Connective Tissue Responses in Negroes in Relation to Disease ANTHONY P. POLEDNAK Birth Defects Institute, State Department of Hectlth, Alb a n y , N e w York KEY WORDS Adaptation . Racial differences . Infectious diseases . Immunoglobulins . Fibroblasts . Pigmentation. ABSTRACT There is considerable evidence that Negroes have a tendency toward overgrowth of those connective-tissue components concerned with two functions - protection against infection (macrophages and plasma cells) and repair after injury (fibroblasts and their products). Thus, adaptation to the tropical environment in Africans may have involved a tendency toward connective-tissue overgrowth, as well as hypertrophy of the pigmentary apparatus. Both tendencies may have consequences in terms of: (1) susceptibility to certain chronic diseases; and (2) responses to disease processes or drug therapies. Some of these possible consequences are discussed. In 1937, Moehlig proposed that Negroes had a tendency, presumably genetic, toward "connective tissue overgrowth." In support of this Moehlig cited the high frequency among Negroes of keloids, or raised scars formed in response to injury. This observation has been confirmed among African Negroes (Alland and Keen, '54; Verhagen, Koten, Chaddah and Patel, '68) and U.S. blacks (Cosman, Crikelair, Ju, Gaulin and Lattes, '61; Kenney, '65). Moehlig's ('37) hypothesis is also supported by racial differences in other diseases involving connective tissue overgrowth, discussed below. We are concerned mainly with connective tissue proper, one of four major types of connective tissue - the others being blood and lymph, cartilage, and bone. In addition to providing mechanical support, the functions of connective tissue include protection against infection and repair after injury. These two functions are discussed, along with their implications for explaining racial differences in certain diseases. Protection against infection The reticuloendothelial system (RES) or macrophage system is a connective tissue component important in the pathology and natural history of infectious diseases. Wassermann ('65) has reviewed AM. J. PHYS. ANTHROP., 41: 49-58 evidence for hypertrophy of the RES in Africans, and suggested adaptation to tropical diseases as an explanation. Relatively high levels of immunoglobulins were considered as evidence for this tendency. In comparison with whites, healthy Negroes-both in Africa (Weithaler and Maruna, '67; McFarlane, '68; Ezeilo, '70) and in the U.S. (Lichtman, Vaughan and Hames, '67; Buckley and Dorsey, '71)have higher levels of serum immunoglobulin. High levels of gamma globulins also characterize certain other tropical populations, including New Guinea natives (Kariks and Hipsley, '61; Curtain, Gajdusek, Kidson, Gorman, Champness and Rodrigue, '65), Australian aborigines (Curnow, '57), Malayan aborigines (Bisseru and Ahmad, '70; Brearley, '70), Indians (Rama Rao, Amrithalochani and Narasimha Rao, '62; Chandra, Guha and Ghai, '70; Sehgal and Aikat, '70), and Mexicans (Golubjatnikov and Steadman, '72). It is uncertain to what extent these differences in gamma globulin level: (1) represent a genetic adaptation to infectious disease; or (2) result from early exposure to infectious disease. Supporting the genetic hypothesis is the finding that Negro-white differences exist within a similar tropical environment - that is, 49 50 ANTHONY P . POLEDNAK Interestingly, high immunoglobulin (IgG) levels are characteristic of this disease, and the myeloma cell is of plasma cell origin. The principal producer of antibodies - i.e., the immune globulins of the blood involved in defense against infection - is the plasma cell, which is a connective tissue component. Thus, connective tissue overgrowth is apparently involved in multiple myeloma. Scleroderma is a rare connective tissue disease involving excessive collagenization, producing a thickening of skin and mucous membranes. Systemic lupus erythematosus (SLE) involves widespread lesions of connective tissue, often with joint pain and swelling. Both diseases are much more frequent in females. In the U.S. both SLE (Siegel, Lee, Widelock, Reilly, Wise, Zingale and Fuerst, ’62; Siegel, Holley and Lee, ’70) and fatal diffuse scleroderma (Masi and D’Angelo, ’67) are more frequent in Negro females than in white females. These diseases “reflect a local response of a particular tissue to irritants or injurious agents” (Gardner, ’72:97). We have mentioned keloids as one example of a local (dermal) response of connective tissue to injury. It has been suggested (Siegel et