680
10 patients with gynaecological cancers were studied. They had had more than 5 episodes of vomiting during the first 24 h of their first chemotherapy cycle despite antiemetic prophylaxis. In the next cycle, propofol was infused at 1 mg/kg per hour, starting 4 h before chemotherapy and continuing for 24 h after. Rescue (metoclopramide 1 mg/kg intravenously) was instituted in the case of more than 5 emetic episodes per 24 h (treatment failure). Total control was defined as no vomiting, retching, or nausea in the first 24 h. Major control constituted 1-2 vomiting or retching episodes and 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 control cycle to 9 in the propofol cycle. The tenth patient had major control. A small increase in sedation was observed in 1 patient. Slight and transient burning at the forearm infusion site occurrred at the beginning of propofol infusion in 1 patient. All patients preferred propofol-supplemented antiemesis for future chemotherapy. Our patients were a subgroup who were not responsive to the most reliable currently available antiemetics. The addition of a low-dose propofol infusion to the 5-HT3 antagonist and dexamethasone resulted in improved antiemetic control during
cisplatin chemotherapy. A. BORGEAT O. H. G. WILDER-SMITH C. H. WILDER-SMITH M. FORNI P. M. SUTER
Departments of Anaesthesiology and Gynaecology and Obstetrics, Geneva University Hospital, 1211 Geneva, Switzerland, and
University Department of Gastroenterology, Inselspital Bern 1 Gralla RJ, Itri
LM, Pisko SE, et al Antiemetic efficacy of high-dose metoclopramide. N Engl Med 1981, 305: 905-09. J 2. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5HT3 antagonist ondansetron with high-dose metoclopramide in the control of cisplatin-induced emesis N Engl J Med 1990; 322: 816-22. 3. McCollum JS, Milligan KR, Dundee JW The antiemetic action of propofol Anaesthesia 1988; 43: 239-40.
Borgeat A, Wilder-Smith OHG, Saiah S, Rifat K Subhypnotic doses of propofol possess direct antiemetic properties Anesth Analg 1992; 74: 539-41. 5. Smith DB, Newlands ES, Rusint GJS, et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatincontaining chemotherapy Lancet 1991; 338: 487-90
4.
Cystic fibrosis
mouse
with intestinal
obstruction SIR,-Cystic fibrosis is characterised by excess mucus in the lungs, intestinal obstruction (meconium ileus), reduced ability to digest and absorb duodenal contents because of pancreatic insufficiency, male sterility, and elevated salt in sweat. The mutated gene, the cystic fibrosis transmembrane conductance regulator (cftr), encodes a chloride channel.1,2 Many mutations have been described in the human cftr gene, including missense, nonsense, splice site alterations, and frameshift deletions and insertions. We have inserted a disrupting genetic element into the mouse cftr locus in embryonal stem cells3 and derived mice carrying a disrupted cftr allele.
Heterozygote carriers were fertile and showed the expected 1/1 segregation of the normal:disrupted cftr allele. The genotypes of the F2 pups were not statistically different from the expected 1/2/1ratio of
wild-type/carrier/homozygote,
which indicates that there is
no
prenatal lethality associated with homozygosity of this mutant allele. Postnatally, however, many homozygote pups failed to thrive and died 2-5 days after birth: Genotype +/+ +; -
exp =
/-
Lme
(exp)
14 1
21 5
}
35 (29) (11)
Dead
3 } 9
13
(exp)
Totals 17
12 (18)
(7)
30 18
Intestine of normal and homozygous null cftr mice.
day 5, stomach (S) contains milk 2 = homozygous cftr day 5, showing meconium (M) blockage of ileum observed through peritoneum 3=2 dissected through peritoneum to show distended proximal intestine (DG); 4=normal, day 17, normal caecum (C) is filled with food, and 5= homozygous cftr mutant, day 17, caecum contains little food, jejunum (B) is blocked 1 =normal,
mutant,
failed to thrive. At day 17 one of these showed an intestinal obstruction in the jejunum and a reduced caecum (figure, 4 and 5). This second-stage blockage is similar in onset to the meconium ileus equivalent observed in older patients with cystic fibrosis. Kristidis et al4 demonstrated that nonsense, frameshift, or splice junction cftr mutations are associated with severe phenotypes m cystic fibrosis patients, including a severe pancreatic insufficiency phenotype. We would therefore expect this mutation in mice to give rise to a severe phenotype with pancreatic insufficiency. In some such severely affected human cases, one of the earliest pathological manifestations is meconium ileus. We interpret the early death of most of the homozygous mice to be due to such a condition. As in the human syndrome, some homozygous animals did not show this condition immediately; presumably any incipient blockage is cleared. Some developed intestinal blockages later. The variation in phenotypic penetrance between homozygotes possibly reflects the genetically diverse background of the animals and in this respect more closely resembles the situation in the outbred human population. Crosses have been set up to maintain the null cftr allele on a known inbred genetic background, which should allow controlled investigations to examine the influence of genetic background on expression and penetrance. This mutation in the murine cftr locus provides an animal model for the most common autosomal recessive disease in north Europeans. Other mutations experimentally introduced into the mouse cftr locus may lead to phenotypes that more closely parallel the milder forms of cystic fibrosis (eg, infertility only). The availability of these mutant mice should greatly facilitate tests of new 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 for helpful advice, and all members of M. J. Evans’ laboratory.
