Age at menarche

One explanation for the conflicting results could be that follicular dendritic cells have a common stem cell with lymphocytes and myeloid cells as indicated by their

In accordance with others7

Hodgkin’s disease.

constant expression of CD45; and also some evidence that they closely related to T lymphocytes. If the cell lines differ in

are

their differentiation before their commitment to lymphocytes or follicular dendritic cells, rearrangements and inconsistent expression of markers for T and B cells could occur in the RS cells in the same way as in malignancies of myeloid cells. We conclude that the presence of the follicular dendritic cell marker ACPI in RS cells supports the suggestion that Hodgkin’s disease, with the exception of the LP type, is derived from follicular dendritic cells. study was supported by the Avro and Inkeri Suominen Foundation, Salo, Finland.

This

Karl-Ove Söderström, Riitta Rinne, Väinö K Hopsu-Havu, Mikko Järvinen, Ari Rinne Department of Pathology, University of Turku, FIN-20520, Turku, Finland; Department of Dermatology, University of Turku, Finland; Department of Pathology, University of Oulu, Oulu, Finland; and Proteinase Laboratory, University of Tromsø, Tromsø, Norway 1 Delsol G, Meggetto F, Brousset P, et al. Relation of follicular dendritic reticulum cells to Reed-Sternberg cells of Hodgkin’s disease with emphasis on the expression of CD21 antigen. Am J Pathol 1993; 142: 1729-38. 2 Curran RC, Jones EL. Dendritic cells and B lymphocytes in Hodgkin’s disease. Lancet 1977; ii: 349. 3 Rinne A, Alavaikko M, Järvinen M, Martikainen J, Karttunen T, Hopsu-Havu V. Demonstration of immunoreactive and cysteine proteinase inhibitor in reticulum cells of lymph node germinal centres. Virchows Arch 1983; 43: 121-26. 4 Griessner H, Feller AC, Mak TW, Lennert K. Clonal rearrangements of T-cell receptor and immunoglobulin genes and immunophenotypic antigen expression in different subclasses of Hodgkin’s disease. Int J Cancer 1987; 40: 157-60. 5 Angel CA, Pringle JH, Naylor J, West KP, Lauder I. Analysis of antigen receptor genes in Hodgkin’s disease. J Clin Pathol 1993; 46: 337-40.

Age at menarche SIR-Rees (Dec 4, p 1375) suggests that the secular trend in age at menarche is increasing as a result of women becoming thinner and more active, and thus that body composition and exercise are associated with delayed menarche. However, the associations between body composition and intense exercise with delayed menarche do not necessarily imply a causative relation. The term later menarche should be used rather than delayed since delayed is interpreted as causative-ie, training delays menarche. Our concern about Rees’ hypothesis is that it is based on two possible falsehoods. The Frisch hypothesisl that a critical body fatness is necessary for the onset of menstrual cycles has not yet been fully tested, and the method they used to estimate fatness has been criticised.2 With respect to activity, British schoolchildren have surprisingly low levels of physical activity;3 in particular, girls’ level of physical activity decreases at secondary school. We have completed a Sports-Council funded longitudinal study investigating the effects of intensive training in a population of elite young British athletes.4 We showed that menarche took place at a significantly later age (14-3 years) in only one of the sports studied (gymnastics), suggesting that training might have been a cause. However, amount of training did not have any effect in this or any other sports studied (swimming and tennis), implying that elite gymnastics were selected for this attribute and that their menarche was late rather than delayed. Our results seem to add further evidence to the hypothesis that menarche is affected by biological selective factors and social factors,5 and that late maturation contributes to a young girl’s decision to continue participation in gymnastics.6

we

suggest that later menarche

commonly recorded in some athletes is to some extent familial. Although age at menarche seems to have stabilised and even increased in recent years, the assertion that this is probably a result of dieting and increased levels of exercise is not in accord with

recent

Adam

studies.

Baxter-Jones, Peter Helms, Michael Preece

Department of Child Health, University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD, UK; and Division of Public Health, Institute of Child Health, University of London 1

2 3

4 5

6

7

Frisch RE, Revelle R. Height and weight at menarche and a hypothesis of critical body weights and adolescent events. Science 1970; 169: 397-99. Malina RM. Menarche in athletes: a synthesis and hypothesis. Ann Hum Biol 1983; 10: 1-24. Armstrong N, Balding J, Gentle P, Kirby B. Patterns of physical activity among 11 to 16 years old British children. BMJ 1990; 301: 203-05. Rowley S. The Training of Young Athletes Study (TOYA): project description. London: Sports Council Publication Unit, 1991. Malina RM, Spirduso WW, Tate C, Baylor AM. Age at menarche and selected menstrual characteristics in athletes at different competitive levels and in different sports. Med Sci Sports 1978; 10: 218-22. Baxter-Jones ADG, Helms P, Baines Preece J, Preece M. Menarche in intensively trained gymnasts, swimmers and tennis players. Ann Hum Biol (in press). Malina RM, Ryan RC, Bonci CM. Age at menarche in athletes and their mothers and sisters. Am J Hum Biol 1993; 5: 137.

