853
Linkage Study data include all contacts with specialist psychiatric services, and because data are linked sequences of episodes of the care of individuals, schizophrenia at first-ever contact can be distinguished from schizophrenia first diagnosed at a later stage. Truncated age-standardardised rates for people aged 15 and over, standardised by the direct method with the 1981 population of Oxfordshire as the standard, are shown in the figure. The total number of people with a first-recorded diagnosis of schizophrenia was much higher than the number diagnosed as schizophrenia at first-ever psychiatric contact alone. In males both these measures, and first-ever inpatient admission rates alone, showed a significant decline in the mid-to-late 1970s similar to that reported by Der et al. The pattern for females was much less clear-cut. Further explanations for the decline in first-contact rates for males include changes in diagnostic fashion, any increased tendency for general practitioners to treat schizophrenics without referral to a specialist, a decrease in severity, and (in local studies) any tendency for people predisposed to schizophrenia to migrate out of the population studied or any increase in inward migration by people not predisposed. Our data add some support to the suggestion that schizophrenia has declined in males, though not in females, in the period 1975-86. Oxford Record
In our view, however, the evidence is not conclusive. We do have comparable data for years before 1975. Unit of Clinical Epidemiology, Oxford University, Oxford Regional Health Authority, Oxford OX3 7LF, UK
not
JACQUELINE ALARCON VALERIE SEAGROATT MICHAEL GOLDACRE DE
1. World Health
Organisation The international pilot study of schizophrenia. Geneva. WHO, 1973. 2. Cooper JE, Kendell RE, Garland BJ, Sharpe L, Copeland JRM, Simon R. Psychiatric diagnosis in New York and London: a comprehensive study of mental hospital admissions (Maudsley Monogr no 20). London: Oxford Univesity Press, 1972.
SiR,—Elsewhere I argue that Kraepelin’s and Bleuler’s concepts of dementia praecox and schizophrenia were mistakenly derived from a population suffering mainly from physical disorders, notably encephalitis lethargica and its sequel, post-encephalitic parkinsonism. The years following von Economo’s descriptions of this infection and its consequences (after Kraepelin and Bleuler had completed their major writings) were characterised by diagnostic confusion; clinicians diagnosed schizophrenia but found it difficult to distinguish the condition from post-encephalitic parkinsonism. Efforts at differentiation were marked by contradiction and non-specificity. More important, they were based on the unfounded assumption that Kraepelin and Bleuler had provided evidence in support of their concepts. In other words, the task of differential diagnosis begged the question of the validity of "dementia praecox" and "schizophrenia".2 The suggestion that Kraepelin and Bleuler were dealing, at least in part, with the neurological sequelae of infectious diseases is very different from the hypothesis that schizophrenia is an infectious disease.3,4That claim, too, is based on an unjustified confidence in the validity of Kraepelin’s and Bleuler’s concepts. My suggestion is that the original concepts of dementia praecox and schizophrenia were mistakenly inferred from at least one now well-described infectious disease and its sequelae. It is difficult to know what implications this claim would have for subsequent rates of schizophrenia diagnosis. Reliable figures for the prevalence of the virus assumed to be implicated in encephalitis lethargica are not available, although it is generally believed to have declined sharply after the epidemic of 1916-27.5 von Economo, however, thought that the virus was passed from mother to fetus, and Sacks has cautioned against the naive assumption that such viruses "disappear" after highly visible epidemics.6 Also the concept of schizophrenia has gradually been transformed from the strongly physical and neurological, as well as behavioural, concept of Kraepelin and Bleuler, to the more behavioural/experiential one of DSM-IIIR. It is quite possible that many patients today who are said to have schizophrenia only superficially resemble Kraepelin’s
and Bleuler’s cases. Nonetheless I suspect that the apparent decline in incidence of schizophrenia is not unrelated to the decline in post-encephalitic parkinsonism. Questions such as "Where have all the catatonic (and severely deteriorated) schizophrenics gone?" may have answers that are at least similar to those to the question "Where have all the cases of post-encephalitic parkinsonism gone?" Department of Psychology, Polytechnic of East London,
MARY BOYLE
London E15 4LZ, UK
1. Boyle M. Schizophrenia: a scientific delusion? London: Routledge, 1990. 2. Boyle M. Is schizophrenia what it was? A re-analysis of Kraepelm’s and Bleuler’s populations. J Hist Behav Sci (in press). 3. Crow TJ. A re-evaluation of the viral hypothesis: is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? Br J Psychiatry 1984; 145: 243-53. 4. Hare EH. Schizophrenia as an infectious disease In: Kerr A, Snaith P, eds. Contemporary issues in schizophrenia. London Royal College of Psychiatrists/ Gaskell, 1986. 5. Pallis CA. Parkinsonism: natural history and clinical features Br Med J 1981; iii. 683-90. 6. Sacks O. Parkinsonism: a so-called new disease? Br Med J 1971; iii: 111.
