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perfusion-eg, arterial occlusion-flow-inducedrelease of NO may control and facilitate the opening ofcollateral vessels.23 It is certain that other therapeuticstrategies will emerge as more is learnt about thebiology of NO.

1. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology,pathophysiology, and pharmacology. Pharmacol Rev 1991; 43:109-42.

2. Kilbourn RG, Gross SS, Jubran A, et al. NG-methyl-L-arginine inhibitstumor necrosis factor-induced hypotension: implications for theinvolvement of nitric oxide. Proc Natl Acad Sci USA 1990; 87:3629-32.

3. Joulou-Schaeffer G, Gray GA, Fleming I, Schott C, Parratt JR, StocletJ-C. Loss of vascular responsiveness induced by endotoxin involves theL-arginine pathway. Am J Physiol 1990; 259: H1038-H1043.

4. Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces thehypotension induced by bacterial lipopolysaccharides in the rat in vivo.Eur J Pharmacol 1990; 182: 591-95.

5. Acki N, Johnson G, Lefer AM. Beneficial effects of two forms of NOadministration in feline splanchnic occlusion shock. Am J Physiol 1990;2587: G275-81.

6. Hutcheson IR, Whittle BJR, Boughton-Smith NK. Role of nitric oxidein maintaining vascular integrity in endotoxin-induced acute intestinaldamage in the rat. Br J Pharmacol 1990; 101: 815-20.

7. Klabunde RE, Ritger RC. NG-monomethyl-L-arginine (NMA) restoresarterial blood pressure but reduces cardiac output in a canine model ofendotoxic shock. Biochem Biophys Res Commun 1990; 178: 1135-40.

8. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role fornitric oxide? Lancet 1991; 337: 776-78.

9. Hibbs JR, Westenfelder C, Samlowski WE. Endogenous nitrate

synthesis from a terminal guanidino nitrogen atom of L-arginine andphysiology of nitrate excretion in patients receiving interleukin-2therapy. Second International Meeting on the Biology of Nitric Oxide.London, October, 1991.

10. Rees DD, Cellek S, Palmer RMJ, Moncada S. Dexamethasone preventsthe induction by endotoxin of a nitric oxide synthase and the associatedeffects on vascular tone: an insight into endotoxin shock. BiochemBiophys Res Commun 1990; 173: 541-47.

11. Griffith OW, Park KH, Levi R, Gross SS. The role of plasma arginine innitric oxide synthesis: studies with arginase-treated rats. Second

International Meeting on the Biology of Nitric Oxide. London,October, 1991.

12. Girerd XJ, Hirsch AT, Cooke JP, Dzau VJ, Creager MA. L-arginineaugments endothelium-dependent vasodilation in cholesterol-fedrabbits. Circ Res 1990; 67: 1301-08.

13. Prast H, Werner ER, Heistracher M, Werner-Felmayer G, Philippu A,Wachter H. Effects of sepiapterin treatment on tetrahydrobiopterinlevels and blood pressure in spontaneously hypertensive rats. SecondInternational Meeting on the Biology of Nitric Oxide. London,October, 1991.

14. Bogle RG, Moncada S, Pearson JD, Mann GE. Identification of selectiveinhibitors of arginine transport and nitric oxide synthase in vascularendothelial cells. Second International Meeting on the Biology ofNitric Oxide. London, October, 1991.

15. Frostell C, Fratacci M-D, Wain JC, Jones R, Zapol WM. Inhaled nitricoxide: a selective pulmonary vasodilator reversing hypoxic pulmonaryvasoconstnction. Circulation 1991; 83: 2038-47.

16. Pepke-Zaba J, Higenbottam TW, Tuan Dinh-Xuan A, Stone D,Wallwork J. Inhaled nitric oxide as a cause of selective pulmonaryvasodilatation in pulmonary hypertension. Lancet 1991; 338:1173-74.

17. Rabson SR, Quilliam JH, Goldblatt E. The elimination of nitrousfumes from blasting gases. J S Afr Inst Min Metall 1960; 61:152-99.

18. Stavert DM, Lehnert BE. Nitrogen oxide and nitrogen dioxide asinducers of acute pulmonary injury when inhaled at relatively highconcentrations for brief periods. Inhal Toxicol 1990; 2: 53-57.

19. Faule KJ, Rossaint R, Keitel M, et al. Successful treatment of severe adultrespiratory distress syndrome with nitric oxide—the first three

patients. Second International Meeting on the Biology of Nitric Oxide,London, October, 1991.

