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accord with Ahmed’s hypothesis that lymphadenopathy maybe related to an agent that exists within the gut wall only. UntilM paratuberculosis is identified in tissues distant from the gut,it is arguable that its presence there may be a result of secondaryinfection. This explanation would, however, have to incorpo-rate the findings that the organism seems to be specific for theinflammation of Crohn’s disease.

Helen M Fidler, John Ibbotson, H Chahal, Y Mussaddeq,R N Allan, N Mcl Johnson, J J McFaddenMolecular Microbiology Group, University of Surrey, Guildford GU2 5XH, UK;Department of Infection, Medical School, University of Birmingham; and Department ofMedicine, University College London Medical School, London Wl

1 Sanderson JD, Moss MT, Tizard ML, Hermon-Taylor J.Mycobacterium paratuberculosis DNA in Crohn’s disease tissue. Gut1992; 33: 890-96.

2 Weinstock JV. The granuloma and Crohn’s disease. In: Zakim D, ed.Inflammatory bowel disease. Amsterdam: Elsevier, 1992:163-76.

3 Green EP, Tizard MLV, Moss MT, Thompson J, Winterbourne DJ,McFadden JJ. Sequence and characteristics of IS900, an insertionelement identified in human Crohn’s disease isolate of Mycobacteriumparatuberculosis. Nucl Acids Res 1989; 17: 9063-73.

4 Saboor SA, Johnson NM, McFadden JJ. The use of the polymerasechain reaction to detect mycobacterial DNA in tuberculosis andsarcoidosis. Lancet 1992; 339: 1012-15.

SIR-Ahmed and colleagues describe an intra-abdominal

granulomatous lymphadenitis (and hepatitis in one patient)and suggest that this may be related to chronic H pyloriexposure in susceptible individuals. One patient had a clearhistory of peptic ulceration of the duodenum and the clinicaldata strongly suggest that the other also had peptic ulceration. Ibelieve that it is too simplistic to suggest that this granulo-matous pathology is related directly to H pylori. A breachedgastric/duodenal mucosa could allow entry of any number offoreign organic or inorganic compounds that could haveinduced such a reaction. For instance, mineral oil granulomasin the liver and spleen are well recognised in duodenal ulcerpatients and materials such as these are much more likely to bethe cause of the granulomatous pathology than an organismthat never incites such a reaction in its usual place of abode andhas never been shown to invade human tissues. Helicobacter

may be responsible for a lot but, please, let us not push it too far.

Neil A ShepherdGloucestershire Royal Hospital, Gloucester GL1 3NN, UK

Felbamate

SIR—Brodie’s questions (June 5, p 1445) are pertinent and Iwill answer some of them. The trials he mentioned proved thatfelbamate is effective against partial-onset seizures and themultiple seizure types of the Lennox-Gastaut syndrome. Thetrials were designed to meet the requirements of regulatoryagencies that require proof of efficacy when the study drug iscompared to a control substance. In my monotherapy triaPmost patients with refractory partial-onset seizures were

receiving carbamazepine during the baseline period. 18 of the22 patients randomised to the felbamate group were success-fully converted to felbamate and completed the entire 112-daytreatment period. When treated with felbamate monotherapyduring the double-blind treatment period, these patients had amean reduction in seizure frequency of 58% as compared withthe baseline period.A detailed analysis of escapes due to secondarily generalised

tonic-clonic seizures (SGTCS) in the monotherarpy trials waspresented to the FDA Advisory Committee. The statisticallysignificantly lower escape frequency among felbamate patients

clearly supported the efficacy of felbamate for SGTCS. Thecommittee recommended approval for the use of felbamate inSGTCS. The 18 patients who completed the felbamate arm ofmy monotherapy trial experienced a 61 % reduction in SGTCSas compared with baseline. My experience with over 120patients in both double-blind and open-label trials confirmsthe excellent efficacy and safety profile of felbamate. Theultimate place of any new drug in the therapeutic arma-mentarium can only be determined after use by clinicians inmany patients.