Coexistence of Raynaud’s syndrome and
erythromelalgia SiR,—Erythromelalgia is known as the inverse Raynaud’s syndrome; the former disease can be induced by treatment of the latter. We report a woman with Raynaud’s syndrome and erythromelalgia. A 40-year-old woman had had, for 5 years, episodes of pallor and blue discolouration of the fingers and toes after cooling and emotional exertion. During these 5 years she also had intolerance to warming of the feet, which manifested attacks of pulsating pain and burning sensations. She had about ten cold and five to seven hot induced paroxysms daily. There were no trophic changes or oedema of the fingers and toes. Distal pulsation remained. Adson’s and Allen’s tests were negative. A cold provocation test induced pallor and blue discolouration of the fingers and toes. A hot provocation test induced pulsating pain and red discolouration of the feet. Biochemical investigation revealed accelerated ADPinduced platelet aggregation. The patient was otherwise healthy. She was given nifedipine (40 mg daily), dihydroergocristine (1-5mg daily), aspirin (750 mg daily), and hyperbaric oxygen sessions (1 ’7 atmospheres absolute, 45 min, seven sessions). After 3 weeks she was discharged and no longer had either hot or cold induced paroxysms.
I cannot explain with certainty how or why the two conditions started together. Their coexistence may have resulted from the dysfunction of arteriovenous anastomoses which are implicated in both diseases. Pathological expansion of the anastomoses while small arteries and arterioles are in cold spasm leads to an attack in Raynaud’s disease, whereas in a warm environment such expansion
might cause erythromelalgia. Kuibyshev Medical Institute, Post Box 703, Post Office 100, Kuibyshev 443100, USSR
G. E. SLUTSKER
Short-term continuous infusion of mitozantrone for advanced breast cancer SIR,-Professor Harris and colleagues (Jan 27, p 186) compare four cycles of mitozantrone with continued treatment in responding breast cancer patients, and record similar disease-free survival in the two groups. Their findings are corroborated by our results in patients with non-pretreated breast cancer, who received continuous infusion of mitozantrone (11mg/m2 daily) over 2 weeks, repeated every 4 weeks for four cycles-a schedule chosen, on the basis of an earlier phase-I study,’ to keep side-effects to a minimum while maintaining optimum efficacy. Ten patients were investigated (mean age 53 years, range 36-68), and two had received cyclophosphamide/methotrexate/5-fluorouracil adjuvant therapy. Responses were complete in two (9 and over 19 months), partial in
854
four (4, 7, 8, and over 16 months), and stable in four (5, 6, 12, and over 20 months). We found leucopenia grade III in fifteen and grade IV in fourteen of forty treatment cycles. Unfortunately, we had to close the study prematurely because of side-effects: implantation of the venous access port resulted in axillary vein thrombosis in four patients (two of whom had pulmonary embolism), demonstrated by a perfusion lung scan; the third patient died suddenly of unknown cause. Two patients had received radiotherapy to this area previously. A clinical syndrome of peripheral vasculitis with cyanotic painful extremities without clotting abnormalities or signs of diffuse intravascular coagulation developed in one patient, but resolved spontaneously after mitozantrone treatment was ended. Despite the short treatment time, four patients are still alive and three remain in remission at 16, 19, and 20 months, respectively, after the start of treatment. These findings are an improvement on the maximum progression-free survival of 50 weeks in responding patients in Harris and colleagues’ study, despite the unfavourable disease sites (liver in one, pleura in one, pulmonary lymphangitis in one). Treatment of short duration may indeed be effective over longer periods, although continuous exposure to the cytostatic drug may offer a therapeutic advantage, being better tolerated, and may be even more effective than bolus therapy.