20. Buckberg GD, Haybron DM, Matheis G, Sherman MP, Ignarro LJ.Myocardial reoxygenation injury after ischaemia is mediated by theL-arginine-nitric oxide pathway. Second International Meeting on theBiology of Nitric Oxide. London, October, 1991.

21. Lefer AM. Cytoprotective actions of nitric-oxide and NO donors inischaemia-reperfusion of coronary and splanchnic circulations. SecondInternational Meeting on the Biology of Nitric Oxide. London,October, 1991.

22. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA.Apparent hydroxl radical production by peroxynitrite: implications forendothelial injury from nitnc oxide and superoxide. Proc Natl Acad SciUSA 1990; 87: 1620-24.

23. Randall MD, Griffith TM. Does EDRF have a role in collateral

perfusion following arterial occlusion? Second International Meetingon the Biology of Nitric Oxide. London, October, 1991.

More bad luck for the X chromosome:&agr;-thalassaemia/mental retardation

Once again the X chromosome stands accused ofharbouring the locus of a mental retardation

syndrome. It has long been recognised that severeretardation is more common in males than females,and a substantial proportion of this excess is nowknown to be attributable to sex-linked disorders, mostnotably the fragile X syndrome.1 To an already longlist we can now add another entity-thea-thalassaemia/mental retardation (ATR-X)syndrome.The assocation of haemoglobin H (HbH) disease

with mental retardation was first documented in three

boys by Weatherall et al in 1981.2 Subsequent analysisof these three cases plus ten new patients indicatedthat they could be divided into two groups on the basisof clinical, cytogenetic, and molecular fmdings. Ineight patients (six male and two female) there was adeletion involving the ot-globin gene complex onchromosome 16p.3 These individuals had mild tomoderate mental retardation and variable clinicalabnormalities that reflected different degrees ofchromosome imbalance.

By contrast, no abnormality of the a-globin genescould be identified in blood from the second group(five patients), all of whom were severely retarded.4These patients had a similar and unusual facial

appearance: microcephaly, hypertelorism, mid-facehypoplasia, and pouting lower lip. A review of sixteenpublished cases5 confirms that other common findingsinclude a high frequency of convulsions, genitalabnormalities, neonatal hypotonia, and short stature.Curiously, the HbH disease in these patients takes avery mild form; the haematological indices may evenbe normal. Absence of HbH on electrophoresis doesnot exclude the diagnosis, which is best achieved byidentification of HbH inclusions in red cells afterincubation at room temperature with 1% brilliant

cresyl blue.The observation that all the non-deletion patients

were chromosomal males (the only "female" had a 46,XY karykotype) rapidly prompted suggestions thattheir condition might be due to a mutation on theX-chromosome.4,6 Absolute confirmation of X-

linkage is still awaited, but reports of several families7-9with multiple affected males related through healthyfemales provide strong circumstantial evidence forsex-linked recessive inheritance. But how might amutation on the X chromosome influence the

synthesis of a-globin chains coded for by genes on

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chromosome 16? The answer is likely to involve aregulatory protein coded by the X chromosome whichinfluences expression of the a-globin genes. Theelucidation of this trans acting factor should providean important insight into morphogenesis and theorigins of associated mental retardation. With a littleluck this accident of nature may lead to much bettei

understanding of the mysterious sequence of eventlinking genotype with phenotype.

1. Neri G, Gurrieri F, Gal A, Lubs HA. XLMR genes: update 1990. Am JMed Genet 1991; 38: 186-89.

2. Weatherall DJ, Higgs DR, Bunch C, et al. Hemoglobin H disease andmental retardation—a new syndrome or a remarkable coincidence? NEngl J Med 1981; 305: 607-12.

3. Wilkie AOM, Buckle VJ, Harris PC, et al. Clinical features and molecularanalysis of the &agr; thalassemia/mental retardation syndromes. I. Casesdue to deletions involving chromosome band 16p13.3. Am J HumGenet 1990; 46: 1112-26.

4. Wilkie AOM, Zeitlin HC, Lindenbaum RH, et al. Clinical features andmolecular analysis of the &agr; thalassemia/mental retardation syndromes.II. Cases without detectable abnormality of the &agr; globin complex. Am JHum Genet 1990; 46: 1127-40.

5. Gibbons RJ, Wilkie AOM, Weatherall DJ, Higgs DR. A newly defined Xlinked mental retardation syndrome associated with &agr; thalassaemia.J Med Genet 1991; 28: 729-33.

6. Harvey MP, Kearney A, Smith A, Trent RJ. Occurrence of the &agr;

thalassaemia-mental retardation syndrome (non-deletional type) in anAustralian male. J Med Genet 1990; 27: 577-81.

