flucytosine were reintroduced. When the central venous line Cglabrata was grown from the tip. It was also isolated from repeat blood cultures over the next 10 days. The thrombocytopenia persisted and the liver function abnormalities increased. The baby still required ventilation on day 23, when the metabolic acidosis returned. The filter in the total parenteral nutrition line was also contaminated with C glabrata. Liposomal amphotericin B was substituted for conventional amphotericin B because higher doses could not be achieved safety. The dose was 1 mg/kg every 24 h, increasing to 2 mg/kg every 24 h after 48 h. The infusion time was only 30 min (versus 6 h for the conventional form). Blood cultures became sterile 2 days after the increase in the dose. Flucytosine was discontinued on day 36 and liposomal amphotericin B on day 44. The baby was discharged home at 94 days of age and after 6 months remains well with normal and

was removed

liver function. This case illustrates

potential benefits of liposomal the B-namely, higher dose without apparent amphotericin increased toxic effects and smaller infusion volumes and shorter infusion times, which are important in the sick baby. We thank Vestar Inc,

Taunton and Somerset Taunton TA1 5DA, UK


California, for providing liposomal amphotericin B.



1. Tollemar J, Duraj F, Ericzon BG. Liposomal amphotericin B treatment in a 9-monthold liver recipient. Mycoses 1990; 33: 251-52.

Microinsemination by sperm transfer SIR,-In-vitro fertilisation (IVF) has been successful for couples where the male consistently produces suboptimum semen, but it is not always successful and in our experience semen often is of such poor quality that IVF is not even attempted. Case-reports1,2 on the micromanipulation of gametes to enhance fertilisation for treatment of male infertility have appeared. Fishel et al3 showed that microinsertion of sperm under the zona pellucida resulted in a significantly higher fertilisation rate than conventional IVF with the same semen. An average of 3-4 sperm were injected giving a fertilisation rate of 15%. However, the low pregnancy rate of 3-5% of patients treated and 6-5% for those undergoing embryo transfer offered "only a glimmer of hope".3 We report more encouraging experience with the microinsemination of oocytes by sperm transfer (MIST) where conventional IVF was not a realistic option. 45 patients (60 cycles) were treated from February, 1990, to May, 1991. 40 couples displayed male infertility well below the WHO guidelines’ for concentration, motility, and morphology (normal >20 x 106/ml, > 50%, and > 50%, respectively). A deficiency in one index was classified as single defect, two as double, and three as triple. In 18 couples IVF had previously failed, and all the other couples were deemed not suitable for conventional IVF, on the basis of our clinical experience. Gamete collection and embryo culture were as previously described5 except that all women had ovarian stimulation by daily leuprolide acetate in conjunction with follicle-stimulating hormone or human menopausal gonadotropin. When the semen sample was contaminated with other cell types and debris, or when the sperm count was less than 106/ml, spermatozoa were prepared by discontinuous ’Percoll’ density gradient centrifugation.6 The equipment for micromanipulation was as previously described? Injection was completed in "hepes" buffered HTF medium with 10% v/v maternal serum on a siliconised depression slide. One or two oocytes were placed in a 100 nl drop and the insemination medium containing prepared sperm was placed next to it. Both were covered with paraffin oil. Spermatozoa, from 20 to 50, were collected into an injection pipette (internal diameter 5-10 µm). With the oocyte held in place by a holding pipette (external diameter 100 µm), so that the first polar body was at 12 o’clock, the injection pipette was inserted under the zona pellucida horizontally near the polar body. 5-30 sperm were injected into the perivitelline space in each oocyte. 34 of the 45 patients treated had at least one oocyte fertilised; 14 became pregnant for a pregnancy rate of 23% per oocyte retrieval

cycle. This compares more than favourably with conventional IVF success

rates.8 The fertilisation

compensated by


rate was

remarkably high

low but

seems to

pregnancy rate per




Fertilisation and pregnancies occurred for all three defect 15-20 sperm seems to be the ideal number, achieving a fertilisation rate of 30-35 %. Of the 25 patients with severe double or triple sperm defect (concentration range 0-5-10 x 106/ml, motility 4-30%, morphological normality 10-30%), 19 (76%) achieved fertilisation after IVF. Of those couples who had previously failed fertilisation with conventional IVF, 12 achieved successful fertilisation. MIST is neither time-consuming nor complex, and gametes are subjected to not much more stress than after IVF. This technique does not damage the membrane of oocytes ;9 nor does it result in an increase in chromosomal abnormalities. 10 Other techniques of gamete micromanipulation (zona drilling or dissection) require sperm of reasonable motility and number. MIST method can be applied even for sperm that are not motile (confirmed by fertilisation achieved in one patient in this trial having impaired motility due to immotile cilia syndrome). The high pregnancy rates reported here, together with the observation that fertilisation and pregnancies occurred even in severe asthenospermic, oligospermia, and teratozoospermia, suggest that MIST could be considered an option for some forms of male infertility.


