1455

and blood transfusions. These patients survived for 11, 12, and 15 weeks. Even though this is not a statistically valid comparison and the phase II study is still under way, our preliminary results seem very different from those reported by Pyrhonen and Valtonen. It must be emphasised that the dose of 5-fluorouracil we give is a little lower than that reported previously; nevertheless, in our experience, the combination regimen does not appear successful in advanced In

quote Brennan and colleagues’3 words: "a more thorough understanding of the cellular biology of this tumour is needed", since there have been "insufficient effort(s) to correlate laboratory insights with clinical

pancreatic

cancer

patients.

conclusion,

we

had much higher concentrations than the others, and we understand that these two undergo substantially greater thermal manipulation during preparation. The three supplements with aminoacids as their protein source had no measurable immunoreactivity. In 26 volunteers who consumed 240 ml of ’Ensure’ plasma concentration cyclo(His-Pro)-like immunoreactivity rose steadily from 1688 (157) pg/ml before to 2144 (146) pg/ml 1 h after

consumption (p = 0-026). Cyclo(His-Pro) inhibits prolactin production

in vitro at concentrations of 10 0 ng/ml. We conclude that this bioactive peptide is readily detectable in several commonly used nutritional supplements and is possibly absorbed when ingested.

outcome". CAMILLO PORTA GUISEPPE NASTASI ADRIANO SPAGHI MAURO MORONI

Institute of Pathological Medicine I, University of Pavia,

Policlinico "San Matteo", I-27100 Pavia, Italy

JA, Goudeau P, Levin B, et al. Phase II study of adriamycin with sequential methotrexate and 5-fluorouracil (AMF) m gastric carcinoma. Cancer Chemother Phamacol 1989; 24: 41-44. 2. Moertel CG, Reitemeier RJ. Advanced gastrointestinal cancer: clinical management and chemotherapy. New York: Harper & Row, 1969. 3 Brennan MF, Kinsella T, Friedman M. Cancer of the pancreas. In: DeVita V Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 1. Ajani

Philadelphia: JB Lippincott Co,

Cyclo(His-Pro)

1989: 800-36.

in nutritional

supplements

SIR,-Peptides with potential biological activity such as exorphins1 (gluten or casein derived peptides with opioid-like activity) and the tripeptide thyrotropin-releasing hormone (TRH)2 have been found in food. Small peptides are highly resistant to degradation by gastrointestinal enzymes3 and are absorbed when given by mouth.4 Dipeptide diketopiperazines with many biological actions are readily generated by thermal manipulation of protein hydrolysates. Histidyl-proline diketopiperazine (cyclo[His-Pro]), a cyclic dipeptide with several activities, is distributed widely in the central nervous system and gut and has a stereospecific receptor in the liver. In view of the biological activitiess of this dipeptide, its anatomical distribution, and its hepatic receptor we wondered if commonly used nutritional supplements might contain cyclo(His-Pro)-like immunoreactivity. Some supplements contain proteins that are partly hydrolysed and thermally manipulated during manufacture. Eleven supplements were studied, eight being chosen as representative of commonly used supplements (table, 1-8) and three (9-11) because they have simple aminoacids as their protein source. Cyclo(His-Pro)-like immunoreactivity was found in all this casein-containing supplements, activity being from synthetic cyclo(His-Pro) by indistinguishable immunoidentity and analysis on ’Sephadex G-25’ and highpressure liquid chromatography. Concentrations ranged from 123 (15) to 4763 (199) pg/ml supplement, 100 to 5000 times the concentrations reported in human plasma.6 Supplements 6 and 7 CYCLO (HIS-PRO)-LIKE IMMUNOREACTIVITY IN NUTRITIONAL SUPPLEMENTS (MEAN AND SE)

*Made by Ross Laboratories, Columbus, Ohio (1-8), Norwich Eaton, Norwich, New York (9), and Travenol Laboratories, Deerfield, Illinois (10 and 11 ) N D = none detected