SIR-The recent trend towards late menarche in the UK to which Rees draws attention should be welcomed for several additional medical and societal reasons other than its possible relation to leaner physiques. Later menarche is not only associated with a decreased frequency of breast cancerl and of coronary heart disease2 but also with later initiation of sexual activity,3 later first pregnancy,4 and taller eventual adult height.5 These further associations, if causal, raise the possibility of future improvements in rates of sexually transmitted disease, teenage pregnancy (with its risk of single motherhood, disrupted education, and poverty), and teenage marriage (with its high risk of divorce). Further, the reduction in mean height difference between the sexes might beneficially affect sexual harassment and discrimination. The public health role of the physical education teacher in primary prevention thus becomes even more important. Peter G Stone Department of Anesthesia and Critical Care, Harvard Medical School, Beth Hospital, Boston MA 02215, USA 1

2

3

4

5

Israel

Pike MC, Krailo MD, Henderson BE, et al. Hormonal risk factors, breast tissue age and the age-incidence of breast cancer. Nature 1983; 303: 767-70. Colditz GA, Willett WC, Stampfer MJ, et al. A prospective study of age at menarche, parity, age at first birth, and coronary heart disease. Am J Epidemiol 1987; 126: 861-70. Soefer EF, Scholl TO, Sobel E, et al. Menarche: target age for reinforcing sex education for adolescents. J Adolesc Health Care 1985; 6: 383-86. Sandler DP, Wilcox AJ, Horney LF. Age at menarche and subsequent reproductive events. Am J Epidemiol 1984; 119: 765-74. Shangold MM, Kelly M, Berkeley AS, et al. Relationship between menarcheal age and adult height. South Med J 1989; 82: 443-45.

SIR-Rees suggests that the reversal of the trend1 to earlier menarche is attributable more to increasing gracility of body form, associated with greater interest in physical exercise and popular fashion, than to deterioration of health and environmental conditions. Before putting forward our somewhat disquieting explanation, we endeavoured to examinezRees’ hypothesis. Over the sixteen years covered by the Warwick data there was no trend to increasing gracility as measured by the

423

ponderal index (height3/weight). Mean weight actually increased, but so did mean height, such that the ponderal index remained unchanged. The data showed the well-established association of menarcheal age and physique to which Rees draws attention, but these changes in body size did not account

were symptomless, 20 had persistent generalised lymphadenopathy, and 27 had AIDS. Surprisingly, we and otherss do not find increased CD45RA+RO+ T cells in patients

stages: 23

for the secular trend to later menarche. This is not to deny a possible effect of exercise as Rees suggests, but if it exists it does not seem to operate through the intermediary of physique. Exercise habits, together with other behavioural and psychological factors, need more attention in studies of secular trends in development than they have hitherto received.

with HIV. Thus it appears that T-cell activation per se does not result in elevated levels of CD45RA’RO’. Recent studies indicate that transition between naive and memory status is not unidirectional, and that cells may shed CD45RO and gain CD45RA.6 Increased T cells co-expressing both markers could be a result of abnormal regulation of the balance between the two CD45 isoforms. Once we have a better understanding of the control of this balance, the question of whether it is abnormal in FEL and autoimmune conditions can be addressed.

T C Dann, D F Roberts

Mark

37 Balsall Street East, Balsall Common, West Midlands CV7 17 Montague Court, Gosforth

1

2

7FQ, UK; and

Dann TC, Roberts DF. Menarcheal age in University of Warwick young women. J Biosoc Sci 1993; 25: 531-38. Roberts DF, Dann TC. Social class and diachronic trends in physique in young University women. J Biosoc Sci 1992; 24: 269-79.

Peakman, Meera Mahalingam, Diego Vergani

1

Co-expression of CD45RA (naive) and

(memory) T-cell markers

SIR-Bujan et al (Nov 20, p 1296) describe a boy with familial erythrophagocytic lymphohistiocytosis (FEL) with high numbers of T cells (49%) expressing both naive (CD45RA+) and memory (CD45RO+) markers. Such T cells are thought to be in transition from naive to memory cells. Two healthy firstdegree relatives of the boy had increased CD45RA+RO+ T cells (49% and 12%), and the authors speculate that this may reflect T-cell hyperactivation. We studied CD45RA+RO+ T cells in other immune-mediated diseases, and our results indicate that co-expression of CD45RA and CD45RO is not confined to patients with FEL; is not inherited, although it may require a genetic predisposition; is associated with lymphocyte activation, but not exclusively; and may reflect abnormal control of the cycling between the CD45RA and CD45RO+ states.