Human Reproduction Unit, Departments of Physiology and Obstetrics and Gynaecology, Univeristy of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia


J, Malter H, Fehilly C, et al. Implantation of embryos after partial opening of oocyte zona pellucida to facilitate sperm penetration. Lancet 1988; h: 162. 2. Ng SC, Bongso A, Ratnam SS, et al. Pregnancy after transfer of sperm under zona. Lancet 1988; ii: 790. 3. Fischel S, Jacson P, Antinori S, Johnson J, Grossi S, Versed C. Subzonal insemination for the alleviation of infertility. Fertil Steril 1990; 54: 828-35. 4. World Health Organisation. WHO laboratory manual for examination of human semen and semen-cervical mucus interaction. Cambridge: Cambridge University Press, 1987. 5. O’Neill C, Collier M, Ammit AJ, Ryan JP, Saunders DM, Pike IL. Supplementation of in-vitro fertilisation culture medium with platelet activating factor. Lancet 1989; ii: 769-71. 6. Hyne RV, Stojanoff A, Clarke GN, Lopata A, Johnston WIH. Pregnancy from in vitro fertilisation of human eggs after separation of motile spermatozoa by density gradient centrifugation. Fertil Steril 1986; 45: 93-96. 7. Krzyminska U, Lutjen J, O’Neill C. Assessment of viability and pregnancy potential of mouse embryos biopsied at different preimplantation stages of development. Hum Reprod 1990; 5: 203-08. 8. National Perinatal Statistics Unit and Fertility Society of Australia. IVF and GIFT pregnandes: Australia and New Zealand, 1987. National Statistics Unit (Australia), 1988. 9. Laws-King A, Trounson A, Sathananthan H, Kola I. Fertilization of human oocytes by microinjection of a single spermatozoon under the zona pellucida. Fertil Steril 1987; 48: 637-42. 10. Kola I, Lacham O, Jansen RPS, Turner M, Trounson A. Chromosomal analysis of human occytes fertilized by microinjection of spermatozoa into the perivitelline space. Hum Reprod 1990; 5: 575-77. 1. Cohen

Control of emesis in bowel obstruction in terminally ill patients SIR,-Vomiting secondary to bowel obstruction is a substantial problem in terminally ill patients with cancer. We have investigated the role of the somatostatin analogue octreotide (Sandoz) in this condition because it reduces intestinal secretions1 and has a direct proabsorptive effect on water and ions in the intestineWe report our preliminary observations in 5 patients with intractable continual



tds=thrice daily.

vomiting caused by small bowel obstruction in the presence of known intra-abdominat malignant disease. The diagnosis of intestinal obstruction was made on clinical grounds and confirmed by plain abdominal radiography, and in 2 patients was also supported by a barium follow-through examination (patients 4 and 5 in table). These patients were terminally ill and surgery was therefore inappropriate. Their vomiting was unresponsive to conventional therapy with prochlorperazine, metoclopramide, cyclizine, and dexamethasone. Several regimens of octreotide were used, beginning with single subcutaneous injection and usually followed by continuous infusion. In every patient, vomiting ceased within 1 hour of start of treatment and, apart from 2 patients in whom treatment was interrupted because of a lack of supplies, symptom relief continued until death. These 2 patients (2 and 3 in table) began vomiting 12 hours after treatment ceased but immediately stopped vomiting once treatment was restarted. 1 patient (5) had a nasogastric tube placed to palliate the vomiting and a striking reduction in aspirate was documented (from about 1000-2000 ml daily to under 300 ml daily) at the time octreotide was started. There was no important toxicity from treatment. Further investigation of the activity of octreotide in this condition is continuing. Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0NN, UK



1. Bloom SR, Polak JM. Somatostatin. Br Med J 1987; 295: 288-90. 2. Anthone GJ, Bastidas A, Orandle MS, Yeo CJ. Direct proabsorptive effect of octreotide on ionic transport in the small intestine. Surgery 1990; 108: 1136-42.

Blood lead in children SiR,—In 1991 the US Centers for Disease Control (CDC) made drastic downward revision to the "intervention level" for blood lead in children, from 25 to 10 g/dl (1 g/dl= 0-048 imol/1). Canada and most European countries have action levels in the 20-25 ug/dl range, usually with the advice that where a person especially a child, is found to have a blood lead concentration over 25 Lg/di, their environment should be investigated and steps taken to reduce lead exposure. With the CDC figure of 10 J-lgfdl it has been estimated that 17% of American children (3 or 4 million) are now "at neurotoxic risk, regardless of race or socioeconomic status".1 What is the impact of the CDC revision likely to be? Is it technically possible to reduce blood lead levels in all children to below 10 J-lgfdl? If "yes", then at what cost to other health priorities? If "no", then at what psychological cost to anxious families? In the WHO/EEC multicentre study on lead neurotoxicity2 in almost 2000 school-age children blood lead concentrations ranged from below 5 (ig/dl to 60 ug/dl. Some neurobehavioural tests showed significant associations with blood lead values but the contribution of the lead concentration to the observed variance in the tests was less than 1%. Psychometric tests of intelligence showed only borderline significance, and there was poor consistency between the eight participating centres. In the UK the 1988 report from the Medical Research Council’s advisory group concluded that "the observed statistical associations detailed in this report are consistent with the hypothesis that low level exposure has a small negative effect on the performance of children in ability and attainment tests; however the limitations of epidemiological studies in drawing causal inferences are such that it is not possible to conclude that exposure to lead at current urban levels is definitely harmful". Nonetheless, along with most other similar bodies, the a

