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Which Thymic Hormone?THYMIC hormones may prove to be useful

therapeutic agents. There are now many anecdotalreports of clinical improvement and even curesresulting from administration of partly refined thymicextracts, 1,2 or synthetic peptides analogous to those inthe extracts.3,4 At an international symposium inLondon (sponsored by Westminster Medical Schooland Serono Symposia)5 there were calls for proof ofeffectiveness by double-blind clinical trials.

Unfortunately even these are likely to be inconclusive,because some of the agents under investigation (eg,thymostimulin and thymosin fraction 5) are mixturesof potential antagonists, and in some trials the thymichormones are being combined with cytotoxic agents orsteroids which may kill the lymphocytes as theyrespond to the thymic hormones. -

Physiological roles have been found for some of thethymic peptides. For example, thymosin beta-3 andbeta-4 are involved in the earliest stages of thymiclymphocyte maturation whereas thymosin alpha-1and alpha-7 act later, on the differentiation of theprothymocyte to the mature thymocyte. Some of thepeptides extracted from the thymus may be involvedonly in local interactions within the gland itself; otherscan induce changes in the peripheral circulating T cellswhich are usually regarded as "maturation".8

1. Davies EG, Levinsky RJ. Treatment of cell-mediated immunodeficiency with calfthymic hormone (TPI). Pediatr Res 1982; 16: 573-78.

2. Wara DW, Goldstein AC, Doyle NE, Ammann AJ. Thymosin activity in patients withcellular immunodeficiency. N Engl J Med 1975; 292: 70-74.

3. Bordigoni P, Faure G, Bene MC, Dardenne M, Duheille J, Olive D. Improvement ofcellular immunity and IgA production in immunodeficient children after treatmentwith synthetic serum thymic factor (FTS). Lancet 1982; ii: 293-97.

4 Fiorilli M, Sirianni MC, Pandolfi F, Quinti I, Tosti U, Aiuti F, Goldstein G.Improvement of natural killer activity and of T cells after thymopoietinpentapeptide therapy in a patient with severe combined immunodeficiency. ClinExp Immunol 1981; 45: 344-51.

5. Hobbs JR, Byrom NA, eds. Thymic factor therapy. (Serono Symp no 51). London:Academic Press (in press).

6 Low TLK, Shu-Kuang Hu, Goldstein AL. Complete amino acid sequence of bovinethymosin B4: a thymic hormone that induces terminal deoxynucleotidyl transferaseactivity in thymocyte populations. Proc Natl Acad Sci USA 1981,78: 1162-66.

7. Shu-Kuang Hu, Low TLK, Goldstein AL. Modulation of terminal deoxynucleotidyltransferase activity by thymosin. Molec Cell Biochem 1981; 41: 49-58.

Thymosin alpha-1 and beta-4 may also take part in athymic-hypothalamic-pituitary network.9uo (There isincidentally a curious similarity between our currentunderstanding of thymic hormones and the under-standing in the 1930s of pituitary hormones; maybe asimilar number of independent active peptides willemerge).

It might seem logical to use thymic hormone therapyfor patients with a deficiency of thymic hormone.Unfortunately it has proved very difficult to deviseassays to measure the levels of these hormones. Afunctional assay for FTS (facteur thymique serique)has been in use for some years," but it is too

cumbersome for routine use. Radioimmunoassaysexist for substances reaching hundreds of pg/mlserum-eg, thymosin alpha-1 peptide’2 and

thymopoietinl3-but peptides such as THF (thymichormonal factor) may be active at considerably lowerand less easily measured concentrations. Comparisonsmay now be made between FTS and thymosin alpha-1 1peptide levels: both are high in normal infants andsome children with thymomas, both are low in old ageand some primary immunodeficiencies; alpha-1 is highand FTS is low in AIDS (acquired immunodeficiencysyndrome), but simultaneous measurements have notbeen made in the same patients. This, together with theimprovement of histiocytosis X on a thymic extractcalled suppressing but deterioration on

thymostimulin (reported at the symposium by R. J.Levinsky) indicates that the hormone for the proposeddouble-blind trials will need to be selected with somecare. In other thymic deficiency states, the peptidesmay have to be used in the correct combinations. As

yet, we do not know enough about the interactions ofthe hormones to understand which combinations to

try.It is much easier to measure the effects of thymic

hormones on peripheral circulating lymphocytes. Forexample, in severe atopic disease or metastaticcarcinoma the circulating T cells have a low surfacedensity of various "receptors". This can be"corrected" by short-term incubation with thymichormones or even fetal calf serum, which presumablycontains a high enough concentration of the relevantpeptides. Similarly, the ability of the peripheral bloodlymphocytes to divide when stimulated by lectins or

8. Jackson TM, Zaman SN. The in vitro effect of the thymic factor thymopoietin on asubpopulation of lymphocytes from severely malnourished children Clin ExpImmunol 1980; 39: 722-27

9 Rebar RW, Miyake A, Low TLK, Goldstein AL. Thymosin stimulates secretion ofluteinizing hormone-releasing factor. Science 1981; 214: 669-71.