Rajesh C SachdeoNew Jersey’s University of the Health Sciences, 97 Paterson Street, New Brunswick,NJ 08903-0019, USA

1 Sachdeo R, Kramer LD, Rosenberg A, Sachdeo S. Felbamatemonotherapy: controlled trial in patients with partial-onset seizures.Ann Neurol 1992; 32: 386-92.

HLA-DR4 subtyping by single-strandpolymorphism analysis

SIR-Difficulties have been encountered with single-strandconformation polymorphism (SSCP) in subtyping HLA-DR4.1 We have used this technique routinely in the study ofHLA susceptibility in rheumatoid arthritis (RA), and havedistinguished ten DR4 subtypes, including two novel alleles(figure). Because SSCP does not rely on identifying alreadyknown sequence differences, it has the potential to detect newalleles2 and can aid their rapid characterisation. The ability ofSSCP to distinguish alleles depends on the electrophoreticmobility of single-strand DNA, which is very sensitive to

temperature, running time, and gel composition. Difficulties inidentifying allelic subtypes of DR4 can be minimised by the useof constant temperature, prolonged gel separation, and therunning of sequenced control DNA on every gel.The ability to distinguish subtypes of HLA-DR4 has been of

major importance in understanding the role of these antigen-presenting molecules in RA, because of the differential

susceptibility that is seen with certain subtypes. The variousaminoacid substitutions of the DR(3 chain that generate theknown subtypes of DR4 are believed to affect the binding andpresentation of antigen to T cells. This effect probablyaccounts for the positive association of RA in the UK with theDR4 subtypes Dw4 and Dwl4 compared with the negative

Figure: HLA-DRB1*04 subtypes distinguished by SSCP200 ng genomic DNA amplified 24 cycles of DR4 specific PCR.’4 fiLofPCR product in formamide loading dye is heat denatured and loaded on a0 75 mm 10% 19/1, polyacrylamide/bisacrylamide, 10% glycerol gel,and separated at 10W/gel for 22 h at 4°C, before silver staining.Subtypes named by mixed lymphocyte typing and DNA sequencenomenclature. Lanes are:

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association with subtypes DwlO and Dw13.3 Although theDwl5 subtype, which shares the same sequence as Dwl4between positions 67-74 of the DR&bgr; chain, confers susceptibi-lity to RA in Japanese people,4 its effects have not previouslybeen established in the UK population.We therefore used SSCP typing to investigate the role of

Dwl5 in RA susceptibility among 304 caucasian patients withclassic or definite RA who were part of the Cardiff and East

Wales long-term study of RA. The Dwl5 phenotype wassignificantly higher in RA patients (9/304) than in controls(1/297; relative risk 9-0; p=0-01, Fisher’s exact test), showingthat the Dwl5 subtype of HLA-DR4 is positively associatedwith RA in UK caucasian patients.

Establishing the exact locus within the major histocompatibi-lity complex responsible for disease susceptibility is facilitatedby the identification of disease susceptibility markers that arecommon to different extended haplotypes in various racial

groups. In Japan, Dwl5 is linked with HLA-DQ4 so that theelement leading to susceptibility within the extended haplotypeHLA-DR4Dwl5-DQ4 is uncertain. Our finding of a positiveDwl5 association, which in the UK is linked to DQ8,5 identifiesDwl5 as the susceptibility allele in common between these twodifferent haplotypes and strengthens the evidence that HLA-DRB1 is the major susceptibility locus in RA.

Kevin Pile, Kathryn Gibson, John Jessop, Jeremy Camilleri,Rachel Emberton, Paul WordsworthNuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK

1 Young NT, Darke C. "Molecular crossmatching" for allogeneic bonemarrow transplants by DNA single-strand polymorphism analysis.Lancet 1993; 341: 183-84.