advisory group recommended that "it is prudent

to continue to reduce the environmental lead to which children are exposed". We much prefer this approach to that of the CDC, which, however well-intentioned, seems to run the risk of increasing psychological damage to children and parents by the widespread labelling of children as having "neurotoxicity" on the basis of blood lead concentrations as low as 10 J-lgfdl.

Department of Health Care and Epidemiology, University of British Columbia, Vancouver, Canada V6T 1Z3


poisoning: a disease for history texts. Am J Publ Health 1991; 81: 685. 2. Winneke G, Brockhaus A, et al Results from the European multicenter study on lead neurotoxicity in children: implications for risk assessment. Neurotoxicol Teratol 1. Needleman HL. Childhood lead

1990; 12: 553. 3. Smith M. The neuropsychological effects of lead m children a review of the research 1984 to 1988: report from the MRC Advisory Group on lead and neuropsychological effects in children. London Medical Research Council, 1988.

Side-effects of octreotide withdrawal SIR,-Dr James and colleagues (Dec 14, p 1527) emphasise the possible adverse effect of rebound gallbladder hypercontractility after abrupt cessation of long-term octreotide treatment. They state that this is "a previously unknown side-effect" of the drug, yet two

previous reports have drawn attention to this possible side-effect. Puel-Bousquet et all described a case of acute cholecystitis following octreotide withdrawal, and we2 reported a case of biliary colic leading to acute pancreatitis in the same therapeutic setting. James and colleagues’ recommendations to avoid this effect are sound, especially those of the once-a-week day-off treatment and the combined use of octreotide and ursodeoxycolic acid, which has also been advocated by others.3 However, one should remember that the day-off treatment may precipitate acute deterioration of diabetes.4 Since continuous subcutaneous administration is often used (the daily dose is then reduced) the between-meals injection regimen seems less appropriate. Finally, these prophylactic measures would not be suitable with longlasting somatostatin analogues such as somatuline.5 Therefore, as James et al emphasise, there is an urgent need to identify the acromegalic patients who are prone to stone formation. Investigating the reasons for a discrepancy between acromegalic and non-acromegalic patients in the prevalence of drug-induced biliary stones after long-term octreotide treatment may be the correct way to address this issue. Also, the development of drugs targeting the pituitary, based on coupling the drug with antireceptor monoclonal immunoglobulins, may eventually help to avoid extrapituitary major side-effects that mav appear after only one day of treatment .6 J.-L. SADOUL Department of Internal Medicine, D. BENCHIMOL Diabetology, and Endocrinology, A. THYSS Hôpital Pasteur, P. FREYCHET 06002 Nice, France Puel-Bousquet C, Bucsaill L, Harris AG, Ribert A, Bayard F, Tauber JP. Incidence de la microlithiase vésiculaire lors du traitement par Sandostatine (SMS) en infusion sous-cutanée continue (ISCC). Ann Endocrinol 1989; 50: 22. 2. Sadoul J-L, Benchimol D, Thyss A, Freychet P. Acute pancreatitis following octreotide withdrawal. Am J Med 1991; 90: 763-64. 3. Buscaill L, Tauber J-P, Puel-Bousquet C, et al. Gallstones and treatment with octreotide in acromegaly. Br Med J 1989; 299: 1162. 4. Abrahamson MJ. Death from diabetic ketoacidosis after cessation of octreotide in acromegaly. Lancet 1990; 336: 318-19. 5. Heron I, Thomas F, Lefur J-J, et al. Somatuline (BIM 23014) à libération prolongée: Pharmacocinétique et effets sur la sécrétion d’hormone de croissance et d’IGFI chez l’acromégale. Ann Endocrinol 1991; 52: 169. 6. Fredenrich A, Sosset C, Bernard J-L, Sadoul J-L, Preychet P. Acute pancreatitis following short-term administration of octreotide. Lancet 1991; 337: 238. 1.

Control of emesis in bowel obstruction in terminally ill patients.

375 flucytosine were reintroduced. When the central venous line Cglabrata was grown from the tip. It was also isolated from repeat blood cultures ove...
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