Department of Medical Oncology, University of Groningen, 9713 EZ Groningen, Netherlands
N. H. MULDER P. H. B. WILLEMSE E. G. E. DE VRIES A. G. NANNINGA D. TH. SLEIJFER
evidence for cosecretion of IAPP and insulin. Reduction of p-cell function and suppression of insulin release in IDDM II, or near complete damage of the endocrine pancreas in DM I, seems to be reflected by reduced or even absent plasma IAPP. Van Jaarsveld and colleagues do not provide data on the sensitivity of their assay system. In our hands, and according to the manufacturer, the lower limit of the linear range of the RIA system is about 10 pg per vial. Therefore the lowest concentration of detectable IAPP-irm would be 40 pg/ml if 05 ml of plasma is used and duplicate measurements are done. If too small an amount of plasma is used the test will be inaccurate, which might account for the high plasma-IAPP concentrations as well as the failure to detect differences between the groups. Our data provide further evidence for cosecretion of insulin and IAPP, and support the idea that DM II might be partly the result of a dysregulation of the physiologically sensitive cosecretion of insulin with its agonist IAPP. University Medical Clinic II, and Ludwig Boltzmann Institute for Clinical Endocrinology, A-1090 Vienna, Austria
1. Westermark
P, Wernstedt C, Wilander E, Hayden DW, O’Bnen TD, Johnson KH. Amyloid fibrils m human insulinoma and islets of Langerhans of the diabetic cat are denved from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA 1987; 84: 3881-85.
2.
3. 1. Greidanus
J, de Vries EGE, Mulder NH, et al. A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone. J Clin Oncol 1989; 7: 790-97.
Reduced
islet-amyloid polypeptide in insulin-dependent diabetes mellitus
SIR,-Dr Van Jaarsveld and colleagues (Jan 6, p 60) report islet-amyloid polypeptide (IAPP) concentrations in human plasma. IAPP has been isolated from human insulinoma tissue1 as well as from pancreas of type 2 diabetic patients.2 IAPP induces insulinresistance.3-5 By its deposition as pancreatic amyloid it destroys the p-cells. IAPP is being investigated as one of the factors in the pathophysiology of diabetes mellitus type 2.6 Our group has also established an IAPP radioimmunoassay (RIA). RIA components are identical to those used by Van Jaarsveld et al (Peninsula, Belmont, CA, USA). We extracted IAPP immunoreactive material (IAPP-irm) from EDTA-plasma (usually 5 ml) by ’Sep-Pak C18’ cartridges (Waters/Millipore, Milford, MA, USA). IAPP-irm is desorbed by a solution containing methanol/tri-fluoroacetic acid/water in the volume ratio of 90/0-5/ 9-5. Vacuum-concentration (’Speed-Vac’, Savant Instruments) yields dry plasma-extracts. These finally are reconstituted in phosphate RIA buffer and IAPP-irm is measured by conventional RIA (second antibody from Sorin/Biomedica, Saluggia, Italy). The linear range of the RIA is 10-100 pg per vial, and within and between run precisions are 10% and 15%, respectively. If 5 ml of plasma is used, the detection limit of the assay is 2-5 pg/ml. We found the following fasting plasma levels of IAPP-irm in healthy controls and in patients with type 2 diabetes (NIDDM II, oral antidiabetic drugs; IDDM II, receiving insulin) and type 1 diabetes
(DM1):
Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB. Purification and characterisation of a peptide from amyloid polypeptide of type 2 diabetic patients. Proc Natl Acad Sci USA 1987; 84: 8628-32. Leighton B, Garth JS, Cooper JS. Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 1988; 335:
632-35. 4.
Cooper GJ, Leighton B, Dimitriadis, GD, et al. Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen
metabolism in skeletal muscle. Proc Natl Acad Sci USA 1988; 85: 7763-66. Johnson KH, O’Bnen TD, Jordan K, Westermark P Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAAP) immunoreactivity in pancreatic beta cells. Am J Pathol 1989; 135: 245-50. 6. Johnson KH, O’Bnen TD, Betsholtz C, Westermark P. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 1989; 321: 513-18 7. Nakazato M, Asai J, Kangawa K, Matsukura S, Matsuo H. Establishment of radioimmunoassay for human islet amyloid polypeptide and its tissue content and plasma concentration. Biochem Biophys Res Commun 1989; 164: 394-99. 5.
