1422
human skin following ultraviolet B irradiation. Br J Clin Pharmacol 1982; 13: 351-54. 12. Punnonen K, Puustinen T, Jansen CT. Ultraviolet B irradiation induces changes in the distribution and release of arachidonic acid, dihomo&ggr;-linolenic acid, and eicosapentaenoic acid in human keratinocytes in culture. J Invest Dermatol 1987; 88: 611-14. 13. Aberer W, Schuler G, Stingl G. Ultraviolet light depletes surface markers of Langerhans cells. J Invest Dermatol 1981; 76: 202-10. 14. Kripke ML. Immunological unresponsiveness induced by ultraviolet radiation. Immunol Rev 1984; 80: 87-102. 15. Howie S, Norval M, Maingay J. Exposure to low-dose ultraviolet radiation suppresses delayed-type hypersensitivity to herpes simplex virus in mice. J Invest Dermatol 1986; 86: 125-28. 16. Edwards EK Jr, Edwards EK Sr, Frank BL. Rosen LB. The effect of an ultraprotective sunscreen on Langerhans cell alteration induced by ultraviolet light in human skin. Int J Dermatol 1986; 25: 327-29. 17. Fisher MS, Menter JM, Willis I. Ultraviolet radiation-induced suppression of contact hypersensitivity in relation to padimate 0 and oxybenzone. J Invest Dermatol 1989; 92: 337-41. 18. Openshaw H, Puga A, Notkins AL. Herpes simplex virus infection in sensory ganglia: immune control, latency and reactivation. Fed Proc 1979; 38: 2660-64. 19. Lycke E, Kristensson K, Svennerholm B, Vahlne A, Ziegler R. Uptake and transport of herpes simplex virus in neurites of rat dorsal root ganglia cells in culture. J Gen Virol 1984; 65: 55-64. 20. Blank H, Haines H. Experimental human reinfection with herpes simplex virus. J Invest Dermatol 1973; 61: 223-25. 21. Hill TJ, Blyth WA. An alternative theory of herpes simplex recurrence and a possible role for prostaglandins. Lancet 1976; i: 397-99. 22. Clements GB, Subak-Sharpe JH. Herpes simplex virus type 2 establishes latency in the mouse footpad. J Gen Virol 1988; 69: 375-83.
SHORT REPORTS
TABLE I-CLINICAL DETAILS OF STUDY PATIENTS I
I
I
i
i
i
i
i
B-bilateral, R = right L=left, EDH=extradural haematoma, SDH=subdural haematoma, ICH Intracerebral haematoma, ICP intracranial pressure =
head
=
include neuronal and axonal damage due to contusions, ischaemic damage, diffuse axonal injury, and raised intracranial pressure.2 We have reported another feature3-the presence of diffuse &bgr;A4 amyloid protein plaques in the cortex-both after a single episode of head trauma3and after repeated domestic violence. The most extreme example of this type of amyloid deposition is the punch-drunk syndrome ofboxers.4 Others have argued that our observations have been limited to extremes of the clinical spectrum. To test our hypothesis that head injury can trigger &bgr;A4 deposition in the cortex, we have begun to examine the brains of head trauma trauma
patients. (fourteen male, two female) were studied (table i). Eight injured in falls, six in road traffic accidents, one in an assault, and one when hit by a train. As well as the head injury, patient 3 had meningitis and vasculitis, patient 4 rupture of spleen and kidney, patient 5 cerebral abscess, patients 12 and 14 multiple fractures, and patient 15 pulmonary embolism. Full necropsy was done in every case. The brain was suspended Sixteen patients
&bgr;A4 amyloid protein deposition
in
brain after head trauma
were
in 10% normal saline for 3-4 weeks. Dissection was done in a standard way: the cerebral hemispheres were sliced in the coronal plane, the cerebellum at right angles to the folia, and the brainstem
Previous reports have suggested that both repetitive head trauma and a single injury can be associated with the presence of diffuse &bgr;A4 amyloid protein plaques in long-term survivors. We have studied sixteen patients (aged 10-63 years) who sustained head injury and survived for only 6-18 days. Immunostaining with an antibody to &bgr;A4 amyloid showed extensive deposits of the protein in the cortex in six of the sixteen patients (38%). Thus, severe head injury can trigger &bgr;A4 deposition in the brain within days.