al., ’62) that the higher rates of SLE in U.S. Negro females might be related to their higher gamma globulin levels relaDiseases of connective tissue tive to whites. In a recent study, mean Certain tumors of connective tissue IgG and IgM levels were both significantly higher in SLE patients than in concommon in some parts of Africa-notably, Burkitt’s lymphoma (Burkitt and trols (Alarcon-Segovia and Fishbein, ’72), Wright, ’70) and Kaposi’s sarcoma (Tay- but abnormal elevation of IgM was the most common pattern. In the Southern lor, Smith, Bull and Pike, ’72)-involve the RES. Evidence is accumulating for U.S., black females have significantly an association between Burkitt’s lym- more IgM than white females (Buckley phoma and malaria (Anon., ’70). Chronic and Dorsey, ’71), but males do not differ. infection with malarial parasites stimu- This finding is interesting because: (1) lates the RES. In tropical populationsSLE is much more common in females; perhaps genetically prone to overgrowth and (2) Negro-white differences in SLE of the RES as an adaptation to infectious frequency are confined to females. diseases - such stimulation may be cruThus, connective tissue hypertrophy cial in tumor formation (Edington, von in Negroes (high immunoglobulin levels) Lichtenberg, Nwabuebo, Taylor and Smith, may be involved in their increased sus’70). ceptibility to SLE, but this is uncertain. Multiple myeloma is one of the most Although most of the cellular, tissue, and common primary malignant tumors of organ damage in SLE can be attributed bone. According to some studies multiple to immunological disturbances (Alexanmyeloma is more frequent in U.S. Negroes der and Good, ’70:106), the role of hyperthan in whites (MacMahon and Clark, gammaglobulinemia in causation is un’56; McPhedran, Heath and Garcia, ’72). clear. The occurrence of “autoimmune” in South Africa (Milner and Calitz, ’71) and Egypt (El-Hehawi, ’69). Also, American Negro-white differences are independent of socioeconomic status (Lichtman, Vaughan and Hames, ’67; Buckley and Dorsey, ’71). Longitudinal (Trevorrow, ’70) and family (Lichtman, McDonough and Hames, ’67) studies suggest that genetic factors may be involved in determining IgG level. Both malaria (Edozien, Boy0 and Morley, ’60) and schistosomiasis (Cook, Woodstock and Jordan, ’72) infection are accompanied by elevation of serum globulin (particularly IgG) as well as by increased phagocytic activity. Thus, these diseases, common in tropical Africa, are associated with overgrowth of the RES. The relative contributions of genetic and environmental factors in causing an RES response, however, remain to be clarified. In any case, an ability to respond to these infections by an RES mechanism presumably would be adaptive. Thus, a tendency toward hypertrophy of certain connective tissue elements may be an adaptation to the tropical African environment, in particular to infectious disease (Wasserman, ’65). On the other hand, this tendency might also predispose to other diseases, to which we now turn. CONNECTIVE TISSUE RESPONSES I N NEGROES diseases, such as SLE, in agammaglobulinemic patients argues against a causal role according to some authors (Rowell, ’67) but not others (Alexander and Good, ’70:116). It was once generally believed that SLE was rare in U.S. Negroes. Similarly, SLE was believed to be rare in tropical Africa, but recent surveys suggest that i t is at least as common as elsewhere and “might be found more often when modern diagnostic methods become available” (Verhagen et al., ’68). Since most of the diseases discussed above (multiple myeloma, scleroderma, and SLE) are chronic disorders affecting primarily older persons, natural selection would not be expected to operate. Burkitt’s lymphoma, however, has a peak incidence at age 5-9 years and apparently involves an infectious (viral) agent. lndividuals with sickle cell trait may be more resistant to Burkitt’s lymphoma (Pike, Morrow, Kisuule and Mafigiri, ’70). This finding, if confirmed, strengthens the argument for an association between malaria and Burkitt’s lymphoma. Thus, individuals with sickle cell trait may be protected both from malaria and Burkitt’s lymphoma. This might be explained by the fact that the incidence of heavy p. falczparum infections is lower in children with the sickling trait than in those without the trait (Allison, ’64). Without chronic malarial infection providing stimulation of the RES, susceptibility to RES tumors might be lower. Repair after injury, and granulomatous diseases Repair of tissues after injury, a function of