serum cholesterol and mortality rates
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These factors in combination may explain the state- of
immunotolerance achieved, but the only element of doubt was inthe use of widely meshed autograft under the allograft.
Skin is the most antigenic of all organs investigated in
transplantation and the secrets of immunotolerance have eludedresearch workers since the late 19th century. The only truesuccesses have been in identical siblings. It has been suggested thatcultured allograft skin is less antigenic because it possesses no
Langerhans cells, and there are varied reports of successful
graftings. At this bums unit we have seen that harvested skincontains Langerhans cells superficial to the dermoepidermaljunction and that they are present for the duration of storage (2-3weeks). The Langerhans cells are not, however, present in theepithelialised interstices of meshed autograft for at least 3 weeks.Based on the hypothesis that cyclosporin would prolong allograft
survival and that after withdrawal of-cyclosporin the originalmeshed allograft would reject to leave a non-contracting dermismatrix and in-vitro cultured keratinocytes, we applied it to theclinical situation. Stored; meshed allograft skin from 19 donors wasapplied to the debrided bums of a 65-year-old man. He had beenestimated as having sustained 25 % caustic soda bums which wereall full thickness. The bums were debrided 3 weeks after admissionand the patient was in poor medical condition with few availabledonor sites. The bums were debrided at one session and there wereno dermal elements remaining before application of the allografts.Meshed autografts were applied to the left lower leg and acted as acontrol. Cyclosporin in a dose of 10 mg/kg per 24 h was given orallyin divided doses, starting with the premedication. About 50 % of theoriginal allografted areas survived and this included the whole of theright lower leg. Autografts were then applied to all the remainingunhealed areas leaving the right lower leg as allograft only. Over thenext 3 weeks the allograft mesh interstices healed by keratinocyteproliferation and this included an area of allograft from a blackdonor. The patient was more or less healed and the cyclosporinwas discontinued. Langerhans cells did not appear in the new skinbut there was an increased number of S 100 positive staining cells inthe recipient bed under the allograft than under the autograft.
Exactly 12 days after withdrawal of the cyclosporin the allograftstarted to reject, including the skin from the black donor. Both thenew layer of keratinocytes and the original ’mesh were lost.Immunotolerance was not therefore achieved by this 3-week courseof cyclosporin, but by this time the patient’s own donor sites hadhealed sufficiently to allow a reharvest and complete replacement ofthe allografted areas by autograft.
It would thus appear that cyclosporin has a potential use inproviding rapid skin cover of burned areas during the period ofmaximum risk. Presumably if immunotolerance is not achieved theallograft can be replaced whenever donor sites on the patientbecome available, and the cyclosporin can be discontinued when thepatient is fully autografted. This is potentially a major advance inthe management of bum victims, though if immunotolerance can beachieved after a longer treatment period bums and reconstructivesurgery management would be revolutionised.
Regional Plastic and Jaw Surgery Centre,Mount Vemon Hospital,Northwood, Middlesex J.D. FRAME
1 Achauer BM, Hewitt CW, Black KS, et al. Long-term allograft survival aftershort-term cyclosporin treatment m a patient with massive bums. Lancet 1986, i:14-15.
2. Green CJ Experimental transplantation. Progr Allergy 1986; 38: 123-58.3. Scheynius A, Johansson C, Van Der Meide PH. In vivo induction of Ia antigens on rat
keratinocytes by &ggr; interferon. Br J Dermatol 1986; 115: 543-49.
SERUM CHOLESTEROL AND MORTALITY RATES
SIR,-Before submitting a patient to a lifelong regimen of diet ordrugs to lower serum cholesterol, a doctor should be convinced thatthe benefits outweigh the costs and inconvenience. Martin et aPshowed that mortality rates vary with the level of serum cholesterolbut gave no quantitative estimates of the benefits of treatment. Theinformation from that paper has’ been applied to 1984 Australianmortality statistics2 to determine the expected causes and medianages of death for the quintiles of serum cholesterol levels and to findthe possible effects of lowering the cholesterol levels of the
TABLE I-AUSTRALIAN MORTALITY RATES IN 1984 BY AGE AND
CAUSE WITH PREDICTED MORTALITY RATES FOR MEN WITH
DIFFERENT CHOLESTEROL LEVELS
population. The calculations depend on the assumptions that: (1)lowering the serum cholesterol reduces the mortality rate to that ofmen naturally at this lower level; (2) the relative risks for thedifferent cholesterol levels are the same at all ages; (3) death fromother causes is independent of cholesterol level; (4) therapy whichalters serum cholesterol has no effect on death from other causes;and (5) that age-specific and disease-specific mortality rates remainconstant over the period modelled. The data base for thecalculations is shown in table i.The calculations were made with an iterative computer program.
