1506

Haematological effects of interleukin-1SiR,—I read with interest the report by Dr Tewari and colleagues(Sept 22, p 712) on the haematological effects of intravenousinterleukin-1 (IL-1). I remain unconvinced that the thrombocytosisobserved was due to a direct action of IL-1. It is much more likelythat the effect is an indirect one, mediated by IL-1-stimulatedrelease of IL-6.

IL-6 production is strongly increased in vitro by inflammatorymediators such as IL-1 and tumour necrosis factor (TNF a and p).Circulating IL-6 is raised during a variety of febrile and even minorinflammatory states. In view of the severe systemic disturbance andfever observed after intravenous IL-1 administration, it isremarkable that an increase in IL-6 was not observed in the patients,especially since administration of other cytokines, such as

granulocyte-macrophage colony-stimulating factor,’ interleukin-2,2 and most potently TNF-a2 (whose activities are similar to IL- 1)is associated with a considerable increase in circulating IL-6.The results allow a simpler alternative explanation. If one

assumes that bioactive IL-6 (not IL-1 as stated in the methods) wasmeasured by the KD83 cell line, the detection threshold of 200pg/ml is far higher than that of other IL-6 dependent cell lines suchas 7TD 1 or B9, which can be used to measure levels as low as 1 to 10pg/ml. Therefore, as Tewari et al admit, the induction of

haemopoietic growth factors below the detection limit of theirassays has not been excluded.

In-vitro and in-vivo reports suggest that IL-6, rather than IL-1,is important in megakaryocytopoesis and thrombocytopoesis .3,4The distinction is critical if one considers the implications for thetreatment of thrombocytopenic states by cytokines. IL-6 lacks mostof the proinflammatory actions of IL-1 such as activation ofendothelial cells, stimulation of prostanoids, and release of

metalloproteinases. On these grounds, therefore, its administrationwould cause less tissue injury than that seen with cytokines such asIL-1 or TNF and would be more acceptable.Rheumatology Unit,Division of Medicine,UMDS,Guy’s Hospital,London SE1 9RT, UK BHASKAR DASGUPTA

1. Hazenberg BPC, Van Leeuwen MA, Van Rijswijk MH, Stem AC, Vellenga E.Correction of granulocytopenia in Felty’s syndrome by GM-CSF, simultaneousinduction of IL-6 release and flare up of arthritis. Blood 1989, 74: 2769-70.

2. Jablons DM, Mule JJ, McIntosh JK, et al IL-6/IFN-&bgr;2 as a circulating hormone.Induction by cytokine administration in humans. J Immunol 1989; 142: 1542-47.

3. Ishibathi T, Kimwia H, Uchida T, Kariyone S, Friese P, Burnstein SA Human IL-6is a direct promoter of maturation of megakaryocytes m vitro. Proc Natl Acad SciUSA 1989; 86: 5953-57.

4. Asano S, Okano A, Ozawa K. In vivo effect of recombinant human IL-6 in primates:stimulated production of platelets. Blood 1990; 75: 1602-05.

*** This letter has been shown to Dr Starnes and Dr Tewari, whosereply follows.-ED. L.

SIR,-In our recent preliminary report we showed that five dailyintravenous infusions of IL-1 resulted in sustained increases inplatelet counts. Crown et ah2 have demonstrated prolongedthrombocytosis in patients after only two daily It- 1 doses. Theyalso observed increases in CFU and expanded early progenitorpools.Dr Dasgupta raises concerns about the toxicity of IL-1, given its

multiple proinflammatory actions, and suggests that the

thrombocytosis after IL-1 1 that we observed was more probably anindirect effect mediated by IL-6 which was induced by IL-1.We were not able to detect elevation of serum IL-6 levels in

response to the doses of IL-1 administered using the KD83plasmacytoma cell line. This bioassay has a threshold of detection of25 pg/ml for the IL-6 signal. However, one must do a 1 in 10 or 1 in100 dilution to account for a non-specific serum effect. It is certainlypossible that with a more sensitive bioassay or ELISA or at higherdoses of IL-1 detectable increases in IL-6 levels would be observed.We and others are addressing these issues.