connective tissue, may occur by substitution. Fibroblasts are the principal agents of this repair. Substitution by fibroblasts may lead to fibrous scars in the tissues involved. Keloids, for example, are dermal scars developed after skin injury. Histologically, keloids consist of elastic fibers and collagen, with a granulomatous infiltrate containing fibroblasts, plasma cells and lymphocytes (Kelley, ’63). In the dermis, Japanese have significantly more fibroblasts than Caucasians (Andrew, Behnke and Sato, ’65), but Negroes apparently have not been studied. In a biopsy study of connective tissue, 51 however, Negroes developed a scleroprotein with a higher percentage of collagen relative to whites (Boucek, Noble, Kao and Elden, ’58). Collagen is produced by fibroblasts, as in the repair of connective tissue. In syphilis, a granulomatous infiammation, the response to tertiary lesions involves “gummas.” Gummas consist of fibroblasts, and “epithelioid cells” (macrophages transformed by ingestion of certain substances). In the earlier literature osseous gummas were reportedly more common in Negroes than in whites with tertiary syphilis (Lewis, ’42). This conclusion was supported by Frazier and Hung-Chiung’s (‘48) study of 11,353 cases of syphilis at Johns Hopkins Hospital in 1920-1931. Chronic granulomatous inflammatory processes are produced by agents other than the spirochete responsible for syphilitic lesions. Sarcoidosis is an infectious granuloma of obscure etiology. The sarcoid granuloma consists of “epithelioid cells” surrounded by fibrous connective tissue, and lesions may occur in various organs. Recent data from the U.S. (Terris and Chaves, ’66; Dauer, Korns and Schuman, ’68; Keller, ’71) indicate that this disease is much more frequent in Negroes than in whites. Hypergammaglobulinemia is found in one-third to one-half of patients with sarcoidosis, and “particularly among Negro patients” (Siltzbach, ’70:831). The disease may involve a tissue response to various agents (viral, fungal, or pollen), or to tuberculosis. Tuberculosis is another granulomatous inflammation which is much more frequent and severe in Negroes than in whites, independently of childhood infection (Lurie, ’64). Further evidence of a tendency of Negroes to form granulomatous connective tissue, in response to injury, may involve endomyocardial fibrosis. Fibroblasts are involved in the healing of defects not only in connective tissue proper, but in other tissues such as heart muscle. Heart muscle that degenerates, following myocardial infarction or other injury, is replaced by a connective tissue scar. In endomyocardial fibrosis (EMF), dense fibrous tissue scars replace the endocardium and adjacent myocardium. 52 ANTHONY P. POLEDNAK Although not confined to the African continent (Davies, ’69), EMF is relatively common in parts of Africa (Shaper and Coles, ’65; Shaper, ’66; Connor, Somers, Hutt, Manion and DArbela, ’68). Few cases have been reported in the United States, but a probable familial occurrence in North American Negroes has been reported (Bishop, Bousvaros, Cunningham, Jain and Davies, ’68). Two diseases apparently related to EMF - i.e., “idiopat hic myocardial hyper trophy” (Phillips and Burch, ’60) and endocardia1 fibroelastosis (McLoughlin, Schiebler and Krovetz, ’66) - are reportedly more common in U.S. blacks than in whites. The initial injury to the heart in these fibrotic diseases may be caused by an infective agent (virus or bacteria). The correspondence in distribution of EMF and Burkitt’s lymphoma suggests that an immunological response to malaria may be involved in EMF (Miall and Bras, ’72). The theory that EMF is an “autoimmune” disease is particularly interesting in view of the above discussion of immunoglobulin levels in Negroes. Thus, Negroes appear to be more susceptible to various diseases or disease manifestations involving granulomatous inflammatory responses. This may be due to a tendency to form granulomatous connective tissue (including fibroblasts and their products) in response to injury. Both African and U.S. Negroes, however, may be more subject to the environmental agents responsible for these injuries - specifically, to various infectious agents. Scleroderma and SLE, as noted above, reflect local tissue responses to irritants or injurious agents. The response is excessive collagen production by fibroblasts, and the injury may be caused by imminological disturbances. ly common in East Africa (Verhagen et al., ’68) and in U.S. blacks (White, Strudwick, Ricketts and Sampson, ’61). The high prevalence of soft-tissue