In head injury, clinical attention focuses on the management of the patient in the first 48 h. However, about a third of patients who survive the initial trauma, experience long-term sequelae, which range from permanent debilitating neurological deficits to more subtle psychiatric symptoms.1 The neuropathological consequences of closed
horizontally. Comprehensive histology was undertaken. We assessed the amount of contusional injury and the severity of any ischaemic damage and diffuse axonal injury, and sought supratentorial expanding lesions which could have caused high intracranial pressure before the head trauma.2 2 All sections were pretreated with 80% formic acid for 5 min then incubated overnight with a monoclonal antibody to the &bgr;A4 protein
TABLE ll-EXTENT OF &bgr;A4 IMMUNOSTAINING IN SIX POSITIVE CASES
*-
negative, + sparse, + + moderate, + + + dense tClasslc plaques V vascular deposit ‡&bgr;A4 immunoreactivity also observed in other neocortical
areas
1423
(Dako Ltd, UK) at a dilution of 1/1000. They were then processed’ and counterstained with haematoxylin. All sections were processed at
the same time to minimise any variation in
K, Tanzi RE, Kogure K. Selective induction of Kunitz-type protease inhibitor domain-containing amyloid precursor protein mRNA after persistent focal ischaemia in rat cerebral cortex. Neurosci
7. Abe
staining.
On microscopy, six of the sixteen patients (38%) showed evidence of pA4 deposition (table 11) in varying amounts. The pA4 deposits differed in nature from, and were more extensive than, those seen in a series of 65 controls without head injury (aged 14-99 years). Two factors emerged on the relation of the amount of pA4 and the clinical and histological features. First, of the six patients with deposits, the four with contusions and skull fractures had greater deposits than the two without, irrespective of age. Second, the deposits were restricted or focal and in patient 7 were found in only one hemisphere. Our findings accord with the hypothesis that head injury can trigger the pathological response of pA4 protein deposition. Substantial pA4 deposits in the cortex are a prominent feature of Alzheimer’s diseased It could be argued that the head-injured patients we examined already had a dementing process that contributed to their head trauma. However, it seems highly unlikely that of the first sixteen patients examined, six should have preclinical Alzheimer’s disease, when the reported prevalence in people under 65 years is less than 0.01%.6 The prevalence in the elderly is, of course, much higher.6 Our most surprising fmding is the short time between head injury and the appearance of pA4 deposits. The process of pA4 deposition and plaque formation in Alzheimer’s disease is assumed to be gradual, over months or years. Our finding that deposition can occur within days of a trigger event is supported by animal studies.7,8 Our results and the data from animal studies suggest that the induction of amyloid precursor protein mRNA in the brain is a normal response to neuronal stress. However, this normal, possibly protective, induction can become a disease process in susceptible individuals. About 20% of cases of Alzheimer’s disease are thought to be familial9 and the remainder are due to environmental factors, which may or may not interact with the patient’s genotype. Head injury is the most consistently associated environmental factor, implicated in 2-20% of Alzheimer’s disease cases Neuropathological studies also support the association. We are now investigating the percentage of long-term survivors of head injury in whom Alzheimer’s disease
develops. This work was supported by the Mental Health Foundation and a Medical Research Council project grant.
Lett 1991; 125: 172-74. 8.
Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 1991; 12: 383-88.
Duijn CM, Hofman A, Kay DWK. Risk factors for Alzheimer’s disease: a collaborative analysis of case-control studies. Int J Epidermol 1991; 20: S4. 10. Mortimer JA, van Duijn CM, Chandra V, et al. Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of casecontrol studies. Int J Epidemiol 1991; 20: S28. 9.
van
ADDRESSES:
Serious Mental Afflictions
Research
Team,
Department of Anatomy, St Mary’s Hospital Medical School, Imperial College of Science, Technology and Medicine, London (G W. Roberts, PhD, S M Gentleman, PhD), and Department of Neuropathology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK (A. Lynch, D I. Graham, FRCPath). Correspondence to Dr G W. Roberts, Department of Anatomy, St Mary’s Hospital Medical School, Norfolk Place, London W2 1 PG, UK.