In insulin-dependent diabetes mellitus (IDDM), CD45RA+RO+ T cells are increased (up to 45% of CD4T cells and 46% of CD8+ T cells).1 They are also increased in non-diabetic identical twins of patients with IDDM, supporting a genetic influence on their expression. However, after diagnosis of IDDM, numbers ofCD45RA +RO+ cells tend to decline and become normal2 in long-term IDDM patients and in their non-identical diabetic co-twins. Therefore nongenetic factors may influence expression of CD45RA and CD45RO. A possible relation between T-cell activation and increased CD45RA+RO+ T cells is supported by our studies in IDDM. The activation proteins HLA-DR and CD25 (the IL-2 receptor) are elevated in patients who also have a high number of CD45RA+RO+ cells. Prince et aP artificially stimulated naive T cells in vitro to the CD45RA+RO+ stage, and demonstrated that they had acquired activation markers. We analysed T-cell populations from 2 patients with IDDM and showed that a proportion of the CD45RA+RO+ cells expressed HLA-DR (16% and 13%) and CD25 (5% and 16%), similar percentages to those in the memory (CD45RA-CD45RO+) population (16% and 9% for HLA-DR, 5% and 9% for CD25). Thus the CD45RA+RO+ population expresses activation markers in vivo. We then examined CD45RA+RO+ T cells in HIV infection, since this disorder is characterised by high numbers of activated T cells in the periphery (up to 90% expressing HLA-DR and up to 45% expressing CD25)4. We studied 70 HIV patients (68 males) at various Center for Disease Control

424

Leslie,

Departments of Immunology, King’s College School of Medicine & Dentistry, London SE5 9PJ, UK; and Department of Diabetes, St Bartholomew’s Hospital, London EC1

2

CD45RO

R David G

3

4

5

6

Smerdon RA, Peakman M, Hussain MJ, et al. Increase in simultaneous co-expression of naive and memory lymphocyte markers at diagnosis of insulin dependent diabetes mellitus. Diabetes 1993; 42: 127-33. Peakman M, Alviggi L, Hussain MJ, et al. Increased expression of T-cell markers of immunological memory in type 1 diabetes: a study of identical twins. Diabetes (in press). Prince HE, York J, Jensen ER. Phenotypic comparison of the three populations of human lymphocytes defined by CD45R0 and CD45RA expression. Cell Immunol 1992; 145: 254-62. Mahalingam M, Peakman M, Davies ET, Pozniak A, McManus TJ, Vergani D. T cell activation and disease severity in HIV infection. Clin Exp Immunol 1993; 93: 337-43. Prince HE, Jensen ER. Three-colour cytometric analysis of CD8 cell subsets in HIV-1 infection. J Acquir Immune Defic Syndr 1991; 5: 97-99. Rothstein D, Yamada A, Schlossman SF, Morimoto C. Cyclic regulation of CD45 isoform expression in a long term human CD4+CD45RA+ T cell line. J Immunol 1991; 146: 1175-83.

Sucralfate and chronic venous stasis ulcers SIR-Non-healing

cutaneous

wounds

are a

difficult clinical

problem in patients with diabetes, venous insufficiency, and peripheral vascular disease. Conventional therapy relies upon leg elevation, elastic stockings, and local dressing and wound care. These methods, however, do not always result in clinical improvement. We suggest a new treatment modality"angiogenic manipulation". Angiogenesis is fundamental to the physiology of wound repair.l Early experiments in angiogenesis research showed that sulphated polysaccharides (eg, heparin) bind to and protect basic fibroblast growth factor (bFGF), a potent angiogenic factor present in many human tissues.2 Sucralfate, a common anti-ulcer medication, is structurally similar to heparin and shares heparin’s affinity for binding bFGF.’ This mechanism may explain why sucralfate can promote neovascularisation and gastric ulcer healing without altering stomach pH. Therefore, we have used sucralfate ointment on the basis of its angiogenesis-promoting properties to treat chronic venous stasis ulcers. We studied 9 patients (10 wounds) with non-healing, full-thickness venous stasis ulcers refractory to 8 weeks of conventional therapy, who had no infections or indications for surgery. With informed consent, the patients received in single-blind fashion either sucralfate ointment or the vehicle alone to their wounds twice a day for 8 weeks. The patients were examined biweekly for the presence of neovascularisation, granulation, and wound contraction. Their wounds were quantified (in mm2) with photo-planimetric techniques. At the end of the study, 2 of the 5 wounds in the sucralfate group were completely healed (2 patients). The other 3 sucralfate-treated wounds (2 patients) showed considerable granulation, neovascularisation, and increased wound contraction (32%