It is likely that several cytokines and growth factors, includingIL-6, play parts in megakaryocytopoiesis and thrombocytopoiesis.To date, only IL-1 and IL-3 administration have resulted in

increased platelet counts consistently in man. There are no reportsof IL-6 administration to patients. We have been unable to blockIL-1-induced splenic megakaryocytopoiesis with a monoclonalantibody against mouse IL-6 in a mouse model, which suggests thatIL-1 may have effects on megakaryocytopoiesis independent ofIL-6.With regard to Dasgupta’s comments about toxicity with IL-1

and potentially less adverse effects of IL-6 administration, we haveshown that It- 1 (3 is well tolerated at doses that consistently raiseplatelet counts. The toxicity of IL-6 in man has not been reported.We are examining whether IL-1-associated thrombocytosis is

produced in the presence of prostaglandin synthesis inhibitors,which reduce IL-1’s side-effects even further. In addition, we haveconcerns about possible toxicity of IL-6. IL-6 is a major mediator ofthe lethal aspects of bacteraemic shock, and monoclonal antibodiesto IL-6 can block lethality of Escherichia coli sepsis as well as TNF-achallenge.3,4 Therefore, IL-6 administration may be associated withsome toxic effects.One additional point should be made concerning the citation for

the cloning of IL-1 from our preliminary report. We cited the paperby March et all because this clone was used to produce therecombinant human IL-1 P administered in our study. Auron et al6cloned human IL-1 in 1984 and Lomedico et aF cloned mouseIL-la7 in 1984.

Department of Surgery,Laboratory of Surgical Metabolism,Stanford University Medical Center,Stanford, California 94305, USA

H. FLETCHER STARNES, JRANAND TEWARI

1. Crown J, Kemeny N, Jakubowski A, et al. Phase I-II trial of recombinant humaninterleukin-1&bgr; (IL-1) m patients (PTS) with metastatic colorectal cancer (MCC)receiving 5-fluorouracil (5FU). Blood 1989, 74 (suppl). 15a (abstr).

2 Crown J, Gabrilove J, Kemeny N, et al. Phase I-II trial of recombinant human

interleukin-1&bgr; (IL-1) in patients (PTS) with metastatic colorectal cancer (MCC)receiving myelosuppressive doses of 5-fluorouracil (5FU) Proc Am Soc Clin Oncol1990; 9: 183 (abstr)

3. Yim JH, Tewari A, Pearce MK, et al. Monoclonal antibody against munne IL-6prevents lethal effects of E coli sepsis and tumor necrosis factor challenge in miceSurg Forum 1990; 41: 114-17.

4. Stames HF, Pearce MK, Tewan A, et al. Anti-interleukin-6 monoclonal antibodiesprotect against lethal E coli infection and lethal TNF-&agr; challenge in mice.

J Immunol (in press)5. March CJ, Mosley B, Larsen A, et al. Cloning, sequence and expression of two distinct

human interleukin-1 complementary DNAs. Nature 1985; 315: 641-47.6. Auron PT, Webb AC, Rosenwasser LJ, et al Nucleotide sequence of human

monocyte interleukin-1 precursor cDNA. Proc Natl Acad Sci USA 1984; 81:7907-11.

7. Lomedico PT, Gubler CP, Hellman CP, et al. Cloning and expression of munneinterleukin-1 cDNA in Escherichia coli. Nature 1984, 312: 458-62.