7. Cole TRP, May A, Hughes HE. &agr; thalassaemia/mental retardationsyndrome (non-deletional type): report of a family supporting X linkedinheritance. J Med Genet 1991; 28: 734-37.

8. Wilkie AOM, Gibbons RJ, Higgs DR, Pembrey ME. X linked &agr;

thalassaemia/mental retardation: spectrum of clinical features in threerelated males. J Med Genet 1991; 28: 738-41.

9. Donnai D, Clayton-Smith J, Gibbons RJ, Higgs DR. The non-deletion &agr;thalassaemia/mental retardation syndrome: further support for Xlinkage. J Med Genet 1991; 28: 742-45.

Bile acids, diarrhoea, and SeHCAT

Bile acids are reabsorbed by an active transportmechanism in the terminal ileum as part of an

enterohepatic circulation. There is also some passivediffusion in the proximal small intestine and colon.Ileal malabsorption can lead to failure of colonicsodium reabsorption, a consequent reduction in waterabsorption, and thus colonic-type diarrhoea. Thischolegenic diarrhoea, which is due to the presence inthe colon of the two dihydroxy bile acids,chenodeoxycholic acid and deoxycholic acid, occurswhen the dihydroxy bile acid concentration in theaqueous faecal phase is greater than 1-5 mmol/1.1Three types of bile acid malabsorption are recognised.Type 1 follows ileal resection or disease (mostcommonly Crohn’s disease) or terminal ileal bypass.Type 2 is due to primary idiopathic malabsorption. Inthis type increased production of bile acids mayoverwhelm the normal ileal transport system or there

may be a selective abnormality in the active ileal

transport of bile acids. The latter possibility is morelikely. This variety of malabsorption seems to be anacquired condition; variation in severity of symptomsmay reflect the colonic pH and concentration ofdihydroxy bile acids from day to day. Type 3 is

associated with cholecystectomy, previous pepticulcer surgery, chronic pancreatitis, coeliac disease,and diabetes mellitus. All types are rare.

7sSe-Iabelled homocholic acid conjugated withtaurine C5SeHCA T) can be used to measure bile acidpool loss. Tauroselcholic acid does not occur naturallybut is an analogue of the naturally occurring bile acidconjugate, taurocholic acid. The physiologicalbehaviour of this analogue is identical to that oftaurocholic acid. The taurine conjugate is moreresistant to deconjugation than the glycine conjugate,and SeHCAT is thought to be absorbed specificallyby the active mechanism in the terminal ileum. Afteroral administration, it becomes mixed with the

endogenous bile acid pool. Malabsorption can beassessed by regular faecal collections or, preferably, byassessing seven-day retention; the manufacturers

(Amersham) suggest that the lower level of retentionfor normal individuals is 19%. The SeHCAT testcorrelates closely with the direct measurement offaecal bile acid excretion, and is much easier to do.3 Itis more sensitive than the older 14C-glycocholatebreath test4 for the detection of bile acid

malabsorption and is not associated with any side-effects.The SeHCAT test has been used to ascertain the

incidence of type 2 primary idiopathic malabsorptionof bile acids in patients with diarrhoea of obscureorigin. This condition is thought to be very rare-eg,one centre with a special interest saw only 12 cases inten years.s The Edinburgh group have now measuredthe seven-day retention opsSeHCA Tin 181 patientswith chronic diarrhoea that was unexplained after fullinvestigation between 1982 and 1989.6 23 patients hadsevere bile acid malabsorption, with a seven-dayretention of 75SeHCAT of less than 5%. All these

patients complained of intermittent watery diarrhoeaand 11 of the 23 had diarrhoea during the night. Themean daily stool weight was 450 g (range 400-800 g)and mean daily stool frequency was 8 (range 4-12).The diarrhoea in these patients was of variableduration, had begun abruptly, and was not associatedwith constitutional upset; in 2 patients diarrhoea hadstarted when they were abroad.There was an excellent response to treatment with

cholestyramine in divided doses in nearly all the

patients; mean dose was 12 g daily with a maximumof 24 g. 2 other patients responded to aluminiumhydroxide. Researchers have previously noted thattreatment with other drugs, especially antidiarrhoealssuch as loperamide, is ineffective. Another 16 patientshad moderate bile acid malabsorption, with a seven-day 7sSeHCAT retention of 5-10%. None of thesepatients had nocturnal diarrhoea. 25% of the treatedpatients responded to cholestyramine 12 g/day and25% to aluminium hydroxide. The Edinburghworkers concluded that all the patients in the severegroup and some in the moderate group had primarytype 2 malabsorption. 21 patients had mild bile acidmalabsorption, which was thought to have the