680

10 patients with gynaecological cancers were studied. They hadhad more than 5 episodes of vomiting during the first 24 h of theirfirst chemotherapy cycle despite antiemetic prophylaxis. In thenext cycle, propofol was infused at 1 mg/kg per hour, starting 4 hbefore chemotherapy and continuing for 24 h after. Rescue

(metoclopramide 1 mg/kg intravenously) was instituted in the caseof more than 5 emetic episodes per 24 h (treatment failure). Totalcontrol was defined as no vomiting, retching, or nausea in the first24 h. Major control constituted 1-2 vomiting or retching episodesand minor control, 3-5 vomiting or retching episodes per 24 h.The addition of propofol increased the number of patients free of

vomiting in the first 24 h post-chemotherapy from 0 in the controlcycle to 9 in the propofol cycle. The tenth patient had major control.A small increase in sedation was observed in 1 patient. Slight andtransient burning at the forearm infusion site occurrred at thebeginning of propofol infusion in 1 patient. All patients preferredpropofol-supplemented antiemesis for future chemotherapy.Our patients were a subgroup who were not responsive to the

most reliable currently available antiemetics. The addition of alow-dose propofol infusion to the 5-HT3 antagonist anddexamethasone resulted in improved antiemetic control duringcisplatin chemotherapy.

Departments of Anaesthesiologyand Gynaecology and Obstetrics,

Geneva University Hospital,1211 Geneva, Switzerland, and

University Department of Gastroenterology,Inselspital Bern

A. BORGEATO. H. G. WILDER-SMITHC. H. WILDER-SMITHM. FORNIP. M. SUTER

1 Gralla RJ, Itri LM, Pisko SE, et al Antiemetic efficacy of high-dose metoclopramide.N Engl J Med 1981, 305: 905-09.

2. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5HT3 antagonist ondansetronwith high-dose metoclopramide in the control of cisplatin-induced emesis N Engl JMed 1990; 322: 816-22.

3. McCollum JS, Milligan KR, Dundee JW The antiemetic action of propofolAnaesthesia 1988; 43: 239-40.

4. Borgeat A, Wilder-Smith OHG, Saiah S, Rifat K Subhypnotic doses of propofolpossess direct antiemetic properties Anesth Analg 1992; 74: 539-41.

5. Smith DB, Newlands ES, Rusint GJS, et al. Comparison of ondansetron andondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy Lancet 1991; 338: 487-90

Cystic fibrosis mouse with intestinalobstruction

SIR,-Cystic fibrosis is characterised by excess mucus in thelungs, intestinal obstruction (meconium ileus), reduced ability todigest and absorb duodenal contents because of pancreaticinsufficiency, male sterility, and elevated salt in sweat. The mutatedgene, the cystic fibrosis transmembrane conductance regulator(cftr), encodes a chloride channel.1,2 Many mutations have beendescribed in the human cftr gene, including missense, nonsense,splice site alterations, and frameshift deletions and insertions. Wehave inserted a disrupting genetic element into the mouse cftr locusin embryonal stem cells3 and derived mice carrying a disrupted cftrallele.

Heterozygote carriers were fertile and showed the expected 1/1 segregation of the normal:disrupted cftr allele. The genotypes of theF2 pups were not statistically different from the expected 1/2/1 ratioof wild-type/carrier/homozygote, which indicates that there is noprenatal lethality associated with homozygosity of this mutant allele.Postnatally, however, many homozygote pups failed to thrive anddied 2-5 days after birth:

Genotype Lme (exp) Dead (exp) Totals

+/+

14 1 } 35 (29) 3 } 12 (18) 17

+; - 21 9 30- /- 5 (11) 13 (7) 18

exp = expected

Postnatal death of homozygotes was significantly correlated withthe absence of a normal cftr allele (p < 0-005, X2). These pups hadsuckled and had a full stomach and distended gut. Their failure tothrive suggests poor food assimilation. The figure (2 and 3) showsthe distended gut, apparently blocked in the ileum by meconium, ofa homozygous pup that failed to thrive. In general, the fewhomozygotes that survived the immediate neonatal period also

Intestine of normal and homozygous null cftr mice.

1 =normal, day 5, stomach (S) contains milk 2 = homozygous cftrmutant, day 5, showing meconium (M) blockage of ileum observedthrough peritoneum 3=2 dissected through peritoneum to showdistended proximal intestine (DG); 4=normal, day 17, normal caecum(C) is filled with food, and 5= homozygous cftr mutant, day 17, caecumcontains little food, jejunum (B) is blocked

failed to thrive. At day 17 one of these showed an intestinalobstruction in the jejunum and a reduced caecum (figure, 4 and 5).This second-stage blockage is similar in onset to the meconium ileusequivalent observed in older patients with cystic fibrosis.

Kristidis et al4 demonstrated that nonsense, frameshift, or splicejunction cftr mutations are associated with severe phenotypes mcystic fibrosis patients, including a severe pancreatic insufficiencyphenotype. We would therefore expect this mutation in mice to giverise to a severe phenotype with pancreatic insufficiency. In somesuch severely affected human cases, one of the earliest pathologicalmanifestations is meconium ileus. We interpret the early death ofmost of the homozygous mice to be due to such a condition. As inthe human syndrome, some homozygous animals did not show thiscondition immediately; presumably any incipient blockage iscleared. Some developed intestinal blockages later. The variation inphenotypic penetrance between homozygotes possibly reflects thegenetically diverse background of the animals and in this respectmore closely resembles the situation in the outbred human

population. Crosses have been set up to maintain the null cftr alleleon a known inbred genetic background, which should allowcontrolled investigations to examine the influence of geneticbackground on expression and penetrance.

This mutation in the murine cftr locus provides an animal modelfor the most common autosomal recessive disease in north

Europeans. Other mutations experimentally introduced into themouse cftr locus may lead to phenotypes that more closely parallelthe milder forms of cystic fibrosis (eg, infertility only). Theavailability of these mutant mice should greatly facilitate tests ofnew drugs and gene therapies.We thank the Cystic Fibrosis Trust and the Wellcome Trust for support

and the animal-house staff for husbandry. We also thank Alan Cuthbert forhelpful advice, and all members of M. J. Evans’ laboratory.

Wellcome/CRC Institute of Cancerand Developmental Biology,

University of Cambridge,Cambridge CB2 1QR, UK,and Department of Biochemistryand Molecular Genetics,

St Mary’s Hospital Medical School,London W2

WILLIAM H. COLLEDGEROSEMARY RATCLIFFDIANE FOSTERROBERT WILLIAMSONMARTIN J. EVANS

1. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis genecloning and characterisation of complementary DNA Science 1989, 245: 1066-73.

2 Kerem B, Rommens JM, Buchanan JA, et al Identification of the cystic fibrosis genegenetic analysis. Science 1989; 245: 1073-80.

3. Ratcliff R, Evans MJ, Doran J, Wainwright BJ, Williamson R, Colledge WH.Disruption of the cystic fibrosis transmembrane conductance regulator gene inembryonic stem cells of gene targeting. Transplant Res 1992, 1: 177-81

4 Kristidis P, Bozon D, Corey M, et al. Genetic determination of exocrine pancreaticfunction in cystic fibrosis. Am J Hum Genet 1992; 50: 1178-84