Hysterical paralysisSIR,-Dr Ellis (Sept 22, p 752) suggests that an ’Amytal’(amylobarbitone) test can confirm the diagnosis of hystericalparalysis without an exhaustive battery of investigations to excludeorganic illness. We describe a similar experience with ’Hypnovel’(midazolam).A 24-year-old woman was admitted with slowly progressive

quadraplegia associated with inability to swallow liquids or solids,and a suprapubic catheter for overflow incontinence. She presentedinitially in 1986 with low-back pain and sciatica, and myelogramdemonstrated a disc lesion. She had spinal fusion of L5/S1 for aruptured disc. In January, 1988, she was investigated for

progressive weakness, and in June, 1988, a muscle biopsy suggestedtype II muscle atrophy. In February, 1989, neurologicalexamination at the Institute of Neurology, London, noted weaknessaffecting the limbs and trunk muscles. There were, however, noupper or lower motor neuron signs and the features were felt to bethose of pseudoparalysis. Electromyography and muscle studiesshowed no evidence of denervation, and volitional activity wastypical of simulated weakness (activity was intermittent and firingrate was low). Muscle biopsy showed scattered atrophy of musclefibres; however, the biopsy specimens were only mildly abnormaland could not explain the severe muscle weakness.Limb weakness progressed, so that by June, 1990, the patient

could not move upper or lower limbs, hands, or feet. She was unableto swallow despite a normal cranial nervous system. Repeat muscle

1507

biopsies confirmed a type II disuse muscle atrophy. Duringplacement of a percutaneous gastric feeding tube 8 mg midazolamwas given intravenously, which resulted in the patient moving allfour limbs in a purposeful and powerful fashion.At the time of this admission computed tomography of the brain

and nuclear magnetic resonance scan of brain, brain stem, andspinal cord were all normal, as was lumbar puncture. Repeat musclebiopsies, repeat electromyography, and nerve conduction studiesagain confirmed simulated weakness. These tests could have beenavoided had an earlier benzodiazepine challenge been done. Thevalue of the test is to enable emotional features, knowledge of whichwill benefit the patient, to come to the fore. In the absence of suchknowledge a firm diagnosis of hysteria cannot be made. Cautionmust still be applied in concluding a diagnosis of hysteria: at leastone third of patients may develop major medical illness and asmaller percentage significant psychiatric illness in the 9 yearsfollowing a diagnosis of hysteria ’

Departments of Medicine and Psychiatry,Trinity College Dublin,St James’s Hospital.Dublin 8, Ireland

J. J. KEATINGT. G. DINANA. CHUAP. W. N. KEELING

1 Slater ETO, Glithero E. A follow up of patients diagnosed as suffering from hysteria.J Psychosom Res 1965; 9: 9-13

2. Lewis A The survival of hysteria. Psychol Med 1975; 5: 9-16

Is reduced salivary flow normal in oldpeople?

SIR,-Salivary gland dysfunction has traditionally been attributedto old age, and complaints of dry mouth (xerostomia) are mostfrequent in the elderly. Saliva plays an essential part in themaintenance of the oral cavity, and dimirushed output results indental caries, altered mucosal integrity, and impaired taste anddeglutition.2 Salivary gland dysfunction has been demonstrated inseveral diseases common in older people (eg, Sjogren’s syndrome3 3and Alzheimer’s disease’) and as a result of therapy for head-and-neck cancer. Elderly people also consume more than averageamounts of prescription and non-prescription medications, many ofwhich are associated with salivary hypofunction.6 However,cross-sectional studies have demonstrated that salivary glandfunction is similar in populations of healthy adults of different ages. 1

To our knowledge, no longitudinal data have been published. Wehave investigated stimulated parotid gland flow rates over 10 yearsin predominantly healthy adults of different ages.One of us (B.J.B.) examined 50 people (27 males, 23 females), and

97 (SD 1-2) years later (range 7-12 years) they were examined bythe other (J.A.S.) Subjects were volunteers in the oral physiologycomponent of the Baltimore Longitudinal Study of Ageing.7 Allwere community-dwelling, generally healthy whites, of middlesocioeconomic class. 24 were not taking medication at eitherexamination. The others had some change in their medication statusat the second examination but they were medically examined andnone had complaints suggestive of xerostomia. 2% citrate

Salivary flow-rate differences over 10-year span among 50generally healthy people aged 29-72 years at initial visit.

