which one brings about a vegetative calcification of the cartilage or of the necrosed tissue. repetition of structure, while the other, a teleological Since no chemical ion or soap in cartilage can be principle, shapes the living thing to its functions.... proved to be an adequate agent in producing the In every species these two forces are at work, and the extent to which the general polarising orvegetative deposition of calcium phosphate and carbonate, it repetition force ’ is subdued by the teleological is an index is interesting to note that Jan Wolf 31 has returned to the problem of chondroitin-sulphuric acid. This of the grade of the species." Evolution is measured by the extent of the triumph substance is a normal constituent of cartilage; it is of ergusia and the fat-soluble vitamins over archusia increased in calcifying cartilage ; it occurs in theamyloid deposits of the spleen, liver, and arteries-, and the water-soluble vitamins. The term metastatic calcification was applied its calcium salt is very soluble. Jan Wolf has shown the small veins draining the costal cartilage by Virchow to the occurrence of deposits of calcium that salts in abnormal sites. There is hardly a tissue in contain a measurable amount of chondroitin-sulphuric the body which does not present numerous examples acid, and that this can be stained in situ by mucicarmin of abnormal calcification, from ganglion cells and or basophilic stains. The acid is not found in the skin on the one hand, to kidney, liver, lungs, and arteries. This suggests that the continuous removal gastric mucosa on the other. Most of the cases of of chondroitin-sulphuric acid from the matrix of a calcification occur in an area of senile or necrosed cartilage is necessary to preserve it from calcification. tissue, with a poor blood-supply and a slow lymph As yet no one has studied the effects on the solubility stream. There are, however, three marked exceptions, product of this acid or its calcium salt in the presence for calcification has been repeatedly reported in the of other ions. Even as long ago as 1891, Schmiedelungs, kidneys, and gastric mucous membrane. These berg 32 suggested that one of the functions of cartilage three areas are the sites of excretion or secretion was the production of chondroitin-sulphuric acid of acid substances, and the tendency to calcification and that this acid served as a mordant and possibly in these areas may be an expression of this fact. as a regulator of the processes of nutrition in other Cartilage, when calcifying, stains deeply with tissues. A chemical study of cartilage from this basophilic dyes, and has an acid reaction. Wells 29 point of view may throw some light upon the metahas stated that the well-known tendency of muscle- bolism of mucin, which hitherto has been unsolved. fibres to calcify in the vicinity of recent wounds, Dentine and the Odontoblast. including laparotomy wounds, may be due to the with the problem of the osteoblast salts lactic associated of calcium set free acid, Closely by precipitation by the injury to the muscle-fibres during the process and bone is the problem of the odontoblast and of degeneration. The question whether a site of dentine. The metabolic processes involved are calcification shall also become a site of bone formation closely related, and the pathological processes are is apparently a question of blood-supply. Tendons, parallel in craniotabes, in dysostosis cleidocranialis.. ligaments, the media of arteries and caseating in osteomalacia, and in experimental rickets. The granulomata rarely produce true bone, but muscle, problem has been discussed recently by Mrs. kidney, lung, suprarenal, and tonsil frequently do, Mellanby,33 W. Fish,34 and D. Stewart,35and attention by reason of the association of primitive connective must be drawn to the disturbing evidence adduced tissue cells with a rich capillary network. Cusbing by Donaldson and French,36 who claim that growth
stream, of fat-soluble blood-borne substances. These fat-soluble, blood-borne substances correspond to the " ergusia " or differentiating, energy-producing substance of Burrows, and to vitamin A proper. The osteoblasts are cells designed for work, not for