Production of interleukin-1-
receptor antagonist during
experimental endotoxaemia
Interleukin-1 (IL-1) has been implicated in the pathogenesis of sepsis. IL-1-receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 activity that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We induced endotoxaemia in 9 healthy human volunteers by injection of Escherichia coli endotoxin, and measured plasma concentrations of IL-1 and IL-1ra by radioimmunoassay during the next 24 h. Peak plasma concentrations of IL-1ra were about a hundred-fold greater than those of IL-1&bgr;. No IL-1 or IL-1ra were detectable in the plasma of 4 volunteers injected with saline. Our results suggest that the predominant natural response to endotoxin in man is the production of antagonist rather than agonist.
REFERENCES 1. Editorial Head trauma victims in the UK: undeservedly underserved. Lancet 1990; 335: 886-87. 2. Graham DI. Trauma. In: Weller RO, ed. Systemic pathology, 3rd ed: vol 4 Nervous system, muscle and eyes. Edinburgh: Churchill Livingstone, 1990: 125-50. 3. Clinton J, Ambler MW, Roberts GW. Post-traumatic Alzheimer’s disease: preponderance of a single plaque type. Neuropathol Appl Neurobiol 1991; 17: 69-74. 4. Roberts GW, Allsop D, Bruton CJ. The occult aftermath of boxing. J Neurol Neurosurg Psychiatr 1990; 53: 373-78. 5. Gentleman SM, Bruton CJ, Allsop D, et al. A demonstration of the advantages of immunostaining in the quantification of amyloid plaque deposits. Histochemistry 1989; 92: 355-58. 6. Alzheimer’s Disease Society. Alzheimer’s disease and the young sufferer. London: Alzheimer’s Disease Society, 1990.
Injection of interleukin-1 (IL-1) can induce severe hypotension in animals and man;l.2 furthermore, IL-1 and tumour necrosis factor can act together to produce a shock-like state with pulmonary changes characteristic of acute respiratory distress syndrome.3 Other host responses to infection, such as fever, neutrophilia, increased circulating cortisol, and hepatic acute-phase-protein synthesis, are also induced by IL-1. Increased synthesis of IL-1 occurs during sepsis, flares of rheumatoid arthritis, transplant rejection, haemodialysis, and experimental
human skin following ultraviolet B irradiation. Br J Clin Pharmacol 1982; 13: 351-54. 12. Punnonen K, Puustinen T, Jansen CT. Ultraviolet B irradiation induces changes in the distribution and release of arachidonic acid, dihomo&ggr;-linolenic acid, and eicosapentaenoic acid in human keratinocytes in culture. J Invest Dermatol 1987; 88: 611-14. 13. Aberer W, Schuler G, Stingl G. Ultraviolet light depletes surface markers of Langerhans cells. J Invest Dermatol 1981; 76: 202-10. 14. Kripke ML. Immunological unresponsiveness induced by ultraviolet radiation. Immunol Rev 1984; 80: 87-102. 15. Howie S, Norval M, Maingay J. Exposure to low-dose ultraviolet radiation suppresses delayed-type hypersensitivity to herpes simplex virus in mice. J Invest Dermatol 1986; 86: 125-28. 16. Edwards EK Jr, Edwards EK Sr, Frank BL. Rosen LB. The effect of an ultraprotective sunscreen on Langerhans cell alteration induced by ultraviolet light in human skin. Int J Dermatol 1986; 25: 327-29. 17. Fisher MS, Menter JM, Willis I. Ultraviolet radiation-induced suppression of contact hypersensitivity in relation to padimate 0 and oxybenzone. J Invest Dermatol 1989; 92: 337-41. 18. Openshaw H, Puga A, Notkins AL. Herpes simplex virus infection in sensory ganglia: immune control, latency and reactivation. Fed Proc 1979; 38: 2660-64. 19. Lycke E, Kristensson K, Svennerholm B, Vahlne A, Ziegler R. Uptake and transport of herpes simplex virus in neurites of rat dorsal root ganglia cells in culture. J Gen Virol 1984; 65: 55-64. 20. Blank H, Haines H. Experimental human reinfection with herpes simplex virus. J Invest Dermatol 1973; 61: 223-25. 21. Hill TJ, Blyth WA. An alternative theory of herpes simplex recurrence and a possible role for prostaglandins. Lancet 1976; i: 397-99. 22. Clements GB, Subak-Sharpe JH. Herpes simplex virus type 2 establishes latency in the mouse footpad. J Gen Virol 1988; 69: 375-83.
