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caused by a gene on chromosome 19; and high levels ofLp(a) are not necessary for penetrance of this defect,because within families affected members have Lp(a)concentrations double those of their unaffected first-

degree relatives.l3 The high Lp(a) is not simplya reflection of the high LDL since other

hyperlipoproteinaemias, with similarly raised LDLconcentrations, are not associated with any increase inLp(a)." A suggestion is that Lp(a) may explain thegreatly increased risk of coronary heart disease in FHcompared with other hyperlipidaemias.11-14Serum Lp(a) may be raised in acquired conditions.

For example, in primary renal disorders associatedwith proteinuria, serum Lp(a) concentrations aretwo-fold higher than they are during remission.15Liver disease leads to low concentrations. 16

Lp(a) binds to plasminogen receptors in vitro17 sothe mechanism linking Lp(a) with coronary heartdisease might be interference with plasminogenactivation, which would promote thrombosis.

Preliminary results from one group studying theinfluence of Lp(a) on the effectiveness of thrombolysisin acute myocardial infarction do not support thishypothesis;18 nor do the findings of an

immunohistochemical study in which Lp(a) was notdetected on plasminogen receptors of colon or breastcarcinomas.l9 Another proposal is that Lp(a) is

important in atherogenesis rather than in thrombosis.The cellular component of the arterial fatty streaksthat precede development of atheroma largely consistsof macrophages engorged with lipid from apo-B-containing lipoproteins.20 Lp(a) binds to fibrin invitro2l (fibrin is abundant in early atheromatouslesions22), to glycosaminoglycans 123 and to

fibronectin.5 There is now direct evidence for

preferential retention of Lp(a) in atheromatous lesionsvia fibrin binding, in contrast to other apo-B-containing LDL.’ Macrophage uptake of Lp(a)could also be encouraged by binding of Lp(a) to thecell surface via plasminogen receptors Oxidationand proteolysis are both active at the macrophagesurface,,’-Is and modification of apo B by eitherprocess leads to rapid receptor-mediated uptake bymacrophages in vitro.2024,25 There is no sign of Lp(a)retreating from the forefront of atherosclerosis

research, development of therapies to modify its

circulating concentration may prove valuable in theprevention of atheroma.

1. Berg K. A new serum type system in man—the LP-system. Acta PatholMicrobiol Scand 1963; 59 :369-89.

2. Utermann G. The mysteries of lipoprotein (a). Science 1989; 246: 904-10.3. Mbewu A, Durrington PN. Lipoprotein (a): structure, properties and

possible involvement in thrombogenesis and atherogenesis.Atherosclerosis 1990; 85: 1-14.

4. McLean JW, Tomlinson JE., Kuang W-J, et al. cDNA sequence ofhuman apolipoprotein (a) is homologous to plasminogen. Nature 1987;300: 132-37.

5. Salonen EM, Jauhiainen M, Zardi I, et al. Lipoprotein (a) binds tofibronectin and has a serine proteinase activity capable of clearing it.EMBO J 1989; 8: 4035-40.

6. Hassted SJ, Williams RR. Three alleles for quantitative Lp(a). GenetEpidemiol 1986; 3: 53-55.

7. Durrington PN, Ishola M, Hunt L, Arrol S, Bhatnagar D.

Apolipoproteins (a), AI, and B and parental history in men with earlyonset ischaemic heart disease. Lancet 1988; i: 1070-73.

8. Boerwinkle E, Menzel HJ, Kraft HG, Utermann G. Genetics of thequantitative Lp(a) lipoprotein trait III: contributions of Lp(a)glycoprotein phenotypes to normal lipid variation. Hum Genet 1989;82: 73-78.

9. Gaubatz JW, Ghanem KI, Guervara J Jr, et al. Polymorphic forms ofhuman apolipoprotein (a): inheritance and relationship of theirmolecular weights to plasma levels of lipoprotein (a). J Lipid Res 1990;31: 603-13.

10. Gavish D, Azrolan N, Breslow J. Plasma Lp(a) concentration is inverselycorrelated with the ration of kringle IV/kringle V encoding domains inthe apo (a) gene. J Clin Invest 1989; 84: 2021-27.

11. Utermann G, Hoppichler F, Dieplinger H, et al. Defects in the LDLreceptor gene affect Lp(a) lipoprotein levels: multiplicative interactionof two gene loci associated with premature atherosclerosis. Proc NatlAcad Sci USA 1989; 86: 4171-74.

12. Wiklund O, Angelin B, Olofsson S-O, et al. Apolipoprotein (a) andischaemic heart disease in familial hypercholesterolaemia. Lancet 1990;335: 1360-63.

13. Mbewu A, Bhatnagar D, Mackness M, et al. Serum lipoprotein (a) levelsin patients with familial hypercholesterolaemia, their relatives andcontrol populations. Clin Sci 1990; 79: 138.