li
493 the molar teeth of the rat after eruption. CANCER OF THE INTESTINE. The crown continues to increase in both dimensions ; as much as 10 per cent. is added to its length and A CLINICAL STUDY. breadth during the first two years, and the growth takes place in the dentine. This startling observation BY RICHARD WARREN, M.D., M.CH. OXF., compels us to regard dentine, like bone, as a tissue F.R.C.S. ENG., .subject to prolonged growth, peculiarly susceptible SURGEON TO THE ALEXANDRA MEMORIAL HOSPITAL, WESTONto changes in the blood calcium, and revealing the SUPER-MARE; LATE SURGEON TO THE LONDON HOSPITAL. same processes of absorption and deposition as bone. The rapid development of caries and the fragmentation Tiiis account is based on observations of 69 cases of the enamel in pregnant and nursing mothers may of cancer of the bowel (excluding the rectum) verified be due to the inroad made on the calcium of the by operation. In all except two cases the cancer dentine and the resulting shrinkage. was of the large intestine. Although distinctly a Still more numerous are the problems afforded by disease of middle and old age, no stage of life affords comparative anatomy, and it is surprising that so immunity to it. The youngest in this series was a little has been added to the original observations of of 15 (much younger cases are on record) and the John Goodsir (1814-1867), who inaugurated the study boy oldest a man of 78. Cancer of the small gut is rare ; of calcification in sponges and molluscs. Pearl and two cases were noted. In the colon the distribuSurface 37 in 1909 performed a classical experiment. only was as follows : csecum to hepatic flexure, 12 ; They anastomosed the gut to the oviduct of the fowlItion transverse colon, 4 ; splenic flexure and descending and showed that the faeces were covered with a shell.I 20 ; sigmoid, 31. It is, therefore, much more The domestic fowl, with its active metabolism and colon, common at the two ends of the colon, especially the great powers of repair, appears to be an ideal animal lower. for the study of calcification and ossification. ConThe onset is usually insidious, taking the form of sidering the extent to which the costochondral a vague dyspepsia or abdominal discomfort which junction and the costal cartilages have figured in the may be regarded lightly by the patient until the literature of rickets and respiratory diseases, it is crisis arrives with a well-marked attack of intestinal evident that a detailed study of the comparative obstruction. The commonest symptoms and signs of these a structures offers field anatomy promising are : (a) in the earlier quiet period-pain, flatulence, for research. The costal cartilages calcify in old and meteorism or distension with gas, alteration in in in adolescence in and and man, goats, age sheep the motions such as constipation and diarrhoea, and they become really ossified in birds. a local (b) the urgent conIt seems that until the chemist explains the colloidal occasionally of acutetumour; intestinal obstruction and of dition-signs processes which lead to the deposition of the salts local or general peritoneal irritation. Most of the of calcium in two tissues so fundamentally distinct early signs are those of early intestinal obstruction as dying cartilage on the one hand and living bone and must be weighed carefully before being regarded on the other, we must continue to regard the osteoas trivial. blast as a splendid being, endowed with genius, Early Stages. sensibility, and intelligence, ever ready to perform In the a mild degree of obstruction is early stages the work at hand. to be the only significant sign. Rarely a local apt Bibliography. tumour can be felt. A woman of 50 who had suffered 1. Keith, Sir A. : Proc. Roy. Soc. Med., 1927, xxi., 301. from metrorrhagia for some years was brought up 2. Brash, J. C.: Lect. Dental Board of U.K., London, 1925. 3. Hunter, John: Essays and Observations, London, 1861, for examination. In addition to the enlarged nodular i., 377. fibroid uterus there was a small mobile lump on the 4. Collip, J. B. : Harvey Lectures (New York), 1926-27. left of, and not definitely attached to, the uterus, but 5. Stump, W. C. : Jour. Anat., 1923, lix., 136. 