fibrosarcomas in Africans, and in other populations such as Afghanistan (Sobin, ’68), may be related to viral and other agents introduced through the skin by arthropod vectors. There is some evidence, although inconclusive, that fibrosarcomas of bone in children may be more common in Uganda than in the U.S. (Dodge, ’64). Fibromas are common benign neoplasms consisting of fibroblasts and collagenous tissue. Uterine fibromas (fibroids, fibromyomas, or leiomyomas) are more frequent in U.S. black women than in whites (Damon, ’60). A small proportion of uterine fibroids become malignant tumors (leiomyosarcomas). There is some evidence that these sarcomas are also more frequent in U.S. blacks than in whites (Christopherson, Williamson and Gray, ’72). Neurofibromas consist of masses of nerve bundles (Schwann cells) and a variable amount of collagen, and occur in the subcutaneous tissue along the course of peripheral nerves. The tumors are classified as fibroblastomas. Multiple neurofibromas (neurofibromatosis or Von Recklinghausen’s disease) is reportedly frequent in some parts of West Africa (Basset, Collomb, Quere, Sicard and Faye, ’66) and East Africa (Verhagen et al., ’68). The frequency of the disease in U.S. blacks is difficult to determine from the literature. Albright’s syndrome, involving fibrous dysplasia of bone, is clinically similar to neurofibromatosis. Normal bone is replaced by fibrous tissue. Apparently, the racial distribution of this disease has not been studied. Fibroblasts and tumors We have mentioned racial differences in certain connective-tissue tumors, namely, Kaposi’s sarcoma and Burkitt’s lymphoma. Both are lymphomas or lymphosarcomas, and involve uncontrolled proliferation of lymphocytes. Malignant neoplasms arising from fibroblasts are known as fibrosarcomas. In addition to dermal scars (keloids), fibrosarcomas of the dermis are reported- Fibroblasts and bony overgrowth There is some evidence that in certain pathologic states, fibroblasts may develop into bone cells (Bloom and Fawcett, ’68:143). This might explain the frequent occurrence of bony hypertrophy in certain diseases among Negroes, but this is speculative at present. Osseous lesions in tertiary syphilis may involve new bone formation, as well as bone destruction and fibrosis (gummas). CONNECTIVE TISSUE RESPONSES I N NEGROES As noted above, osseous lesions are more frequent in U.S. Negroes than in whites (Frazier and Hung-Chiung, '48). Among West African Negroes in Dakar, Senegal, bony hypertrophy is reportedly common in Von Recklinghausen's disease (Basset et al., '66). The origin of these bony overgrowths is unclear, although a mesenchymal source has been postulated (Basset et al., '66). Bony overgrowth -cysts (lined by fibrous tissue) and elephantiasis - is rare in whites with neurofibromatosis (Benedict, Szabo, Fitzpatrick and Sinesi, '68; Sane, Yunis and Greer, '71). Griffith, McKinney, Monroe and Howell ('72) reported three cases of bone cysts in 50 patients with neurofibromatosis in Chicago children. Interestingly, eight of the 50 cases (16%) were Negroes, but the racial distribution of bone symptoms was not reported. 53 by melanocytes is increased. Hyperplasia, or an increase in the number of cells (melanocytes), is not involved in racial differences in pigmentation (Szabo, Gerald, Pathak and Fitzpatrick, '69). This is in contrast to the connective tissue overgrowth described above, which may involve both hypertrophy (increased immunoglobulin production by plasma cells, or collagen production by fibroblasts) and hyperplasia (increased numbers of plasma cells, macrophages, and fibroblasts). This distinction is partly hypothetical, since the actual numbers of these cells have not been studied in Negroes and whites. There is evidence of decreased adrenocortical activity in Africans. Barnicot and Wolffson ('52) found that 17-ketosteroid excretion was significantly lower in West Africans than in whites. Politzer and Tucker ('58) found no difference in 17-ketosteroid excretion in healthy South Possible analogy with hypertrophy African Bantu and whites, but 17-ketoof pigmentary apparatus genic steroid excretion was significantly An analogy to the above relationships lower in men. While part of the total urimay involve pigmentation of skin and nary 17-ketosteroids are derived from other organs. Increased amount and dis- testicular secretions, 17-ketogenic persal of melanin in dark-skinned popu- steroids are produced in the suprarenal lations (including Negroes) is believed to cortex only. This suggests decreased proaccount for their low