Wellcome/CRC Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge CB2 1QR, UK, and Department of Biochemistry and Molecular Genetics, St Mary’s Hospital Medical School, London W2
WILLIAM H. COLLEDGE ROSEMARY RATCLIFF DIANE FOSTER ROBERT WILLIAMSON MARTIN J. EVANS
expected
Postnatal death of homozygotes was significantly correlated with the absence of a normal cftr allele (p < 0-005, X2). These pups had suckled and had a full stomach and distended gut. Their failure to thrive suggests poor food assimilation. The figure (2 and 3) shows the distended gut, apparently blocked in the ileum by meconium, of a homozygous pup that failed to thrive. In general, the few homozygotes that survived the immediate neonatal period also
JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene cloning and characterisation of complementary DNA Science 1989, 245: 1066-73. Kerem B, Rommens JM, Buchanan JA, et al Identification of the cystic fibrosis gene genetic analysis. Science 1989; 245: 1073-80. Ratcliff R, Evans MJ, Doran J, Wainwright BJ, Williamson R, Colledge WH. Disruption of the cystic fibrosis transmembrane conductance regulator gene in embryonic stem cells of gene targeting. Transplant Res 1992, 1: 177-81 Kristidis P, Bozon D, Corey M, et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992; 50: 1178-84
1. Riordan 2
3.
4
10 patients with gynaecological cancers were studied. They had had more than 5 episodes of vomiting during the first 24 h of their first chemotherapy cycle despite antiemetic prophylaxis. In the next cycle, propofol was infused at 1 mg/kg per hour, starting 4 h before chemotherapy and continuing for 24 h after. Rescue (metoclopramide 1 mg/kg intravenously) was instituted in the case of more than 5 emetic episodes per 24 h (treatment failure). Total control was defined as no vomiting, retching, or nausea in the first 24 h. Major control constituted 1-2 vomiting or retching episodes and 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 control cycle to 9 in the propofol cycle. The tenth patient had major control. A small increase in sedation was observed in 1 patient. Slight and transient burning at the forearm infusion site occurrred at the beginning of propofol infusion in 1 patient. All patients preferred propofol-supplemented antiemesis for future chemotherapy. Our patients were a subgroup who were not responsive to the most reliable currently available antiemetics. The addition of a low-dose propofol infusion to the 5-HT3 antagonist and dexamethasone resulted in improved antiemetic control during
cisplatin chemotherapy. A. BORGEAT O. H. G. WILDER-SMITH C. H. WILDER-SMITH M. FORNI P. M. SUTER
Departments of Anaesthesiology and Gynaecology and Obstetrics, Geneva University Hospital, 1211 Geneva, Switzerland, and
University Department of Gastroenterology, Inselspital Bern 1 Gralla RJ, Itri
LM, Pisko SE, et al Antiemetic efficacy of high-dose metoclopramide. N Engl Med 1981, 305: 905-09. J 2. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5HT3 antagonist ondansetron with high-dose metoclopramide in the control of cisplatin-induced emesis N Engl J Med 1990; 322: 816-22. 3. McCollum JS, Milligan KR, Dundee JW The antiemetic action of propofol Anaesthesia 1988; 43: 239-40.
Borgeat A, Wilder-Smith OHG, Saiah S, Rifat K Subhypnotic doses of propofol possess direct antiemetic properties Anesth Analg 1992; 74: 539-41. 5. Smith DB, Newlands ES, Rusint GJS, et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatincontaining chemotherapy Lancet 1991; 338: 487-90
4.