Silica and
*Two-tailed Kruskall-Wallis test.
lung
cancer
SIR,-Dr Infante-Rivard and colleagues (Dec 23/30, p 1504) review
retrospective cohort of Quebec males with silicosis receiving compensation. The study was carefully designed and analysed, and is clearly described. However, the implication of a causative role for silica exposure in the development of lung cancer must remain speculative. Infante-Rivard et al acknowledge the selection bias intrinsic in those who had received compensation in 1938-85, on criteria adhered to with varying rigour by compensation boards. Exposure, clinical signs, and radiographic features were the three criteria. One may assume compensated males to have more silicosis (ie, exposure) than non-compensated males. Alternatively, those compensated may have had less pulmonary reserve and were thus more likely to seek and to receive such compensation. Any factor (eg, smoking) affecting pulmonary reserve would move the standardised mortality ratio (SMR) away from the null hypothesis. Smoking may have been a confounder (93% "ever-smokers" in the cohort vs 82% in the standard Quebec male population) but we a
know how much was smoked-critical information, since all lung cancer epidemiological data since Doll and Hill’s landmark paper have shown that SMRs for lung cancer vary directly with amount smoked. In the Vermont granite workers’ study1 almost all the workers had smoked, and Costello and Graham rightly hestitated to link silica exposure independently with an increased risk of lung cancer. In the Quebec cohort no deaths from lung cancer were reported among those who had never smoked. The study lacks the statistical power to detect a stable lung cancer rate among compensated non-smokers; nonetheless we need a better handle on this critical confounder, for only then can we begin to move from a qualified association to an ability to trace causality. can never
IAPP values for controls are in accord with those of Nakazato et al7 The significantly reduced IAPP levels in IDDM II and DM I are
E. HARTTERT. SVOBODA B. LELL M. SCHULLER B. LUDVIK W. WOLOSZCZUK R. PRAGER
Linkage Study data include all contacts with specialist psychiatric services, and because data are linked sequences of episodes of the care of individuals, schizophrenia at first-ever contact can be distinguished from schizophrenia first diagnosed at a later stage. Truncated age-standardardised rates for people aged 15 and over, standardised by the direct method with the 1981 population of Oxfordshire as the standard, are shown in the figure. The total number of people with a first-recorded diagnosis of schizophrenia was much higher than the number diagnosed as schizophrenia at first-ever psychiatric contact alone. In males both these measures, and first-ever inpatient admission rates alone, showed a significant decline in the mid-to-late 1970s similar to that reported by Der et al. The pattern for females was much less clear-cut. Further explanations for the decline in first-contact rates for males include changes in diagnostic fashion, any increased tendency for general practitioners to treat schizophrenics without referral to a specialist, a decrease in severity, and (in local studies) any tendency for people predisposed to schizophrenia to migrate out of the population studied or any increase in inward migration by people not predisposed. Our data add some support to the suggestion that schizophrenia has declined in males, though not in females, in the period 1975-86. Oxford Record
In our view, however, the evidence is not conclusive. We do have comparable data for years before 1975. Unit of Clinical Epidemiology, Oxford University, Oxford Regional Health Authority, Oxford OX3 7LF, UK
not
JACQUELINE ALARCON VALERIE SEAGROATT MICHAEL GOLDACRE DE
1. World Health
Organisation The international pilot study of schizophrenia. Geneva. WHO, 1973. 2. Cooper JE, Kendell RE, Garland BJ, Sharpe L, Copeland JRM, Simon R. Psychiatric diagnosis in New York and London: a comprehensive study of mental hospital admissions (Maudsley Monogr no 20). London: Oxford Univesity Press, 1972.