LSU Medical Center, New Orleans, Louisiana 70112, USA, and Pennington Biomedical Research Center, Baton Rouge, Louisiana

CHARLES W. HILTON CHANDAN PRASAD FRANK SVEC PHUONG VO SADDA REDDY

1. Ziodrou C, Streaty RA, Klee WA. Opioid peptides derived from food. J Biol Chem 1979; 254: 2446-49. 2. Jackson IMD. Abundance of immunoreactive thyrotropin-releasing hormone-like material in the alfalfa plant. Endocrinology 1981; 108: 344-46. 3. Masson MA, Mcreau O, Deburie B, Rips R. Evidence for the resistance of thyrotropin-releasing hormone (TRH) and pseudo-hormone, pyroglutamyl histidyl-amphetamine to degradation by enzymes of the digestive tract in vitro. Biochemie 1979; 61: 847-52. 4. Staub JJ, Girard J, Mueller-Brand, et al. Blunting of TSH response after repeated oral administration of TRH in normal and hypothyroid subjects. J Clin Endocrinol Metab 1978; 46: 260-66. 5. Prasad C. Neurobiology of cyclo(His-Pro). Ann NY Acad Sci 1989; 553: 232-51. 6. Hilton CW, Prasad C, Wilber JF, Wolf GC, Rogers D. Radioimmunoassay of cyclo(His-Pro) in unextracted human plasma: report of a normal range and definition of factors critical for successful assay. Neuropeptides 1989; 13: 65-70. 7. Yanagisawa T, Prasad C, Peterkofsky A. The subcellular and organ distribution and natural form of histidyl-proline diketopiperazine in rat brain determined by a specific radioimmunoassay. J Biol Chem 1980; 255: 10290-98.

Acute renal graft rejection after treatment with human growth hormone SIR,-A prominent feature of chronic renal insufficiency in growth retardation. Although many patients show catch-up growth after successful renal transplant, especially when the dose of prednisolone is reduced to maintenance levels, some fail to grow adequately. Therefore, trials have been done of growth hormone replacement with recombinant growth hormone. We childhood is

report on 2 cases where this treatment seems to have evoked acute rejection of the renal graft. Case 1. An 8-year-old boy with dysplastic kidney disease had a cadaveric renal transplant in January, 1985. The postoperative course was uneventful, and the patient was maintained on cyclosporin 240 mg per day and prednisolone 10 mg every second day. Because of inadequate longitudinal growth, human growth hormone therapy was started in December, 1988. Serum creatinine at that time varied between 50-115 pmol/1 and insulin clearance was 56 ml/minute per 1-73 m2. 5 months later creatinine suddenly increased to a maximum of 214 lunol/1. Kidney biopsy revealed diffuse oedema and an interstitial inflammatory infiltrate dominated by plasma cells, lymphocytes, and histiocytes. There was no fibrosis or signs of chronic rejection. Methylprednisolone (1-25 g over 4 days) was given as antirejection treatment, whereupon serum creatinine fell to a minimum of 137 µmol/l. Treatment with human growth hormone was continued. 3 weeks later, serum-creatinine suddenly increased to a maximum of 183 µmol/1, and biopsy again showed signs compatible with acute rejection. Creatinine fell to 150 (imol/1 after a further course of methylprednisolone. Human growth hormone was discontinued, and serum creatinine has now stabilised at 140 lunol/1 after 17 months, with a glomerular filtration rate of 40 ml/min per 1 ’73 m2. Case 2. A 4-5-year-old boy with dysplastic kidneys and congenital hydronephrosis had a successful renal transplant with the father as donor in April, 1987. Apart from a mild interstitial rejection episode 1 month postoperatively, successfully treated with methylprednisolone, the immunological course was benign. The patient was maintained on 160 mg of cyclosporin per day and 10 mg of prednisolone every second day. Because of failure to grow,