Cystic fibrosis
mouse
with intestinal
obstruction SIR,-Cystic fibrosis is characterised by excess mucus in the lungs, intestinal obstruction (meconium ileus), reduced ability to digest and absorb duodenal contents because of pancreatic insufficiency, male sterility, and elevated salt in sweat. The mutated gene, the cystic fibrosis transmembrane conductance regulator (cftr), encodes a chloride channel.1,2 Many mutations have been described in the human cftr gene, including missense, nonsense, splice site alterations, and frameshift deletions and insertions. We have inserted a disrupting genetic element into the mouse cftr locus in embryonal stem cells3 and derived mice carrying a disrupted cftr allele.
Heterozygote carriers were fertile and showed the expected 1/1 segregation of the normal:disrupted cftr allele. The genotypes of the F2 pups were not statistically different from the expected 1/2/1ratio of
wild-type/carrier/homozygote,
which indicates that there is
no
prenatal lethality associated with homozygosity of this mutant allele. Postnatally, however, many homozygote pups failed to thrive and died 2-5 days after birth: Genotype +/+ +; -
exp =
/-
Lme
(exp)
14 1
21 5
}
35 (29) (11)
Dead
3 } 9
13
(exp)
Totals 17
12 (18)
(7)
30 18
Intestine of normal and homozygous null cftr mice.
day 5, stomach (S) contains milk 2 = homozygous cftr day 5, showing meconium (M) blockage of ileum observed through peritoneum 3=2 dissected through peritoneum to show distended proximal intestine (DG); 4=normal, day 17, normal caecum (C) is filled with food, and 5= homozygous cftr mutant, day 17, caecum contains little food, jejunum (B) is blocked 1 =normal,
mutant,
failed to thrive. At day 17 one of these showed an intestinal obstruction in the jejunum and a reduced caecum (figure, 4 and 5). This second-stage blockage is similar in onset to the meconium ileus equivalent observed in older patients with cystic fibrosis. Kristidis et al4 demonstrated that nonsense, frameshift, or splice junction cftr mutations are associated with severe phenotypes m cystic fibrosis patients, including a severe pancreatic insufficiency phenotype. We would therefore expect this mutation in mice to give rise to a severe phenotype with pancreatic insufficiency. In some such severely affected human cases, one of the earliest pathological manifestations is meconium ileus. We interpret the early death of most of the homozygous mice to be due to such a condition. As in the human syndrome, some homozygous animals did not show this condition immediately; presumably any incipient blockage is cleared. Some developed intestinal blockages later. The variation in phenotypic penetrance between homozygotes possibly reflects the genetically diverse background of the animals and in this respect more closely resembles the situation in the outbred human population. Crosses have been set up to maintain the null cftr allele on a known inbred genetic background, which should allow controlled investigations to examine the influence of genetic background on expression and penetrance. This mutation in the murine cftr locus provides an animal model for the most common autosomal recessive disease in north Europeans. Other mutations experimentally introduced into the mouse cftr locus may lead to phenotypes that more closely parallel the milder forms of cystic fibrosis (eg, infertility only). The availability of these mutant mice should greatly facilitate tests of new 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 for helpful advice, and all members of M. J. Evans’ laboratory.
Wellcome/CRC Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge CB2 1QR, UK, and Department of Biochemistry and Molecular Genetics, St Mary’s Hospital Medical School, London W2
WILLIAM H. COLLEDGE ROSEMARY RATCLIFF DIANE FOSTER ROBERT WILLIAMSON MARTIN J. EVANS
expected
Postnatal death of homozygotes was significantly correlated with the absence of a normal cftr allele (p < 0-005, X2). These pups had suckled and had a full stomach and distended gut. Their failure to thrive suggests poor food assimilation. The figure (2 and 3) shows the distended gut, apparently blocked in the ileum by meconium, of a homozygous pup that failed to thrive. In general, the few homozygotes that survived the immediate neonatal period also
JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene cloning and characterisation of complementary DNA Science 1989, 245: 1066-73. Kerem B, Rommens JM, Buchanan JA, et al Identification of the cystic fibrosis gene genetic analysis. Science 1989; 245: 1073-80. Ratcliff R, Evans MJ, Doran J, Wainwright BJ, Williamson R, Colledge WH. Disruption of the cystic fibrosis transmembrane conductance regulator gene in embryonic stem cells of gene targeting. Transplant Res 1992, 1: 177-81 Kristidis P, Bozon D, Corey M, et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992; 50: 1178-84
1. Riordan 2
3.
4