Males= 40; females =.... Linear regression analysis yelds r2 = 0,005(p>0 05)

stimulated saliva was collected from a single parotid gland Tocalibrate saliva collections by the two investigators stimulatedparotid flow rates from 247 and 148 healthy people not being treatedfor any medical conditions, collected by the first and second

investigators, respectively, were compared. Average flow ratesobtained by the first investigator were 67% greater than thosecollected by the second investigator, and analysis of co-variancetests revealed that these differences were accounted for byinvestigator differences alone, and not by age or gender relatedeffects. Flow rates from the first investigator were therefore acorrected and transformed flow rates from the initial examinationwere subtracted from those found 10 years later.

Flow-rate differences were not significantly different from zero(one-sample analysis using medians, p > 0-05) and the regression offlow-rate differences on age did not have a significant slope (figure).Furthermore neither flow-rate differences nor the non-significantregressions of flow-rate differences on age differed between malesand females (data not shown). The use of medications had noinfluence on salivary flow either.These data demonstrate that there are no age-related changes in

stimulated parotid flow rates over a 10 year period in generallyhealthy adults. They extend conclusions from cross-sectionalstudies about the constancy of salivary gland output in healthyindividuals across the human life span. The clinical significance ofthese findings is that complaints of dry mouth and salivary glanddysfunction in an older person should not be considered normal.Such patients should be carefully evaluated9 and placed onpreventive oral health regimens to less the harmful impact ofsalivary gland dysfunction. 10Clinical Investigationsand Patient Care Branch.

National Institute of Dental Research,Bethesda, Maryland 20892, USA

J. A. SHIPB. J. BAUM

1. Baum BJ Salivary gland fluid secretion dunng aging. J Am Ger Soc 1989, 37: 453-582. Mandel ID The role of saliva in maintaining oral homeostasis. J Am Dent Assoc 1989;

119: 298-304.3 Atkmson JC, Travis WD, Pillemer SR, et al Major salivary gland function in primary

Sjogren’s syndrome and its realtion to clinical features J Rheumatol 1990; 17:318-22

4. Ship JA, DeCarli C, Friedland RP, Baum BJ Diminished submandibular salivaryflow in dementia of the Alzheimer type. J Gerontol 1990; 45: M61-66.

5 Dreizen S Description and incidence of oral complications. NCI Monogr 1990; 9:11-15.

6. Sreebny LM, Schwartz SS. A reference guide to drugs and dry mouth. Gerodontology1986; 5: 75-99.

7 Shock NW, Greulich RC, Andres R, et al. Normal human aging. the Baltimorelongitudinal study of aging (NIH publ no 84-2450) Washington, DC: USGovernment Printing Office, 1984

8. Baum BJ. Evaluation of stimulated parotid saliva flow rate in different age groupsJ Dent Res 1981, 60: 1292-96.

9. Fox PC, van der Ven P, Sonies BC, et al. Xerostomia evaluation of a symptom withincreasing significance. J Am Dent Assoc 1985; 110: 519-25

10 Wright WE Management of oral sequelae J Dent Res 1987; 66: 699-702.

Airborne mite antigenSIR,-Dr Price and colleagues (Oct 13, p 895) have evaluateddifferent methods of assessing a child’s exposure to the dust mite(DermatophagOldes pteronyssinus) allergen, Der p I. Since mostasthmatic children in the UK are sensitised to mites, and since thereis good evidence to support a causal relation between mite allergenexposure and asthma, the issue is important. However, the

argument that a spot assessment of the very low levels of airborne

allergen is an improvement on the current method of measuring thereservoir levels in carpets and bedding, from which it is derived,needs to be considered with caution. Airborne allergen collection isfraught with difficulty.’ The amount of airborne mite allergen isvery small (typically 2-20 ng Der p 11m3) when compared with0 5-100 )J.g/g found in collected dust. Measurement of nanogramamounts is at the limit of the sensitivity of an ELI SA. Price et al donot refer to any cut-off for the presence or absence of airborne

allergen against the inevitable background noise of the assay (seetheir fig 2). Standardisation of the domestic disturbance requiredfor mite allergen to become airborne is very difficult. How can"normal domestic activity" (vacuum cleaning, walking, or bedmaking) be compared or objectively standardised world wide? The