SiR,—Elsewhere I argue that Kraepelin’s and Bleuler’s concepts of dementia praecox and schizophrenia were mistakenly derived from a population suffering mainly from physical disorders, notably encephalitis lethargica and its sequel, post-encephalitic parkinsonism. The years following von Economo’s descriptions of this infection and its consequences (after Kraepelin and Bleuler had completed their major writings) were characterised by diagnostic confusion; clinicians diagnosed schizophrenia but found it difficult to distinguish the condition from post-encephalitic parkinsonism. Efforts at differentiation were marked by contradiction and non-specificity. More important, they were based on the unfounded assumption that Kraepelin and Bleuler had provided evidence in support of their concepts. In other words, the task of differential diagnosis begged the question of the validity of "dementia praecox" and "schizophrenia".2 The suggestion that Kraepelin and Bleuler were dealing, at least in part, with the neurological sequelae of infectious diseases is very different from the hypothesis that schizophrenia is an infectious disease.3,4That claim, too, is based on an unjustified confidence in the validity of Kraepelin’s and Bleuler’s concepts. My suggestion is that the original concepts of dementia praecox and schizophrenia were mistakenly inferred from at least one now well-described infectious disease and its sequelae. It is difficult to know what implications this claim would have for subsequent rates of schizophrenia diagnosis. Reliable figures for the prevalence of the virus assumed to be implicated in encephalitis lethargica are not available, although it is generally believed to have declined sharply after the epidemic of 1916-27.5 von Economo, however, thought that the virus was passed from mother to fetus, and Sacks has cautioned against the naive assumption that such viruses "disappear" after highly visible epidemics.6 Also the concept of schizophrenia has gradually been transformed from the strongly physical and neurological, as well as behavioural, concept of Kraepelin and Bleuler, to the more behavioural/experiential one of DSM-IIIR. It is quite possible that many patients today who are said to have schizophrenia only superficially resemble Kraepelin’s
and Bleuler’s cases. Nonetheless I suspect that the apparent decline in incidence of schizophrenia is not unrelated to the decline in post-encephalitic parkinsonism. Questions such as "Where have all the catatonic (and severely deteriorated) schizophrenics gone?" may have answers that are at least similar to those to the question "Where have all the cases of post-encephalitic parkinsonism gone?" Department of Psychology, Polytechnic of East London,
MARY BOYLE
London E15 4LZ, UK
1. Boyle M. Schizophrenia: a scientific delusion? London: Routledge, 1990. 2. Boyle M. Is schizophrenia what it was? A re-analysis of Kraepelm’s and Bleuler’s populations. J Hist Behav Sci (in press). 3. Crow TJ. A re-evaluation of the viral hypothesis: is psychosis the result of retroviral integration at a site close to the cerebral dominance gene? Br J Psychiatry 1984; 145: 243-53. 4. Hare EH. Schizophrenia as an infectious disease In: Kerr A, Snaith P, eds. Contemporary issues in schizophrenia. London Royal College of Psychiatrists/ Gaskell, 1986. 5. Pallis CA. Parkinsonism: natural history and clinical features Br Med J 1981; iii. 683-90. 6. Sacks O. Parkinsonism: a so-called new disease? Br Med J 1971; iii: 111.
Coexistence of Raynaud’s syndrome and
erythromelalgia SiR,—Erythromelalgia is known as the inverse Raynaud’s syndrome; the former disease can be induced by treatment of the latter. We report a woman with Raynaud’s syndrome and erythromelalgia. A 40-year-old woman had had, for 5 years, episodes of pallor and blue discolouration of the fingers and toes after cooling and emotional exertion. During these 5 years she also had intolerance to warming of the feet, which manifested attacks of pulsating pain and burning sensations. She had about ten cold and five to seven hot induced paroxysms daily. There were no trophic changes or oedema of the fingers and toes. Distal pulsation remained. Adson’s and Allen’s tests were negative. A cold provocation test induced pallor and blue discolouration of the fingers and toes. A hot provocation test induced pulsating pain and red discolouration of the feet. Biochemical investigation revealed accelerated ADPinduced platelet aggregation. The patient was otherwise healthy. She was given nifedipine (40 mg daily), dihydroergocristine (1-5mg daily), aspirin (750 mg daily), and hyperbaric oxygen sessions (1 ’7 atmospheres absolute, 45 min, seven sessions). After 3 weeks she was discharged and no longer had either hot or cold induced paroxysms.