14. Seed M, Hoppichler F, Reaveley D, et al. Relation of serum lipoprotein(a) concentration and apolipoprotein (a) phenotype to coronary heartdisease in FH. N Engl J Med 1990; 322: 1494-99.

15. Short CD, Mallik NP, Durrington PN. Ischaemic heart disease andlipoprotein abnormalities in human membranous nephropathy.International Symposium on Lipid Abnormalities in Renal Disease,Porto Cervo, Italy, Oct 1-2, 1990.

16. Marth E, Cazzolato G, Bittolo Bon G, et al. Serum concentrations ofLp(a) and other lipoprotein parameters in heavy alcohol consumers.Ann Nutr Metab 1982; 26: 56-62.

17. Gonzalez-Gronow M, Edelberg JM, Pizzo SM. Further characterizationof the cellular plasminogen binding sites: evidence that plasminogen 2and lipoprotein (a) compete for the same site. Biochemistry 1989; 28:2374-77.

18. Armstrong VW, Neubauer C, Schütz E, Tebbe U. Lack of associationbetween raised serum Lp(a) concentration and unsuccessful

thrombolysis after acute myocardial infarction. Lancet 1990; 336: 1077.19. Correc P, Kostner GM, Burtin P. A comparative study of the localisation

of plasminogen and apolipoprotein (a) in human carcinomas. ThrombRes 1990; 58: 213-20.

20. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.Beyond cholesterol. Modifications of low density lipoprotein thatincrease its atherogenicity. N Engl J Med 1989; 320: 915-24.

21. Harpel PC, Gordon BR, Parker TS. Plasmin catalyzes binding oflipoprotein (a) to immobilized fibrinogen and fibrin. Proc Natl AcadSci USA 1989; 86: 3847-51.

22. Smith EB, Cochran S. Factors influencing the accumulation in fibrousplaques of lipid derived from low density lipoprotein II: preferentialimmobilization of lipoprotein (a) (Lp(a)). Atherosclerosis 1990; 84:173-81.

23. Bihari-Varga M, Gruber E, Rotherender M, et al. Interaction of

lipoprotein Lp(a) and low density lipoprotein with glycosaminoglycansfrom human aorta. Arteriosclerosis 1988; 8: 851-57.

24. Leake DS, Rankin SM. The oxidative modification of low-densitylipoproteins by macrophages. Biochem J 1990; 270: 741-48.

25. Leake D S, Rankin SM, Collard J. Macrophage proteases can modify lowdensity lipoproteins to increase their uptake by macrophages. FEBSLett 1990; 269: 209-12.

Pelvic congestion"Beside the well-established organic lesions and

certain disorders definitely attributable to endocrinedysfunction there still exists in gynecology a group ofconditions of uncertain cause. These have thecommon characteristic of producing chronic painwithout evidence of inflammation or other obvious

pathologic process." So wrote Howard C. Taylor in1949.1 little has changed. Young women with chronicpelvic pain are still commonly seen in general practice,and referred to gynaecologists. Clinical assessmentand additional investigations, which may now include

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ultrasonography and laparoscopy, often fail to

demonstrate any abnormality-eg, endometriosis orchronic infection-which can reasonably be assumedto be causal. For some women, anxiety about the causeof the pain is more disturbing than the symptom itself;a simple explanation that no serious disease is presentis sufficient. For others, the pain is the outstandingproblem. When no adequate explanation or treatmentcan be offered, the patient is understandablydisappointed, even bitter. Any improvement in ourunderstanding of this common disorder would bewelcome, and it is mainly to St Mary’s Hospital,London, that we must look for recent insights.The St Mary’s workers contend that pelvic

congestion is responsible for most cases of otherwiseunexplained pelvic pain. This is not a new idea-Taylor’s review mentioned several reports, includingthat of Lawson Tait, which were written during the19th century to support this notion.1 What the St

Mary’s group has done is to apply modem as well astraditional techniques to provide us with a clinical"identikit".2 The patient is always premenopausal andis typically in her late 20s or early 30s. She is morelikely to have had children than not. She complains ofa dull aching pain in her pelvis which is worsened bywalking and other postural changes, and she is

especially troubled by postcoital ache. Acute episodesof severe pain may have provoked hospital admission.Although she may have bowel symptoms, she does notreport a consistent change in bowel habit withoccurrence of her pain, in contrast to patientsdiagnosed as having irritable bowel syndrome. 3

Dysfunctional bleeding and dysmenorrhoea of the"congestive" type are common. She reportstenderness on palpation of the ovarian point, one thirdof the distance from umbilicus to anterior superioriliac spinel When she undergoes laparoscopy, nolesions are seen.