rates of skin cancer. duction and excretion of adrenocortical In contrast to infectious diseases, how- steroids in African Negroes (Politzer and ever, skin cancer may occur too late in Tucker, '58). Noteworthy in this regard life to be a major factor in natural selec- is the smaller size of the adrenal cortex tion. Wassermann ('65) has proposed in relation to the medulla in American that dark pigmentation in tropical popu- Negroes (Swinyard, '40) and East Afrilations may represent a secondary adap- cans (Allbrook, '56) relative to whites. tation to infectious disease. Since hydrocortisone (cortisol) supA tendency toward hyperpigmentation presses the secretion of melanocyte-stimmay predispose Negroes to certain dis- ulating hormone (MSH), Wassermann eases, and to certain responses to disease ('65) has suggested that reduced adrenoor drugs. Thus, the skin of Negroes is cortical activity could be a mechanism for especially liable to postinflammatory hy- increased pigmentation in Africans. perpigmentation (Kenney, '65). Excessive Adrenocortical steroids (glucocortipigmentation is characteristic of Kaposi's coids) also alter the response of connecsarcoma (Master, Taylor, Kyalwazi and tive tissue to injury. Cortisone, which is Ziegler, '70) and SLE (Verhagen et al., closely related to hydrocortisone, depress'68) in African Negroes, and is of diag- es serum gamma globulin levels (Snell nostic importance. A tendency toward and Nicol, '56; Batchelor, '71). Adrenohyperpigmentation in Negroes is also an cortical steroids inhibit the formation of important consideration in the drug treat- new fibroblasts and macrophages (Fauve, ment of acne (Anon., '68), and in busul- '70; Thompson and Van Furth, '70) and, fan (Myerland) treatment of leukemia hence, reduce the inflammatory reaction and related disorders (Desai, '65). to toxic and mechanical injury. CorticoIt should be noted that increased pig- steroids, namely hydrocortisone and its mentation in Negroes involves hypertro- derivatives (e.g., "kenalog" or triamcinophy, in the sense that pigment production lone acetonide) have been used with some 54 ANTHONY P. POLEDNAK the production of macrophages, and plasma cells (the principal producers of antibodies). There is evidence of increased production of certain antibodies (immunoglobulins) in Negroes, which may account for their susceptibility to certain diseases involving hypergammaglobulinemia. The role of natural selection and genetic factors in determining these connective tissue responses, however, remains uncertain. Relative to whites, U.S. Negroes tend to be more subject to the environmental factors producing these responses - in particular, to infectious CONCLUSIONS diseases. Differences in disease patterns It appears that the process of tissue re- between African and U.S. Negroes also pair after injury, involving substitution may be due to environmental differences. of fibrous connective tissue, is more prom- In the absence of malaria infection, for inent in Negroes than in whites. This may example, we would expect that certain help to explain the higher frequency in RES tumors (Burkitt's lymphoma and Negroes of certain granulomatous inflam- Kaposi's sarcome) would not be frequent matory diseases, and various tumors in- in U.S. Negroes, and this is indeed the volving fibroblasts. This capacity to re- case (Phillips and Burch, '60; Dorfman, spond to injury may have developed by '6 5). Whatever mechanisms are involved, natural selection in response to infectious diseases in the tropical African environ- the connective tissue responses described above may help to explain some racial ment. Collagen is produced by fibroblasts in differences in disease frequency. Table 1 the repair of connective tissue, and ex- summarizes the possible relationships. cessive collagenization is involved in Further studies of the racial distribuseveral diseases more frequent among tion of disease may clarify, or, conceivably, Negroes (Africans, U.S. blacks, or both) contradict the relationships postulated. than among whites. These diseases in- Racial distributions of cases of fibrosarclude scleroderma, systemic lupus erythe- coma, for example, are seldom reported in the literature. Even if available, such matosus (SLE), and neurofibromatosis. In defense against infection, the local data from hospital admissions would be reactive process of inflammation involves of limited value as an indication of the success in the treatment of keloids in blacks and whites (Cosman et al., '61; Kelley, '63; Murray, '63) and in other racial groups (Alhady and