From cohorts of 100 000 men starting at age 20 years, the number ofdeaths from each cause in each group was calculated annually, thedeaths deducted and the reduced cohort used as the base for the next
year’s calculations. Each run simulated a 60-year period-ie, from20 years to the 80th birthday. The logarithms of mortality rates werelinear with age, so interpolations of logarithms of mortality rateswere used to estimate the annual age-specific mortality rate for eachcause. The results of the calculations are shown in table 11.
TABLE II-CAUSES OF DEATH AND MEDIAN AGE AT DEATH OF
VARIOUS COHORTS OF MEN*
*Each cohort starts at 20 years of age and is followed for 60 years.
Lowering the serum cholesterol of the population would havetwo effects. The first is a slight prolongation of median life span.Transposing a subject from one quintile of cholesterol levels to thenext one down prolongs median life by about 1 year, except for thosein the highest quintile where the prolongation of life is about 3 years.However, the main effect is to alter the cause of death. When thelowest quintile of cholesterol levels is compared with the highest,the proportion of deaths from heart disease is almost halved, but theproportion from malignancies is almost doubled. Lowering theserum cholesterol of the whole population by 10 % should lengthenmedian life by 1 year. Lowering the serum cholesterol of the topquintile of the population down to the level of the next quintile, butignoring the rest of the population, would have almost the sameeffect on the whole population, even though the benefit is confinedto a small subgroup.These results are based on data from specific areas. The
age-specific and disease-specific mortality rates for Australian menare similar to those for other developed countries and the excess
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mortality related to high levels of serum cholesterol is probablysimilar in other populations. Although caution is obviously needed,the results derived here can be generalised. There is no goodevidence that social engineering can lower the serum cholesterollevels of populations and any benefits would depend critically on therole of cholesterol as a risk factor and not merely as a risk indicator.Even if these assumptions are proved correct, the increases in deathsfrom other causes are likely to offset the benefits of any suchendeavour. The main result for the health services would be atransfer of case loads and resources from cardiac to cancer units.
I do not suggest that we abandon attempts to lower serumcholesterol but rather that we should widen our horizons when
assessing the cost/benefit of public health strategies. A decrease inserum cholesterol of a population by 10 %, even if this were possible,would be expensive in money and manpower. The benefits wouldbe small and perhaps not liked by the subjects. We all die and, at thecost of one year, heart disease may be preferable to cancer. Effortshould be devoted to those few with high cholesterol levels. The restof us could then eat for pleasure, comforted by the knowledge thatthe health cost is likely to be small.
Human Nutrition Research Group,Department of Child Health,University of Queensland,St Lucia,Queensland 4067 Australia A. E. DUGDALE
1. Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol,blood pressure, and mortality: implications from a cohort of 361 662 men. Lancet1986; ii: 933-36
2 Australian Bureau of Statistics. Causes of death in Australia 1984. Canberra.
Australian Bureau of Statistics, 1986.
TREATMENT OF ACUTE RENAL FAILURE,SYMMETRICAL PERIPHERAL GANGRENE, ANDSEPTICAEMIA WITH PLASMA EXCHANGE AND
EPOPROSTENOL
SIR,-Peripheral symmetrical gangrene has been treated withplasma exchange’ and epoprostenol (prostacyclin) infusion Wereport a similar case associated with acute renal failure anddisseminated intravascular coagulation. Treatment with epopro-stenol resulted in rapid reversal of oliguria and recovery of renalfunction.A 32-year-old woman presented with a 24-hour history of feeling
unwell with a progressive purpuric rash on hands and legs. She hada history of spina bifida, ureteroileostomy, and recurrent urinarytract infection. She was febrile (39°C), blood pressure 100/70 mmHg, with a confluent purpuric rash on the nose, small areas of thetrunk, both hands, and legs with gangrene in the extremities. Aperipheral blood smear showed microangiopathic haemolyticanaemia. Prothrombin time was 31 s (control [C] 15 s), partialthromboplastin time 63 s (C 37 s), thrombin time 23 s (C 12 s), fibrindegradation products 256 mg/dl, platelet count 25 000/ul, plasmacreatinine 400 Ilffiol/l, and urea 30 mmol/1 with haematuria (4 +)and proteinuria (2 +). Blood and urine cultures grew Proteusmirabilis. She was treated with antibiotics (gentamicin, cefuroxime),plasma exchange (2 1 daily for 7 days with fresh frozen plasmareplacement solution), low dose dopamine (5 I1g/kg per min), andventilation because of adult respiratory distress syndrome. Shedeteriorated over the next 24 h with progression of rash andgangrenous areas. Additionally macroscopic haematuria developedand she became oliguric (plasma creatinine 600 pmol/1) which didnot respond to intravenous frusemide 500 mg. Blood pressureremained stable (100/70 mm Hg) and pulmonary capillary wedgepressure was maintained at 15 mm Hg. Epoprostenol was infused(6-10 ng/kg per min) with an on/off regimen at 8 hourly intervals toavoid tachyphylaxis. Oliguria was rapidly reversed (figure). Renalfunction returned to normal one week later (plasma creatinine 70prnol/1). The infusion also warmed affected skin areas and
prevented further progression of the rash. The patient survived butrequired extensive surgery with amputation of both legs below theknee, right hand, and all digits of the left hand.