6. Fell, H. B. : Jour. Morph. and Phys., 1925, xl., 417. sufficiently close to lead to the conclusion that it was 7. Bast, T. H., Sullivan, W. E., and Geist, F. D.: Anat. a very mobile subperitoneal fibroid. At operation Record, 1925, xxxi., 255. the small lump proved to be a cancer of the sigmoid. 8. Carey, E. J., and Zeit, W.: Ibid., 1927, xxxvi., 51. 9. Goering, D. : Zeitschr. f. d. ges. Neur. and Psych., 1924, The caecum is the part where a cancerous tumour is most commonly noted early. xlii., 1. 10. Wells, Gideon : Harvey Lectures (New York), 1910-11. 1. The pain tends to be intermittent and varies from W. B.: 11. Howland, J., Marriott, Jour. M., and Kramer, Biol. Chem., 1926, lxviii., 721. abdominal discomfort to fairly severe colic as the 12. Robison, R. : Biochem. Jour., 1926, xx., 388. obstruction becomes more advanced. It may have 13. Stewart, C. P., and Percival, G. H.: Ibid., 1927, xxi., 301. a relation to meals and is, in fact, one of the forms 14. Barillé : Jour. de Pharm. et Chim., 1910, i., 342. 15. Watt, J. C. : Biol. Bull., 1923, xliv., 280. of dyspepsia. The time relation is not, however, 16. Crétin, A. : Recherches sur l’ossification et sur la réparation constant, like that of peptic ulcer, and the associated des os fracturés, Le Mans, 1925. 17. Carrel, A., and Burrows, M. T.: Jour. Amer. Med. Assoc., flatulence renders it more likely to be confused with 1910, lv., 1379. gall-bladder dyspepsia. In a great many instances 18. Fischer, A. : Jour. Exp. Med., 1922, xxxvi., 379. is not enough to make the patient seek 19. Strangeways, T. S. P. : Proc. Roy. Soc. B., 1922-23, the pain advice before acute obstruction. supervenes. More xciv., 137. 20. Policard, A., and Boucharlat, M.: Arch. f. Exper. Zellforsch., rarely there is pain of a different type in the vicinity 1925, ii., 223. of the growth, as in one case where there was a large 21. Wjerinski, A. O. : Virchows Arch., 1924, ccli., 268. 22. Burrows, M. T.: Proc. Soc. Exp. Biol. and Med., 1927, growth of the caecum simulating a renal tumour, but not reducible into the loin. In other patients xxiv., 899. 23. Harrison, R. G.: Jour. Exp. Zool., 1914, xvii., 521. spread of the growth from the splenic flexure along 24. Loeb, L., and Fleischer, M. S. : Med. Res., 1917, xxxvii., 75. the lieno-renal ligament gave severe pain, which in 25. Harris, H. A.: Arch. Int. Med., 1926, xxxviii., 785. 26. Burrows, M. T. : Proc. Soc. Exper. Biol. and Med., 1925, one instance preceded any signs of obstruction by xii., 201. some weeks and drew attention to the kidney rather 27. Carrel, A. : Jour. Amer. Med. Assoc., 1924, lxxxii., 255. Localised pain from ulceration of, 28. Owen, Richard : Lect. on Invertebrate Animals, London, than the bowel. 1843, 171. and peritonitis over, the distended caecum is discussed 29. Wells, Gideon: Jour. Exp. Med., 1909, xi., 1. 30. Cushing, H., and Weed, L. : Johns Hopk. Hos. Bull., 1915, later. 2. Flatulence is a word covering various conditions. xxvi., 297. 31. Wolf, Jan : Bull. d. l’Acad. d. Sci. de Bohême, 1926. may refer to eructation of gas associated with pain 32. Schmiedeberg, O.: Arch. f. exp. Path. u. Pharm., 1891, or discomfort, or to a feeling of fullness and distension, xxviii., 355. 33. Mellanby, May: Brit. Dent. Jour., 1927, xlviii., 737. is by passage of the gas past the obstruc34. Fish, E. W. : Proc. Roy. Soc. Med. (Odontol), 1927, xx., 1. tion with gurgling and tinkling noises known as 35. Stewart, D. : Jour. of Anat., 1927, lxi., 439. Such noises and eructations are so 36. Donaldson, H. H., and French, H. E. : Anat. Record, 1927, borborygmi. xxxiv., 277. commonly due to errors in diet, neurosis, &c., that 37. Pearl, R., and Surface, F. M. : Science, 1909, xxix., 428. unless they are of recent development and recur For further references see Wells, Gideon, The Harvey A. : and Sir Menders of the Keith, Maimed, frequently, accompanied by pain which is relieved Lectures, 1910-11, London, 1919. by the passage of gas, they have little significance.
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