Sivanantharajah, '69). Corticosteroid therapy is also useful in granulomatous diseases such as sarcoidosis (Siltzbach, '71). Thus, decreased adrenocortical activity could be a more direct mechanism underlying both increased pigmentation and increased connective tissue response (gamma globulin synthesis, fibroplasia, and granulomatous inflammation) in Negroes relative to whites. TABLE 1 S u m m a r y of possible relationships b e t w e e n Connective t i s s u e overgrowth and disease in Negroes Environmental agent Response Disease manifestation Viruses, parasites (?) Overgrowth of reticuloendothelial system (RES); i.e., increased macrophage production and immunoglobulin synthesis by plasma cells Production against infection Burkitt's lymphoma, Kaposi's sarcoma (Africa) Systemic lupus erythematosus, scleroderma, multiple myeloma ( U S . ) Irritants, injurious agents (?) Growth of fibrous connective tissue (fibroplasia) Keloids, dermal neoplasms (Africa, U.S.); fibromas and fibrosarcomas, granulomatous inflammations Overgrowth of bone, possibly derived from fibroblasts Bony growths in tertiary syphilis (U.S.), and in neurofibromatosis (Africa) CONNECTIVE TISSUE RESPONSES IN NEGROES true disease frequency. The best data available are from surveys of hospital records (or tumor registries) and death certificate data - as in SLE (Siegel, Holley and Lee, '70) and multiple myeloma (McPhedran, Heath and Garcia, '72). Again, these data have fundamental limitations in epidemiology. At the histological level the mechanisms underlying the apparently enhanced fibroplasia in Negroes could be investigated. First, the relative numbers of fibroblasts and other connective tissue components could be determined in Negroes and whites. Second, racial differences in cultured fibroblast activity could be investigated, in health and disease. ACKNOWLEDGMENT Part of this work was supported by the Fund for Research and Teaching of the Department of Nutrition, Harvard University School of Public Health, Boston. Part of this work was done while the author was Research Associate in Biological Anthropology in that Department. LITERATURE CITED Alarcon-Segovia, D., and E. Fishbein 1972 Serum immunoglobulins in systemic lupus erythematosus. Clin. Sci., 43: 121-131. Alexander, J. W., and R. A. Good 1970 Immunobiology for Surgeons. W. B. Saunders, Philadelphia. Alhady, S. M. A,, and K. Sivanantharajah 1969 Keloids in various races. A review of 175 cases. Plast. Reconstr. Surg., 44: 5 6 4 3 6 6 . Allan, J. C., and P. Keen 1954 The management of keloid in the South African Bantu. South African Med. J., 28: 1034-1037. Allbrook, D. 1956 Size of adrenal cortex in East African males. Lancet, 2: 606-607. Allison, A. C. 1964 Polymorphism and natural selection in human populations. Cold Spring Harbor Symposia on Quantitative Biology, 29: 137-1 49. Andrew, W., R. H. Behnke and T. Sato 1965 Changes with advancing age in the cell population of human dermis. Gerontologia, 10: 1-19. Anon. 1968 Acne in Negroes found similar to Caucasians. .l. Amex. Med. Assoc.. 205: 30. Anon. 1970 " Burkitt lymphoma' and malaria. Lancet, 2: 300-301. Barnicot, N. A,, and D. Wolffson 1952 Daily urinary 17-ketosteroid output of African Negroes. Lancet, 1 : 893-895. Basset, A., H. Collomb, N. A. Qukre, D. Sicard and I. Faye 1966 Quelques aspects de la maladie de Recklinghausen en Afrique de l'ouest. A propos de 35 cas observes zi Dakar de 1959 B 1964. Ann. Derm. Syphil., 93: 4 3 5 1 . Batchelor, J. R. 1971 Hormonal control of antibody formation. In: Regulation of Antibody Re- 55 sponse. Second ed. B. Cinader, ed. C. C Thomas, Springfield, pp. 276-293. Benedict, P. H., G. Szabo, T. B. Fitzpatrick and S. J. Sinesi 1968 Melanotic macules in Albright's syndrome and in neurofibromatosis. J. Amer. Med. Assoc., 205: 6 1 8 4 2 6 . Bishop, M. B., G. Bousvaros, T. J. Cunningham, A. C. Jain and J. N. P. Davies 1968 Endomyocardial fibrosis in a North American Negro. Probable familial incidence. Lancet, 2: 750751. Bisseru, B., and A. A. Ahmad 1970 Intestinal parasites, eosinophilia, haemoglobin, and gamma globulin of Malay, Chinese and Indian schoolchildren. Med. J. Malaya, 25: 2 9 3 3 . Bloom, W., and D. W. Fawcett 1968 A Textbook of Histology. Ninth ed. W. B. Saunders, Philadelphia. Boucek, R. J., N. L. Noble, K-Y. T. Kao and H. R. Elden 1958 The effects of age, sex, and race upon the acetic acid fractions of collagen (human biopsy-connective tissue). J. Gerontol., 1 3 : 2-9. Brearley, A. 1970 Serum proteins, haematocrits, heights and weights of aborigine subjects of West Malaysia. Med. J. Malaya, 24: 