1456

with human growth hormone was started 2 years after transplantation. Glomerular filtration rate at that time was 47 treatment

ml/min

per 1 73 m2. After 7 months of treatment with human

growth hormone, serum creatinine suddenly increased from 60 to 164 umol/1. Biopsy revealed slight arteritis and interstitial oedema with focal haemorrhage, and increased fibroblasts and fibrosis were noted-findings compatible with acute rejection. Treatment with human growth hormone was stopped and methylprednisolone (1-25 g over 4 days) was given. Serum creatinine then fell to 80 µmol/1 and has remained stable for 12 months, the glomerular filtration rate being 41 ml/min per 1-73 m2. In both cases renal function was stable for several years before human growth hormone was given. Although treatment with growth hormone continued for some months before the acute rejection episodes, a relation between growth hormone treatment

Other cases of spontaneously resolving meningococcaemia have been reported.1 Meningococcal disease has also been recorded as presenting with a maculopapular rash2 only or evolving after this into the typical purpuric rash.3,4 Our patient is noteworthy because

this

atypical macropapular rash, associated with a spontaneously resolving meningococcaemia, did not evolve into the classic rash. In a prospective study of meningococcal disease between 1988 and 1989 in Merseyside, UK, 13% (9 of 69) of patients had only a

macropapular rash which did not evolve during their illnessThe rapid evolution and "flea-bitten" appearance of the maculopapular rash in our patient are typical of these others and suggestive of meningococcaemia. We recommend that meningococcal disease should be considered in similar cases even when there is no purpuric element to the rash.

likely since there were no other therapeutic changes and concentrations of cyclosporin in blood were adequate

Royal Liverpool Children’s Hospital Alder Hey, Liverpool L1 2 2AP, UK,

and stable. Furthermore, spontaneous acute rejection seldom after such a long immunologically benign postoperative period. Growth hormone is thought to be involved in immunoregulation. It has important immunomodulatory activities, such as augmenting antibody synthesis, increasing interleukin-2 synthesis, stimulating proliferation of human lymphoblastoid cells, and increasing the activity of cytotoxic T -lymphocytes. We suggest, therefore, that when human growth hormone therapy is initiated in transplant patients, basal immunosuppressive therapy should be increased and graft function carefully monitored during the first months of treatment.

Hey

and

rejection

seems

and Institute of Child Health, Royal Liverpool Children’s Hospital Alder

F. A. I. RIORDAN O. MARZOUK D. C. DAVIDSON

occurs

Departments of Transplantation Surgery, Paediatrics and Pathology, Karolinska Institute, Huddinge Hospital, 141 86 Huddinge, Stockholm, Sweden 1.

GUNNAR TYDÉN ULLA BERG FINN REINHOLT

Kelly KW. Growth hormone, lymphocytes and macrophages. Biochem Pharmacol 1989; 38: 705-13.

Benign meningococcaemia: diagnosis?

a

rash

SIR,-We report a baby with meningococcaemia presenting with an atypical rash which seems to have resolved spontaneously. A 3-month-old girl presented to this hospital with a 3-day history of diarrhoea and vomiting, for which she had received no antibiotics. For the preceeding 24 h she had been pyrexial and increasingly irritable. A rash had developed behind her ears a few hours before presentation. She had a fever of about 40°C but was otherwise alert with no focus of infection. A diffuse pink macular rash was noted on the trunk and limbs, but it had no purpuric elements. The rash seemed to spread over her trunk during her

initial examination. Her white cell count was 19.9/µl (78% neutrophils); cerebrospinal fluid contained 14 red blood cells and 7 white blood cells per µl, protein 0-4 g/1, and glucose 3-5 mmol/1, no