Pelvic varicosities5--the single consistent positivefinding in such patients-have, until lately, requiredthe use of transuterine or selective ovarian

venography6 for demonstration. Varicosities, it is

surmised, are associated with vascular stasis,congestion of the pelvic organs, and consequent painin the same way as varicose veins in the legs mayproduce pain. That intravenous injection of theselective vasoconstrictor dihydroergotamine causesconstriction of the pelvic varicosities and

improvement in symptoms suggests a direct link.Varicosities have been reported in 91% of womenwith otherwise unexplained chronic pelvic pain, butonly rarely in symptom-free controls.s Their causeremains uncertain. Valvular incompetence of theovarian veins has been suggested by some

researchers.8 Others have concentrated on ovarianhormones because the condition affects only womenin the reproductive age group. Endocrine studies havenot been carried out but the physical dimensions oftarget organs have been investigated by use of

ultrasound for accurate measurement of uterine size,endometrial thickness, and ovarian volume.9 Adams etapo suggested that either an excess of oestrogen, or anexcessive response to it, might not only be responsiblefor pelvic congestion but also cause uterine andendometrial hypertrophy; these features were indeedseen in women with pelvic varicosities. Anothercommon finding was the presence of polycysticovaries. Further studies have used transvaginalultrasound; this technique gives higher quality imagesof pelvic organs" and can show pelvic varicositieswithout the need for venography. 12

Because of the proposed, if unproven, suggestionthat an excessive oestrogenic influence may contributeto pelvic congestion, a randomised controlled trial ofhigh-dose progestagen treatment (medroxypro-gesterone acetate) has been conducted at St Mary’sHospital. 13 Oestradiol levels fell with treatment andshort-term improvement in pain was better withprogestagen than with psychotherapy or placebo.Combined medroxyprogesterone acetate and

psychotherapy achieved the best long-term relief.What should objective observers make of it all?

Some techniques and scientific findings travel betterthan others. The St Mary’s workers have

monopolised publications on this subject because theyhave been almost alone in addressing this conditionsystematically. It would be reassuring if similar resultscould be obtained by other groups. Some researchersmay still feel uncomfortable about the whole concept.It is perhaps surprising that such a large proportion ofpatients with a disorder of obscure aetiology shouldprove to have a simple unifying explanation (pelvicvaricosities) that responds to simple inexpensivetreatment (medroxyprogesterone acetate}-but it is

up to the sceptics to disprove the conclusions.How about management in general practice or a

gynaecology outpatient department? Pelvic

venography is unacceptably invasive but transvaginalultrasound appears to identify pelvic varicosities

reliably. A multicentre randomised placebo-controlled trial of medroxyprogesterone acetate that isnow under way in the UK should help to establishtherapeutic guidelines. If the efficacy of progestagenis confirmed, this approach will be far more

attractive than surgery8 or radiologically directed

sclerotherapy;6 other hormonal methods of ovariansuppression would then merit similar investigation.

1. Taylor HC. Vascular congestion and hyperemia. Their effect on structureand function in the female reproductive system. 1: physiological basisand history of the concept. Am J Obstet Gynecol 1949; 57: 211-27.

2. Beard RW, Reginald PW, Wadsworth J. Clinical features of women withchronic lower abdominal pain and pelvic congestion. Br J ObstetGynaecol 1988; 95: 153-61.

3. Farquhar CM, Hoghton GBS, Beard RW. Pelvic pain—pelviccongestion or the irritable bowel syndrome? Eur J Obstet GynecolReprod Biol 1990; 37: 71-75.

4. Beard RW, Reginald PW, Pearce S. Pelvic pain in women. Br Med J1986; 293: 1160-62.

5. Beard RW, Highman JH, Pearce S, Reginald PW. Diagnosis of pelvicvaricosities in women with chronic pelvic pain. Lancet 1984; ii: 946-49.

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6. Kennedy A, Hemingway A. Radiology of ovarian varices. Br J Hosp Med1990; 44: 38-43.

7. Reginald PW, Beard RW, Kooner JS, et al. Intravenous

dihydroergotamine to relieve pelvic congestion with pain in youngwomen. Lancet 1987; ii: 351-53.

8. Hobbs JT. The pelvic congestion syndrome. Br J Hosp Med 1990; 43:200-06.

9. Saxon DW, Farquhar CM, Rae T, Beard RW, Anderson MC,Wadsworth J. Accuracy of ultrasound measurement of female pelvicorgans. Br J Obstet Gynaecol 1990; 97: 695-99.

10. Adams J, Reginald PW, Franks S, Wadsworth J, Beard RW. Uterine sizeand endometrial thickness and the significance of cystic ovaries inwomen with pelvic pain due to congestion. Br J Obstet Gynaecol 1990;97: 583-87.