I cannot explain with certainty how or why the two conditions started together. Their coexistence may have resulted from the dysfunction of arteriovenous anastomoses which are implicated in both diseases. Pathological expansion of the anastomoses while small arteries and arterioles are in cold spasm leads to an attack in Raynaud’s disease, whereas in a warm environment such expansion
might cause erythromelalgia. Kuibyshev Medical Institute, Post Box 703, Post Office 100, Kuibyshev 443100, USSR
G. E. SLUTSKER
Short-term continuous infusion of mitozantrone for advanced breast cancer SIR,-Professor Harris and colleagues (Jan 27, p 186) compare four cycles of mitozantrone with continued treatment in responding breast cancer patients, and record similar disease-free survival in the two groups. Their findings are corroborated by our results in patients with non-pretreated breast cancer, who received continuous infusion of mitozantrone (11mg/m2 daily) over 2 weeks, repeated every 4 weeks for four cycles-a schedule chosen, on the basis of an earlier phase-I study,’ to keep side-effects to a minimum while maintaining optimum efficacy. Ten patients were investigated (mean age 53 years, range 36-68), and two had received cyclophosphamide/methotrexate/5-fluorouracil adjuvant therapy. Responses were complete in two (9 and over 19 months), partial in
854
four (4, 7, 8, and over 16 months), and stable in four (5, 6, 12, and over 20 months). We found leucopenia grade III in fifteen and grade IV in fourteen of forty treatment cycles. Unfortunately, we had to close the study prematurely because of side-effects: implantation of the venous access port resulted in axillary vein thrombosis in four patients (two of whom had pulmonary embolism), demonstrated by a perfusion lung scan; the third patient died suddenly of unknown cause. Two patients had received radiotherapy to this area previously. A clinical syndrome of peripheral vasculitis with cyanotic painful extremities without clotting abnormalities or signs of diffuse intravascular coagulation developed in one patient, but resolved spontaneously after mitozantrone treatment was ended. Despite the short treatment time, four patients are still alive and three remain in remission at 16, 19, and 20 months, respectively, after the start of treatment. These findings are an improvement on the maximum progression-free survival of 50 weeks in responding patients in Harris and colleagues’ study, despite the unfavourable disease sites (liver in one, pleura in one, pulmonary lymphangitis in one). Treatment of short duration may indeed be effective over longer periods, although continuous exposure to the cytostatic drug may offer a therapeutic advantage, being better tolerated, and may be even more effective than bolus therapy.
Department of Medical Oncology, University of Groningen, 9713 EZ Groningen, Netherlands
N. H. MULDER P. H. B. WILLEMSE E. G. E. DE VRIES A. G. NANNINGA D. TH. SLEIJFER
evidence for cosecretion of IAPP and insulin. Reduction of p-cell function and suppression of insulin release in IDDM II, or near complete damage of the endocrine pancreas in DM I, seems to be reflected by reduced or even absent plasma IAPP. Van Jaarsveld and colleagues do not provide data on the sensitivity of their assay system. In our hands, and according to the manufacturer, the lower limit of the linear range of the RIA system is about 10 pg per vial. Therefore the lowest concentration of detectable IAPP-irm would be 40 pg/ml if 05 ml of plasma is used and duplicate measurements are done. If too small an amount of plasma is used the test will be inaccurate, which might account for the high plasma-IAPP concentrations as well as the failure to detect differences between the groups. Our data provide further evidence for cosecretion of insulin and IAPP, and support the idea that DM II might be partly the result of a dysregulation of the physiologically sensitive cosecretion of insulin with its agonist IAPP. University Medical Clinic II, and Ludwig Boltzmann Institute for Clinical Endocrinology, A-1090 Vienna, Austria
1. Westermark
P, Wernstedt C, Wilander E, Hayden DW, O’Bnen TD, Johnson KH. Amyloid fibrils m human insulinoma and islets of Langerhans of the diabetic cat are denved from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA 1987; 84: 3881-85.
2.
3. 1. Greidanus
J, de Vries EGE, Mulder NH, et al. A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone. J Clin Oncol 1989; 7: 790-97.