This patient probably developed a Shwartzman reaction withperipheral gangrene, consumption coagulopathy, and acute renalfailure. The acute renal failure may result from lesions of glomerular
Effect of epoprostenol (prostacyclin) on urine output in oliguria.
thrombosis and cortical necrosis. 3,4 In this case the progressivereduction in urinary output and development of macroscopichaematuria strongly suggest glomular thrombosis. Althoughrecovery of renal function may have been related to otherconcurrent treatment, epoprostenol therapy may ameliorateprogression of associated renal lesions in this condition.
Department of Medicine,University College London,
and University College Hospital,London WC1E 6JJ
B. LEAKERR. MILLERS. COHEN
1. Drenger B, Israeli A, Or R, Leitersdorf E. Plasmapheresis for streptococcal sepsis?Lancet 1985; ii: 943.
2 Denning DW, Gilliland L, Hewlett A, Hughes LO, Reid CDL. Peripheralsymmetrical gangrene successfully treated with epoprostenol and tissue
plasminogen activator. Lancet 1986, ii: 1401-02.3. Meyers BR, Hirschman SZ, Sloan W. Generalized Shwartzman reaction after a dog
bite. Ann Intern Med 1970; 73: 433-384 Rahal JJ, MacMahon E, Weinstein L. Thrombocytopenia and peripheral symmetrical
gangrene associated with staphylococcal and streptococcal bacteraemia. Ann InternMed 1969; 69: 35-41.
NECROPSY FINDINGS IN HTLV-I ASSOCIATEDMYELOPATHY
SiR,-Human T-lymphotropic virus type I (HTLV-1)associated myelopathy (HAM)1 is characterised by slowlyprogressing with spastic paraparesis, pyramidal signs, and mildsensory and sphincter disturbances. Myelograms are normal butantibodies to HTLV-1 are found in the serum and cerebrospinalfluid (CSF). We report here the first case of HAM studied atnecropsy.A 56-year-old woman from Oita, in southern Japan, had mitral
and aortic valve replacement July, 1983, when she had bloodtransfusion. 6 months later she had back and leg pain, muscleweakness, hypoaesthesia in the legs, and bladder and rectal
dysfunction. Muscle weakness and hypoaesthesia progressed to T9and she became unable to stand up. Her arms were slightly and legsseverely spastic. A myelogram was normal. Serum and CSFantibodies to HTLV-I were positive at titres of 1280 and 64,respectively, by immunofluorescence assay and specific IgG bands(pl4, p24, and p28 in serum and p24 in CSF) were detected bywestern blot. There was slight improvement on steroid therapy, butthe patient died of congestive heart failure on July 19, 1986.
In this case of HAM the disease mainly affected the spinal cord,especially the thoracic cord. The most striking post-mortemchanges, in both the white and grey matter, were proliferation ofcapillaries, perivascular cuffing with lymphocytes, and loss ofmyelin and axon. There were also proliferation of gemistocyticastrocytes and infiltration of foamy macrophages. These changeswere more severe in the lateral and anterior columns. Perivascular
cuffing with lymphocytes were also seen in the medulla, pons, andwhite-matter of cerebrum and cerebellum. In the subarachnoid
space, collagenous thciening and partial adhesion with lymphocyticinfiltration were observed. Blood vessels, particularly small veins, in