11. Editorial. Transvaginal ultrasound. Lancet 1989; ii: 19-20.12. Stones RW, Rae T, Rogers V, Fry R, Beard RW. Pelvic congestion in

women: evaluation with transvaginal ultrasound and observation ofvenous pharmacology. Br J Radiol 1990; 63: 710-11.

13. Farquhar CM, Rogers V, Franks S, Pearce S, Wadsworth J, Beard RW.A randomized controlled trial of medroxyprogesterone acetate andpsychotherapy for the treatment of pelvic congestion. Br J ObstetGynaecol 1989; 96: 1153-62.

Antibiotics as biological responsemodifiers

Immunomodulation became an immunological"buzz word" in the late 1980s; next month the firstinternational symposium on biological responsemodifiers (BRM) will be held in Quebec, Canada. ABRM has been defined as an agent capable of

"augmenting and/or restoring effector mechanisms ormediators of host defence, decreasing deleterious

components of the host’s reaction; replacing thedamaged effector or mediator mechanisms with

natural biological or synthetic derivatives;augmenting the host response to vaccines and

chemotherapeutic agents".1Can antibiotics function as BRMs ? In this respect,

antibiotics fall into four groups: (a) those that have noeffect on host defences-p-lactams; (b) those thatdepress immune functions-tetracyclines; (c) thosethat display synergy with the immune system-macrolides and quinolones; and (d) those that enhanceimmune function--certain cephalosporins. Evidencethat has accumulated over the past 10-12 yearsindicates that antibiotics at concentrations below theminimum inhibitory concentration (sub-MIC) mayhelp to eradicate bacterial pathogens via host immunemechanisms. This effect may be related to changes inbacterial morphology and/or metabolism which

potentiate the susceptibility of organisms to humoral(complement and antibody) and cellular (phagocyticcells) immune defences.

Bacterial susceptibility to phagocytosis usuallydepends on the deposition of opsonins, complement,and antibody on the bacterial cell surface, whichmakes the bacterium recognisable by specificreceptors on the host cell. Many antibiotics, byaltering the surface topography of bacterial cells, canaccelerate this process, so that more bacteria are

ingested and killed,z and some also enhance theoxidative response of the polymorphonuclearleucocytes directly. Some drugs affect non-opsonin-dependent phagocytosis mediated by surface lectins of

bacteria. Stimulation of this defence mechanism

might be especially important in protection againstbacteria that are capable of evading normal

opsonophagocytosis-eg, bacteria that do not activatethe complement cascade or that invade serum-

depleted sites or complement-deficient hosts.A BRM may stimulate some or all aspects of the

immune system whereas an immunomodulator, also aBRM, may upregulate or downregulate a specific cellphenotype or cytokine without necessarily causingany biological or clinical changes. Do we haveantimicrobial agents with such activity? When

arsphenamine was used to treat patients with syphilis,it was recognised that although Treponema pallidumwas killed by the drug, sudden release of antigen andits interaction with circulating antibody could causeHerxheimer’s anaphylaxis in certain patients. Morerecently, polymyxin, because of its ability to bind andinactivate endotoxin, has been tried therapeutically inrats with septic shock, but the amounts of drugnecessary to neutralise the endotoxin were too toxicfor clinical use.4,5

Cefodizime, one of the newest third-generationcephalosporins, increases the survival of mice

challenged with Toxoplasma gondii or Candidaalbicans when it is given in low doses prophylactically.6This drug also seems to downregulate production oftumour necrosis factor and interleukin-1 by humanmonocytes.7 Cefodizime stimulates non-oxidative

killing of non-opsonised bacteria by phagocytic cells.Structure-activity studies have shown that thechemical structure involved in immunomodulation isthe thio-thiazolyl moiety at position 3 of the cephemnucleus; most other structural alterations of this

side-chain result in complete loss of

immunomodulating activity.Ex-vivo data suggest that cefodizime enhances

phagocyte or lymphocyte functions in healthyvolunteers9 and can even restore natural killer cellfunction in an immunocompromised patient.10

Potent antibiotics may also have negative qualitiesas BRMs. Thus the cell-killing action of an antibioticmay release membrane components, intracellular

enzymes, and extracellular toxins which can affect theimmune system directly. It is possible that septicshock, acute respiratory distress syndrome, or

multiple organ failure might ensue. In any

inflammatory response endogenous BRMs are

released in the host, each capable of effecting change,whether independently or in concert with others.

It is not easy to compare an antibiotic that has

immunomodulatory activity (BRM) with another thatlacks such activity. Any trial seeking to show a

significant increase in cure rate would need to enrolthousands of patients to satisfy the statisticians.

Nevertheless, the development of drugs that combinein-vitro antibacterial efficacy with the ability to restoreor enhance the immune system could open up newavenues in the treatment of microbial infections.