organisms were seen on gram stain, and latex agglutination for Neisseria meningitidis was negative. She received no antibiotics and her temperature settled soon after admission and remained normal for 48 h. At this time all cultures were negative and she was discharged. Her rash had resolved leaving four petechial spots. The following day N meningitidis type B was isolated from blood cultures taken on admission and her nose swab was also positive. The patient was recalled from home where she had remained well; examination was normal. She received a 5-day course of intravenous penicillin and remained well throughout. Repeat blood cultures before treatment failed to isolate N meningitidis, although the organism was grown from both nose and throat swabs. Both latex for agglutination and counter immunoelectrophoresis meningococcal antigen in serum were negative. Her white cell count was 10.4/µl (21 % neutrophils), and erythrocyte sedimentation rate and C-reactive protein were not raised. She was readmitted with a viral illness 5 months later and proved to have a high level of meningococcal antibodies. N meningitidis was again isolated from her throat swab, despite conventional prophylaxis for her and her immediate contacts on her first admission. She received no treatment before discharge.

1.

Dashevsky B, Teele DW, Klein JO. Unsuspected meningococcaemia. JPediatr 1983;

102: 69-72. 2. Rubenstem R, Esterly N. Meningococcal meningitis with a benign skin rash. Paediatr Dermatol 1986; 3: 414-16. 3. Baxter P, Priestley B. Meningococcal rash. Lancet 1988; i: 1166-67. 4. Carter PE. Meningococcal meningitis. Br Med J 1990; 300: 1584. 5. Marzouk O, Thomson APJ, Sills JA, Hart CA, Harris F. Meningococcal disease may present with a maculopapular rash. Pediatr Rev Commun (in press).

Occupational infection among anaesthetists 3 editorial (p 1103), in which the risk for transmission of HIV and hepatitis B virus to occupational anaesthetists is discussed, deserves some comment. Failure of anaesthetists to adhere to the recommended guidelines when exposing themselves to blood is a major difficulty despite many information campaigns aimed at health workers.’ In a survey of Norwegian anaesthetists and surgeons we found that 52% of the respondents did not always use gloves while doing clinical procedures with the potential for blood exposure, although they were well aware of HIV transmission.2 65% of the group underestimated their own crude risk for meeting an HIV-infected patient, and 31 % also underestimated the 2-year risk for seroconversion after parenteral exposure to HIV-infected material, compared with what is estimated from epidemiological data.3 This shows, as you suggest, that some anaesthetists tend to ignore this risk of acquiring HIV-infection despite what seems to be sufficient knowledge of modes of transmission. Anaesthetists now seem to have the necessary knowledge to adopt safe behaviour. Therefore they, as well as other health personnel, should be vigilant and always consider blood as infectious material. Strict adherence to the recommended protective measures when doing clinical procedures that could lead to blood contact must be as habitual as washing one’s hands.’

SIR,-Your Nov

Department of Anaesthesia and Intensive Care, Hammerfest Hospital, N-9601 Hammerfest, Norway

GUTTORM BRATTEBØ TORBEN WISBORG

guidelines for prevention of transmission of human immunodeficiency virus and hepatitis B virus to health care and public safety workers. MMWR 1989; 38 (suppl S6). 2. Brattebø G, Wisborg T, Sjursen H. Health workers and the human immunodeficiency virus: knowledge, ignorance and behaviour. Publ Health 1990; 104: 123-30. 3. Marcus R. CDC Cooperative Needlestick Surveillance Group. Surveillance of health care workers exposed to blood from patients infected with the human immunodeficiency virus. N Engl J Med 1988; 319: 1118-23. 1. Centers for Disease Control. 1989

CORRECTIONS Management of epilepsy. In this letter by Dr J. H. Livingston and DrE. G. H. Lyall (Nov 3, p 1125) the last sentence of the fifth paragraph should have read ... 75 mmol/I saline solution is preferable to 30 mmol/1... Borrelia burgdorferi and tropical spastic paraparesis. In this letter by Dr B. Bucher and colleagues (Nov 3, p 1135) the sixth author’s name should have been spelt Hilary Koprowski.

Acute renal graft rejection after treatment with human growth hormone.

1455 and blood transfusions. These patients survived for 11, 12, and 15 weeks. Even though this is not a statistically valid comparison and the phase...
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