183186. Buckley, C. E., 111, and F. C. Dorsey 1971 Serum immunoglobulin levels throughout the life-span of healthy man. Ann. Intern. Med., 75: 673682. Burkitt, D., and D. H. Wright 1970 Burkitt's Lymphoma. Livingstone, Edinburgh. Chandra, P. K., D. K. Guha and 0. P. Ghai 1970 Serum immunoglobulins in the newborn. Ind. J. Pediat., 37: 361-365. Christopherson, W. M., E. 0. Williamson and L. A. Gray 1972 Leiomyosarcoma of the uterus. Cancer, 29: 1512-1517. Connor, D. H . , K. Somers, M. S. R. Hutt, W. C. Manion and P. G. D'Arbela 1968 Endomyocardial fibrosis in Uganda (Davies' disease). Part 11. An epidemiologic, clinical and pathologic study. Amer. Heart J., 75: 107-124. Cook, J. A., L. Woodstock and P. Jordan 1972 Immunoloeical studies in Schistosoma rnansoni infection & St. Lucia. Ann. Trop. Med. Parasitol., 66: 369-373. Cosman, B., G. F. Crikelair, D. M. C. Ju, J. C. Gaulin and R. Lattes 1961 The surgical treatment of keloids. Plast. Reconstr. Surg., 27: 335-358. Curnow, D. H. 1957 The serum proteins of aborigines i n the Warburton Range area. Med. J. Aust., 2: 608-609. Curtain, C. C., D. C. Gadusek, C. Kidson, J. Gorman, L. Champness and R. Rodrigue 1965 A study of the serum proteins of the peoples of Papua and New Guinea. Amer. J. Trop. Med. Hyg., 14: 678-690. Damon, A. 1960 Host factors in cancer of the breast and uterine cervix and corpus. J. Nat. Cancer I n s t , 24: 483-516. Dauer, C. C., R. F. Korns and L. M. Schuman 1968 Infectious Diseases. Harvard University Press, Cambridge, Mass. Davies, J. N. P. 1969 The African cardiomyopathies. Ann. N. Y. Acad. Sci., 156: 498-503. Desai, R. G. 1965 Pigmentation after busulfan therapy. New Engl. J . Med., 272: 8 0 8 4 0 9 . 56 ANTHONY P. POLEDNAK Dodge, 0. G. 1964 Bone tumours in Uganda Africans. Brit. J. Cancer, 18: 627-633. Dorfman, R. F. 1965 Childhood lymphosarcoma in St. Louis, Missouri, clinically and histologically resembling Burkitt’s tumor. Cancer, 18: 418430. Edington, G. M., F. von Lichtenberg, I. Nwabuebo, J. R. Taylor and J. H. Smith 1970 Pathologic effects of schistosomiasis in Ibadan, Western State of Nigeria. I. Incidence and intensity of infection; distribution and severity of lesions. Amer. J. Trop. Med. Hyg., 19: 982-995. Edozien, J. C., A. E. Boy0 and D. C. Morley 1960 The relationship of serum gamma-globulin concentration to malaria and sickling. J . Clin. Path., 13: 118-123. El-Hehyawi, G. E. 1969 Variation of blood proteins and amino acids i n African arabs and Negroes. J. Egypt. Med. Assoc., 52: 853-864. Ezeilo, G. C. 1970 Normal serum protein patterns in adult Zambians. E. Afr. Med. J., 47: 681-685. Fauve, R. M. 1970 The effect of corticosteroids on some functions of macrophages. In: Mononuclear Phagocytes. R. V a n Furth, ed. Blackwell Scientific Publications, Oxford, pp. 265280. Frazier, C. N., and L. Hung-Chiung 1948 Racial Variations in Immunity to Syphilis. A Study of the Disease in the Chinese, White, and Negro Races. University of Chicago Press, Chicago. Gardner, A. F. 1972 Paramedical Pathology. C. C Thomas, Springfield, Illinois. Golubjatnikov, R., and M. Steadman 1972 Serum levels of immunoglobulins in Mexican preschool children. Amer. J. Epidemiol., 95: 542448. Griffth, B. H., P. McKinney, C. W. Monroe and A. Howell 1972 Von Recklinghausen’s disease in children. Plast. Reconstr. Surg., 49: 647-653. Kariks, J., and E. H. Hipsley 1961 Serum protein levels in mothers and newborn infantsA comparison of New Guineans and white Australians. Med. J. Aust, 1 : 853-856. Keller, A. Z. 1971 Hospital, age, racial, occupational, geographical, clinical and survivorship characteristics in the epidemiology of sarcoidosis. Amer. J. Epidemiol., 94:222-230. Kelley, E. W., Jr. 1963 The effects of tetrahydroxyquinone on connective tissue. J. Chron. Dis., 16: 335-342. Kenney, J. A,, Jr. 1965 Management of dermatoses peculiar to Negroes. Arch. Derm., 91: 126-129. Lewis, J. H. 1942 The Biology of the Negro. University of Chicago Press, Chicago. Lichtman, M. A., J. R. McDonough and C. G. Hames 1967 Serum gamma globulin concentration in related and non-related subjects. Hum. Biol., 39: 307-315. Lichtman, M. A., J. H. Vaughan and C. G. Hames 1967 The distribution of serum immunoglobulins, anti- -G globulins (“rheumatoid factors”) and antinuclear antibodies in white and Negro subjects in Evans County, Georgia. Arth. Rheum., 10:204-215. Lurie, M. B. 1964 Resistance to Tuberculosis. Harvard University Press, Cambridge, Massachusetts. MacMahon, B., and D. W. Clark 1956 The inci- dence of multiple myeloma. J. Chron. Dis., 4 : 5 0 8 6 15. McFarlane, H. 1968 Comparative quantitation