Reduced
islet-amyloid polypeptide in insulin-dependent diabetes mellitus
SIR,-Dr Van Jaarsveld and colleagues (Jan 6, p 60) report islet-amyloid polypeptide (IAPP) concentrations in human plasma. IAPP has been isolated from human insulinoma tissue1 as well as from pancreas of type 2 diabetic patients.2 IAPP induces insulinresistance.3-5 By its deposition as pancreatic amyloid it destroys the p-cells. IAPP is being investigated as one of the factors in the pathophysiology of diabetes mellitus type 2.6 Our group has also established an IAPP radioimmunoassay (RIA). RIA components are identical to those used by Van Jaarsveld et al (Peninsula, Belmont, CA, USA). We extracted IAPP immunoreactive material (IAPP-irm) from EDTA-plasma (usually 5 ml) by ’Sep-Pak C18’ cartridges (Waters/Millipore, Milford, MA, USA). IAPP-irm is desorbed by a solution containing methanol/tri-fluoroacetic acid/water in the volume ratio of 90/0-5/ 9-5. Vacuum-concentration (’Speed-Vac’, Savant Instruments) yields dry plasma-extracts. These finally are reconstituted in phosphate RIA buffer and IAPP-irm is measured by conventional RIA (second antibody from Sorin/Biomedica, Saluggia, Italy). The linear range of the RIA is 10-100 pg per vial, and within and between run precisions are 10% and 15%, respectively. If 5 ml of plasma is used, the detection limit of the assay is 2-5 pg/ml. We found the following fasting plasma levels of IAPP-irm in healthy controls and in patients with type 2 diabetes (NIDDM II, oral antidiabetic drugs; IDDM II, receiving insulin) and type 1 diabetes
(DM1):
Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB. Purification and characterisation of a peptide from amyloid polypeptide of type 2 diabetic patients. Proc Natl Acad Sci USA 1987; 84: 8628-32. Leighton B, Garth JS, Cooper JS. Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 1988; 335:
632-35. 4.
Cooper GJ, Leighton B, Dimitriadis, GD, et al. Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen
metabolism in skeletal muscle. Proc Natl Acad Sci USA 1988; 85: 7763-66. Johnson KH, O’Bnen TD, Jordan K, Westermark P Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAAP) immunoreactivity in pancreatic beta cells. Am J Pathol 1989; 135: 245-50. 6. Johnson KH, O’Bnen TD, Betsholtz C, Westermark P. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med 1989; 321: 513-18 7. Nakazato M, Asai J, Kangawa K, Matsukura S, Matsuo H. Establishment of radioimmunoassay for human islet amyloid polypeptide and its tissue content and plasma concentration. Biochem Biophys Res Commun 1989; 164: 394-99. 5.
Silica and
*Two-tailed Kruskall-Wallis test.
lung
cancer
SIR,-Dr Infante-Rivard and colleagues (Dec 23/30, p 1504) review
retrospective cohort of Quebec males with silicosis receiving compensation. The study was carefully designed and analysed, and is clearly described. However, the implication of a causative role for silica exposure in the development of lung cancer must remain speculative. Infante-Rivard et al acknowledge the selection bias intrinsic in those who had received compensation in 1938-85, on criteria adhered to with varying rigour by compensation boards. Exposure, clinical signs, and radiographic features were the three criteria. One may assume compensated males to have more silicosis (ie, exposure) than non-compensated males. Alternatively, those compensated may have had less pulmonary reserve and were thus more likely to seek and to receive such compensation. Any factor (eg, smoking) affecting pulmonary reserve would move the standardised mortality ratio (SMR) away from the null hypothesis. Smoking may have been a confounder (93% "ever-smokers" in the cohort vs 82% in the standard Quebec male population) but we a
know how much was smoked-critical information, since all lung cancer epidemiological data since Doll and Hill’s landmark paper have shown that SMRs for lung cancer vary directly with amount smoked. In the Vermont granite workers’ study1 almost all the workers had smoked, and Costello and Graham rightly hestitated to link silica exposure independently with an increased risk of lung cancer. In the Quebec cohort no deaths from lung cancer were reported among those who had never smoked. The study lacks the statistical power to detect a stable lung cancer rate among compensated non-smokers; nonetheless we need a better handle on this critical confounder, for only then can we begin to move from a qualified association to an ability to trace causality. can never
IAPP values for controls are in accord with those of Nakazato et al7 The significantly reduced IAPP levels in IDDM II and DM I are
E. HARTTERT. SVOBODA B. LELL M. SCHULLER B. LUDVIK W. WOLOSZCZUK R. PRAGER