SHORT REPORTS
TABLE I-CLINICAL DETAILS OF STUDY PATIENTS I
I
I
i
i
i
i
i
B-bilateral, R = right L=left, EDH=extradural haematoma, SDH=subdural haematoma, ICH Intracerebral haematoma, ICP intracranial pressure =
head
=
include neuronal and axonal damage due to contusions, ischaemic damage, diffuse axonal injury, and raised intracranial pressure.2 We have reported another feature3-the presence of diffuse &bgr;A4 amyloid protein plaques in the cortex-both after a single episode of head trauma3and after repeated domestic violence. The most extreme example of this type of amyloid deposition is the punch-drunk syndrome ofboxers.4 Others have argued that our observations have been limited to extremes of the clinical spectrum. To test our hypothesis that head injury can trigger &bgr;A4 deposition in the cortex, we have begun to examine the brains of head trauma trauma
patients. (fourteen male, two female) were studied (table i). Eight injured in falls, six in road traffic accidents, one in an assault, and one when hit by a train. As well as the head injury, patient 3 had meningitis and vasculitis, patient 4 rupture of spleen and kidney, patient 5 cerebral abscess, patients 12 and 14 multiple fractures, and patient 15 pulmonary embolism. Full necropsy was done in every case. The brain was suspended Sixteen patients
&bgr;A4 amyloid protein deposition
in
brain after head trauma
were
in 10% normal saline for 3-4 weeks. Dissection was done in a standard way: the cerebral hemispheres were sliced in the coronal plane, the cerebellum at right angles to the folia, and the brainstem
Previous reports have suggested that both repetitive head trauma and a single injury can be associated with the presence of diffuse &bgr;A4 amyloid protein plaques in long-term survivors. We have studied sixteen patients (aged 10-63 years) who sustained head injury and survived for only 6-18 days. Immunostaining with an antibody to &bgr;A4 amyloid showed extensive deposits of the protein in the cortex in six of the sixteen patients (38%). Thus, severe head injury can trigger &bgr;A4 deposition in the brain within days.
In head injury, clinical attention focuses on the management of the patient in the first 48 h. However, about a third of patients who survive the initial trauma, experience long-term sequelae, which range from permanent debilitating neurological deficits to more subtle psychiatric symptoms.1 The neuropathological consequences of closed
horizontally. Comprehensive histology was undertaken. We assessed the amount of contusional injury and the severity of any ischaemic damage and diffuse axonal injury, and sought supratentorial expanding lesions which could have caused high intracranial pressure before the head trauma.2 2 All sections were pretreated with 80% formic acid for 5 min then incubated overnight with a monoclonal antibody to the &bgr;A4 protein
TABLE ll-EXTENT OF &bgr;A4 IMMUNOSTAINING IN SIX POSITIVE CASES
*-
negative, + sparse, + + moderate, + + + dense tClasslc plaques V vascular deposit ‡&bgr;A4 immunoreactivity also observed in other neocortical
areas
1423
(Dako Ltd, UK) at a dilution of 1/1000. They were then processed’ and counterstained with haematoxylin. All sections were processed at
the same time to minimise any variation in
K, Tanzi RE, Kogure K. Selective induction of Kunitz-type protease inhibitor domain-containing amyloid precursor protein mRNA after persistent focal ischaemia in rat cerebral cortex. Neurosci
7. Abe
staining.