10. Rebar RW, Morandini IC, Benirschke K, Petze JE. Recued gonadotropins in athymicmice: prevention by thymic transplantation. Endocrinology 1981; 108: 120-26.

11. Bach JF, Bach MA, Blanot D, et al Serum thymic factor (FTS) Bull Inst Pasteur 1978;76: 325-98.

12. Michael SD, Kaplan SB, Macmillan BT, McClure JE, Goldstein AL. RIAdetermination of circulating thymosin alpha-1, A thymic polypeptide hormone, inmaturing male and female mice. Fed Proc 1981; 40: (no 3, part II) abstr 3316.

13. Lisi PJ, Teipel JW, Goldstein G, Schiffman M. Improved radioimmunoassaytechnique for measuring serum thymopoietin. Clin Chim Acta 1980; 107: 111-19.

14. Osband ME, Lipton JM, Lavin P, Levey R, Vawter G, Greenberger JS, McCaffrey RP,Parkman R. Histiocytosis-X. Demonstration of abnormal immunity, T-cell

histamine H2-receptor deficiency, and successful treatment with thymic extract NEngl J Med 1981; 304: 146-53

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allotypic cells may be modified by thymic hormones. Ifthe concentration of the hormones and mitogen arechosen carefully, the changes can be interpreted as a"correction" of the "defect" in the disease group. Butwe should note that high and low concentrations of thesame hormone mixture can have opposite effects inthese in-vitro tests. -

There is no absolute correlation between in-vitrotests and clinical response to thymic hormones. In theprimary immunodeficiencies, for example, patients’lymphocytes have responded to thymic hormones buttreatment with the same hormone has produced noclinical improvement. Other patients have had

lymphocytes unresponsive in culture to thymichormones, but have shown real clinical improvementon thymic hormone treatment. This is not surprising ifthe hormones act on central lymphoid organs ratherthan circulating lymphocytes. The in-vitro response ofatopic patients has already been mentioned: clinicaltrials of thymostimulin in eczema have been verydisappointing with no demonstrable clinical

improvement (R. C. D. Staughton5) while thymosinfraction 5 produced a slight improvement in the skin(0. Strannegard5). Neither extract changed the IgElevel.

If most of the hormones cannot be measured, and thelaboratory tests on circulating lymphocytes have scantpredictive value, how should we choose which patientsto treat, and which peptide or group of peptides theyshould receive? The conditions in which thymichormones have been tried are numerous, ranging fromthe obvious (congenital thymic insufficiency), throughthe obscure (eg, sarcoidosis, in which our knowledge ofthe pathology could be summarised as "somethingwrong with the control of T cell function"), to

malignancy, in the time-honoured tradition of trying toboost the "immunological surveillance". In reality weare still at a stage of trial and error, using the hormonesin any condition where they might possibly be expectedto help. Fortunately the extracts and peptides arerelatively harmless, with only a few adverse reactionsreported (mostly allergic reactions to calf thymusextracts in people with pre-existing bovine proteinallergy).T lymphocyte abnormalities occur in many of the

primary immunodeficiencies. In DiGeorge syndromethere are low levels of thymosin alpha-1 and FTS. Mostof the thymic hormones have been tried in thiscondition, with some successes and some failures, thesuccesses often being more noticeable in tests of

lymphocyte function than clinically. (It must beremembered that immune function can improvespontaneously in DiGeorge Syndrome.) Combinedimmunodeficiency, severe combined immuno-

deficiency, and common variable hypogammaglobu-linaemia each includes many different patterns of

immunological deficit-almost to the extent that every

15 Wara WM, Wara DW, Neely MH, Ammann AJ. Head and neck cancer treatment withthymosin Proc Am Soc Clin Oncol 1981; 22: abstr C-171

patient has a unique condition. Thymic hormones havebeen tried in many of these patients, but centres havetended to use their own thymic hormone preparation,with usually fewer than half a dozen cases in any onegroup, so that general conclusions cannot be drawn. Inthe absence of adverse effects, it is worth persisting forthree months with treatment; the guide should beclinical improvement rather than changes in laboratoryindices. Most of the primary T cell deficiencies whichrespond need continuous treatment with the thymichormones, but some "Nezelof syndrome" patientshave had normal T cell function permanently restoredby a course of hormones (D. W. Wara5), corroboratingother evidence indicating that, in some of these patientsat least, the defect may be secondary to infection-?viral.