of immunoglobulins in Nigerians. West. Afr. Med. J., 17: 149-152. McLoughlin, T. G., G. L. Shiebler and L. J. Krovetz 1966 Endocardia1 fibroelastosis in American Negro children: A distinct entity? Amer. Heart J., 71: 748-756. McPhedran, P., C. W. Heath, Jr. and J. Garcia 1972 Multiple myeloma incidence in metropolitan Atlanta, Georgia: Racial and seasonal variations. Blood, 39: 866-873. Masi, A. T., and W. A. D’Angelo 1967 Epidemiology of fatal systemic sclerosis (diffuse scleroderma). A 15-year survey in Baltimore. Ann. Intern. Med., 66: 870-883. Master, S. P., J . F. Taylor, S. K. Kyalwazi and J. L. Ziegler 1970 Immunological studies in Kaposi’s sarcoma in Uganda. Brit. Med. J., I : 600-602. Miall, W. E., and G. Bras 1972 Heart disease in the tropics. Brit. Med. Bull., 28: 79-86. Milner, L. V., and F. Calitz 1971 Serum immunoglobulin levels in white, Asiatic and Bantu blood donors. South Afr. Med. J., 45: 683-685. Moehlig, R. C. 1937 The mesoderm of the N e gro. Amer. J. Phys. Anthrop., 22: 2 9 7 3 1 4 , Murray, R. D. 1963 Kenalog and the treatment of hypertrophied scars and keloids in Negroes and whites. Plast. Reconst. Surg., 31 : 275-280. Phillips, J. H., Jr., and G. E. Burch 1960 A review of cardiovascular diseases in the white and Negro races. Medicine, 39: 241-288. Pike, M. C., R. H. Morrow, A. Kisuule and J. Mdgiri 1970 Burkitt’s lymphoma and sickle cell trait. Brit. J. Prev. SOC. Med., 24: 39-41. Politzer, W. M., and B. Tucker 1958 Urinary 17-ketosteroid and 17-ketogenic steroid excretion in South African Bantu. Lancet, 2: 778-779. Rama Rao, A. V. S. S., R. Amrithalochani and B. G. V. Narasimha Rao 1962 Serum thymol and zinc sulphate turbidity tests in a population with a low albumimglobulin ratio. Indian J. Med. Res., 50: 895-904. Rowell, N. R. 1967 Aetiology of certain connective tissue diseases. Clin. Exper. Immunol., 2 (Suppl.): 813-825. Sane, S., E. Yunis and R. Greer 1971 Subperiosteal or cortical cyst and intramedullary neurofibromatosis - Uncommon manifestations of neurofibromatosis. J. Bone Joint. Surg., 53A: 1194-1200. Sehgal, S., and B. K. Aikat 1970 Serum immunoglobulines in healthy Indians. Indian J. Med. Res., 58: 289-296. Shaper, A. G. 1966 Studies in heart disease in Uganda. Uganda J., 30: 183-189. Shaper, A. G., and R. M. Coles 1965 The tribal distribution of endomyocardial fibrosis in Uganda. Brit. Heart J., 27: 121-127. Siegel, M., H. L. Holley and S. L. Lee 1970 Epidemiologic studies on systemic lupus erythematosus. Comparative data for New York City and Jefferson County, Alabama, 19561965. Arth. Rheum., 13: 802-811. Siegel, M., S. L. Lee, D. Widelock, E. B. Reilly, G. J. Wise, S. B. Zingale and H. T. Fuerst 1962 The epidemiology of systemic lupus erythematosus: Preliminary results in New York City. J. Chron. Dis., 15: 131-140. CONNECTIVE TISSUE RESPONSES IN NEGROES Siltzbach, L. E. 1971 Sarcoidosis. In: CecilLoeb Textbook of Medicine. P. B. Beeson and W. McDermott, eds. W. B. Saunders, Philadelphia, pp 826-834. Snell, R. S., and T. Nicol 1956 Effect of cortisone on the serum gamma globulin. Nature, 177: 578. Sobin, L. H. 1968 Sarcomas i n Afghanistan. Nature, 21 7: 1072-1073. Swinyard, C. A. 1940 Volume and corticomedullary ratio of the adult human suprarenal gland. Anat. Rec., 76: 69-79. Szabo, G., A. B. Gerald, M. A. Pathak and T. B. Fitzpatrick 1969 Racial differences in the fate of melanosomes in human epidermis. Nature, 222: 1081-1082. Taylor, J. F., P. G. Smith, D. Bull and M. C. Pike 1972 Kaposi’s sarcoma in Uganda: Geographic and ethnic distribution. Brit. J. Cancer, 2 6 : 483497. Terris, M., and A. D. Chaves 1966 An epidemiologic study of sarcoidosis. Amer. Rev. Respir. Dis., 94: 50-55. 57 Thompson, J., and R. Van Furth 1970 The effect of glucocorticosteroids on the kinetics of monocytes and peritoneal macrophages. In: Mononuclear Phagocytes. R. Van Furth, ed. Blackwell Scientific Publications, Oxford, pp. 255-264. Trevonow, V. E. 1970 Gamma globulin studied longitudinally between the ages of four and 20 years. Hum. Biol., 42: 598-618. Verhagen, A. R. H. B., J. W. Koten, V. K. Chaddah and R. I. Pate1 1968 Skin diseases in Kenya. A clinical and histopathological study of 3,168 patients. Arch. Derm., 98: 577-586. Wassermann, H. P. 1965 Human pigmentation and environmental adaptation. Arch. Environ. Health, 1 1 : 691494. Weithaler, K., and R. F. L. Maruna 1967 Serum protein in the Ethiopian population. Ethiop. Med. J., 5: 137-141. White, J. E.,W. J. Strudwick, W. N. Ricketts and C. Sampson 1961 Cancer of the skin in N e groes. A review of 31 cases. J. Amer. Med. AsI 78: 845-847.