2 Cornélis F, Pile K, Loveridge J, et al. Systematic study of human &agr;&bgr; Tcell receptors V segments shows allelic variations resulting in a largenumber of distinct T cell receptor haplotypes. Eur J Immunol 1993; 27:1277-83.

3 Wordsworth BP. Lanchbury JSS, Sakkas LI, Welsh KI, Panayi GS,Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritisindicate that DRB1 is the major susceptibility locus within the HLAclass II region. Proc Natl Acad Sci USA 1989; 86: 10049-53.

4 Ohta N, Nishimura YK, Tanimoto K, et al. Association between HLAand Japanese patients with rheumatoid arthritis. Hum Immunol 1982; 5:123-32.

5 Morel C, Zwahlen F, Jeannet M, Mach B, Tiercey J-M. Completeanalysis of HLA-DQB 1 polymorphism and DR-DQ linkagedisequilibrium by oligonucleotide typing. Hum Immunol 1990; 29:64-77.

Shrinkage of inoperable adenomas Incavernous sinus with high-dose octreotide

SiR-The long-acting somatostatin analogue octreotide is usedin the treatment of acromegaly. Although it reduces hormonesecretion, reduction in tumour size is variable.We report a 48-year-old woman who, 11 years previously,

had a pituitary tumour removed which was found histologicallyto be a necrotic, probably non-secreting, adenoma. Despite noobvious acromegalic features, insulin-like growth factor

(IGF-I) (5-4 U/mL) and growth hormone (GH) (94 ng/mL)concentrations were increased, and not suppressed during aglucose tolerance test. Acromegaly was suspected and sup-ported by the increased thickness of the heel pad (23 mm,normal <21). Magnetic resonance imaging (MRI) showedadenomas in the cavernous sinuses (figure A). After injection ofradiolabelled octreotide, both tumours showed a marked

uptake of radioactivity. As the tumours were inoperable,treatment with subcutaneous daily octreotide injections(300 g) was started. Headaches resolved but IGF-I remainedraised. The dose was then increased to 1500 ug, which

produced a decrease of GH to 5 ng/mL and IGF-I to 36U/mL. After 18 months on this treatment, substantial

F16ulc;. ,",UIUIIGI 1...lnl m I’ILUILalJ aucnumaa m mc WaVONINVU0sinus (Indicated by arrows) before (A) and after (B) 18 months’s)nus (!nd)cated by arrows) before (A) and after (B) 18 months’treatment with high-dose octreotlde

shrinkage of both tumours was noted on MRI (figure B). Noside-effects were observed.

Clinicians should be aware of this alternative and safe

treatment, which can be applied to inoperable adenomas whensomatostatin receptors are present.

J Donckier, C Gilliard, M BuysschaertDepartment of Endocnnology, Internal Medicine and Neurosurgery, University Hospitalof Mont-Godmne, B-5530 Yvoir, Belgium

Renal artery stenosis and congestive heartfailureSIR&mdash;The demonstration by Missouris and colleagues (June12, p 1521) that patients with severe, bilateral renal arterydisease display the signs and symptoms of cardiac failure isinteresting but not surprising. Since the heated debates earlierthis century, when it was argued that the concept of "forwardfailure" better explained the haemodynamic changes of heartfailure than the old idea of "backward failure", it has beenaccepted by most cardiovascular physiologists that the peri-pheral oedema and increased blood volume seen in heart failureare due to impaired secretion of salt and water by the kidneys.lImpaired renal perfusion in renal artery stenosis would beexpected to mimic this impaired perfusion in heart failure.What I do find surprising and disappointing is the failure of themajority of medical students and clinicians to appreciate that itis altered kidney function that produces raised venous pressureand oedema. Thus a patient with peripheral and pulmonaryoedema and raised venous pressure will be automaticallylabelled as having heart failure even when their heart is

managing to generate higher-than-average arterial pressure, asin the cases described by Missouris et al. If I told my centralheating engineer that the pressure in the pipes going to theradiators was too high and therefore the pump must be failinghe would rightly suspect I knew nothing about circulatorysystems.