Viral infections may be particularly severe in

secondary immunodeficiency, and may themselves beimmunosuppressive. There are indications that

thymic hormone therapy in the secondary immuno-deficiency of lymphoid and non-lymphoid malignantdisease may offer useful protection againstinfection, 15, 16 and may help recovery after viralinfections. P. A. T ovos has obtained particularlyhopeful results in haemorrhagic varicella, with six outof seven patients recovering. Uncontrolled trial resultsin encephalitis suggest that thymostimulin may speedrecovery and prevent after-effects. Several otherobservations seem worth pursuing, such as slow

improvement in subacute sclerosing panencephalitisafter THF therapy (N. Trainin5). Like every otherform of immunostimulatory treatment, thymichormones have been tried in AIDS. The results havebeen disappointing-possibly because the treatmentwas given too late in the course of the disease and therewere no thymocytes or T cells left to stimulate.

After bone-marrow transplantation lymphoidreconstitution is normally slow. The numbers of thedifferent subpopulations are grossly imbalanced formany weeks and normal function (such as skin testreactivity) is slow to return. Thymic hormonetreatment has been tried some time after the graft, andhas enhanced graft-versus-host reactions. Two

patients, however, have been given TP5 from the timeof the graft, and they had engraftment without GVHand with early return of cellular immunity (L.Burincos).Tumour immunotherapy with thymic hormones

works in mice if combined with cytotoxic drugs.’ 1;Shoham et al16 found that the only significantadvantage in human beings was protection from

infection, but Benengo and co-workers5,18 report anti-

16. Shoham J, Theodor E, Brenner HJ, Goldman B, Lusky A, Chaitchick S Enhancementof the immune system of chemotherapy-treated cancer patients by simultaneous

treatment with thymic extract, TP-1 Cancer Immunol Immunother 1980, 9: 173-817 Klein AS, Shoham J. Effect of the thymic factor, thymostimulin (TP-1), on the survival

rate of tumor-bearing mice Cancer Res 1981, 41: 3217-2118. Benengo MG, Barbera C, De Matteis A, Meregalli M, Zina G In vitro effects of a calf

thymus extract in one hundred melanoma patients and preliminary results in vivoIn: Aiuti F, Wigzell H, eds. Thymus, thymic hormones and T lymphocytes (Serono)Symp no 38). London: Academic Press, 1980.

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tumour effects in malignant melanoma and renal cellcarcinoma. Maybe the negative results obtained bysome, groups were partly due to incorrect timing ofthymic hormone treatment in relation to cytotoxicdrugs.

It will clearly be a long time before thymic hormonetherapy comes of age. There must be better

understanding of which cells respond to which

peptides, and assays are needed that are simple enoughfor routine use. Meanwhile there are already a fewclinical applications for the hormones which should beenough to sustain physicians’ interest in the subject.

PREOPERATIVE DEPILATION

THE practice of shaving patients’ skin preoperativelyprobably dates from the days of Lister and Semmelweis.’Many surgeons still regard hair as a source of contaminationand insist on extensive skin depilation, usually with a

disposable razor on the day before surgery. Scanning electronmicrographs have shown that any skin shave acceptable to thesurgeon causes epidermal damage and permits bacterialcolonisation of the skin.2 A shave on the day before surgerywill increase the degree of colonisation and therefore,presumably, the chance of wound infection.3,4

’

Although several workers had shown that a depilatorycream is not harmful to skin,4-6 the traditional preoperativeshave remained unchallenged until 1971. Seropian andReynolds compared two matched groups of patients andshowed that the postoperative wound infection rate after useofa depilatory cream was only 0’ 6%, compared with 5’ 6% inthe group having a traditional shave. The wounds weregraded according to the system of the American NationalResearch Council,8 which separates operations into clean,clean-contaminated, contaminated, or dirty according to thedegree of potential infection. No wound infections werefound in the clean and clean-contaminated groups after use ofa depilatory cream whereas in the same categories managedwith a razor the infection rate was 6’4%. 155 patients wereexcluded from this trial because they had had no preoperativeskin preparation; the overall wound infection rate in thisgroup was only 0’6%.These findings were confirmed by Cruse and Foord9 who

studied 23 649 surgical wounds prospectively. The samewound grading system was used and in the 18 090 cleanwounds that were examined there was a 2’ 3% infection rateafter shaving, as against 0-9% with no skin preparation.

1. Wangensteen OH, Wangensteen SO. The rise of surgery from empiric craft to scientificdiscipline. Minneapolis: University of Minnesota Press, 1978. 353.

2. Hamilton HW, Hamilton KR, Lone FJ. Pre-operative hair removal. Can J Surg 1971;20: 269-75.

3. Altemeier WA. Infection in hospitals. Epidemiology and control. In: Williams R,Shooter RA, eds. Oxford: Blackwell, 1963: 209.

4. Prigot A, Garnes AL, Nwagbo U. Evaluation of a chemical depilatory for pre-operativepreparation of 515 surgical patients. Am J Surg 1962; 104: 900-06.

5. Stephens FO. The use of a depilatory cream in surgery. Med J Aust 1966; i: 886-88.6. Almersjo O, Hulten L, Rydberg B, Wahlquist L, Amren C. Wound healing after

depilation with a meratolytic cream. Acta Chir Scand 1967; 133: 355-62.7 Seropian B, Reynolds BM. Wound infections after pre-operative depilatory versus

razor preparation. Am J Surg 1971; 121: 251-54.8. Howard JM, Barker WF, Culbertson WR, et al. Post-operative wound infections: The

influence of ultraviolet irradiation of the operating room and of various otherfactors. Ann Surg 1964; 160 (suppl); 1-192.

9 Cruse PJE, Foord R. A five-year prospective study of 23 649 surgical wounds. ArchSurg 1973; 107: 206-10.

Court-Brownl° did a prospective study on patientsundergoing abdominal surgery, comparing the effect of

shaving, cream depilation, and no preparation on the post-operative wound infection rate. The same wound gradingsystem was used and the surgical materials and use ofperoperative antibiotics were standardised. The overallinfection rates were 12-4% after shaving, 7-9% after creamdepilation, and 7-8% with no preparation. When only theclean and clean-contaminated wounds were compared theinfection rate after shaving was 10’4%, as against 3-9% forthe cream group and 2 - 9% for the no preparation group. Theincrease in the infection rate in the shaved group was

statistically significant.The role ofpreoperative hair clipping has been investigated

by Alexander et al." In populations again matched accordingto the ANRC grading system the infection rate in the cleanwounds was 4’ 0% in the shaved group and 1’ 4% in the

clipped group. Despite the low infection rate with clipping,these workers felt that the method entailed some skin damageand that infection rates might be higher than those aftercream depilation or no preparation.The timing of the skin preparation affects the wound

infection rate. If the interval between a preoperative shaveand subsequent surgery is prolonged, the infection raterises. 7, 10 Seropian and Reynolds showed that if the shave wasdone immediately before operation the infection rate was3’1%. Extending the interval to over twenty-four hoursincreased the infection rate to more than 20%. This timedifference is not seen with depilatory creams. 10Since preoperative shaving increases the rate of post-

operative wound infection, this traditional surgical practiceshould be dropped. If the surgeon wishes to have a hairlessfield then a depilatory cream should be used; failing that, thepreoperative shave should be done immediately beforesurgery. A depilatory cream is particularly useful in

orthopaedic or cardiothoracic surgery where shaving isdifficult. Hair clippers undoubtedly lower the incidence ofwound infection but probably still cause skin damage.Wound infections delay patient discharge by an average of7’ 312 to 9. 113 days. It has been suggested that if the practiceof preoperative shaving was abandoned in the USA, theannual saving could exceed$3 billion. l

COLONOSCOPY—ESSENTIAL SERVICE IN AGENERAL HOSPITAL

THE first British reports of complete examination of thecolon with a flexible endoscope were published about tenyears ago.I,2 At the time, most clinicians were happy withrigid sigmoidoscopy and barium enema, and were less thanenthusiastic about colonoscopy, because the instrumentswere expensive and fragile and the techniques were moreexacting and time-consuming than those of fibreopticgastroscopy. This has all changed. The ability to examine the

10. Court-Brown CM. Pre-operative skin depilation and its effect on post-operative woundinfections. J Roy Coll Surg Edinb 1981; 26: 238-41.

11. Alexander JW, Fischer JE, Boyajian M, Palmquist J, Morris MJ The influence of hair-removal methods on wound infections: Arch Surg 1983; 118: 347-52.

12. Lowenthal J. Sources and sequelae of surgical sepsis. Br Med J 1962; i: 1437-40.13. Cruse PJE. Incidence of wound infection on the surgical services. Surg Clin N Am

1975; 55: 1269-75.1. Williams CB, Muto T. Examination of the whole colon with the fibreoptic

colonoscope. Br Med J 1972; iii: 278-81.2. Teague RH, Salmon PR, Read AE. Fibreoptic examination ofthe colon: a review of 255

cases. Gut 1973; 14: 139-42.