On microscopy, six of the sixteen patients (38%) showed evidence of pA4 deposition (table 11) in varying amounts. The pA4 deposits differed in nature from, and were more extensive than, those seen in a series of 65 controls without head injury (aged 14-99 years). Two factors emerged on the relation of the amount of pA4 and the clinical and histological features. First, of the six patients with deposits, the four with contusions and skull fractures had greater deposits than the two without, irrespective of age. Second, the deposits were restricted or focal and in patient 7 were found in only one hemisphere. Our findings accord with the hypothesis that head injury can trigger the pathological response of pA4 protein deposition. Substantial pA4 deposits in the cortex are a prominent feature of Alzheimer’s diseased It could be argued that the head-injured patients we examined already had a dementing process that contributed to their head trauma. However, it seems highly unlikely that of the first sixteen patients examined, six should have preclinical Alzheimer’s disease, when the reported prevalence in people under 65 years is less than 0.01%.6 The prevalence in the elderly is, of course, much higher.6 Our most surprising fmding is the short time between head injury and the appearance of pA4 deposits. The process of pA4 deposition and plaque formation in Alzheimer’s disease is assumed to be gradual, over months or years. Our finding that deposition can occur within days of a trigger event is supported by animal studies.7,8 Our results and the data from animal studies suggest that the induction of amyloid precursor protein mRNA in the brain is a normal response to neuronal stress. However, this normal, possibly protective, induction can become a disease process in susceptible individuals. About 20% of cases of Alzheimer’s disease are thought to be familial9 and the remainder are due to environmental factors, which may or may not interact with the patient’s genotype. Head injury is the most consistently associated environmental factor, implicated in 2-20% of Alzheimer’s disease cases Neuropathological studies also support the association. We are now investigating the percentage of long-term survivors of head injury in whom Alzheimer’s disease
develops. This work was supported by the Mental Health Foundation and a Medical Research Council project grant.
Lett 1991; 125: 172-74. 8.
Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 1991; 12: 383-88.
Duijn CM, Hofman A, Kay DWK. Risk factors for Alzheimer’s disease: a collaborative analysis of case-control studies. Int J Epidermol 1991; 20: S4. 10. Mortimer JA, van Duijn CM, Chandra V, et al. Head trauma as a risk factor for Alzheimer’s disease: a collaborative re-analysis of casecontrol studies. Int J Epidemiol 1991; 20: S28. 9.
van
ADDRESSES:
Serious Mental Afflictions
Research
Team,
Department of Anatomy, St Mary’s Hospital Medical School, Imperial College of Science, Technology and Medicine, London (G W. Roberts, PhD, S M Gentleman, PhD), and Department of Neuropathology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK (A. Lynch, D I. Graham, FRCPath). Correspondence to Dr G W. Roberts, Department of Anatomy, St Mary’s Hospital Medical School, Norfolk Place, London W2 1 PG, UK.
Production of interleukin-1-
receptor antagonist during
experimental endotoxaemia
Interleukin-1 (IL-1) has been implicated in the pathogenesis of sepsis. IL-1-receptor antagonist (IL-1ra) is a naturally occurring inhibitor of IL-1 activity that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We induced endotoxaemia in 9 healthy human volunteers by injection of Escherichia coli endotoxin, and measured plasma concentrations of IL-1 and IL-1ra by radioimmunoassay during the next 24 h. Peak plasma concentrations of IL-1ra were about a hundred-fold greater than those of IL-1&bgr;. No IL-1 or IL-1ra were detectable in the plasma of 4 volunteers injected with saline. Our results suggest that the predominant natural response to endotoxin in man is the production of antagonist rather than agonist.
REFERENCES 1. Editorial Head trauma victims in the UK: undeservedly underserved. Lancet 1990; 335: 886-87. 2. Graham DI. Trauma. In: Weller RO, ed. Systemic pathology, 3rd ed: vol 4 Nervous system, muscle and eyes. Edinburgh: Churchill Livingstone, 1990: 125-50. 3. Clinton J, Ambler MW, Roberts GW. Post-traumatic Alzheimer’s disease: preponderance of a single plaque type. Neuropathol Appl Neurobiol 1991; 17: 69-74. 4. Roberts GW, Allsop D, Bruton CJ. The occult aftermath of boxing. J Neurol Neurosurg Psychiatr 1990; 53: 373-78. 5. Gentleman SM, Bruton CJ, Allsop D, et al. A demonstration of the advantages of immunostaining in the quantification of amyloid plaque deposits. Histochemistry 1989; 92: 355-58. 6. Alzheimer’s Disease Society. Alzheimer’s disease and the young sufferer. London: Alzheimer’s Disease Society, 1990.
Injection of interleukin-1 (IL-1) can induce severe hypotension in animals and man;l.2 furthermore, IL-1 and tumour necrosis factor can act together to produce a shock-like state with pulmonary changes characteristic of acute respiratory distress syndrome.3 Other host responses to infection, such as fever, neutrophilia, increased circulating cortisol, and hepatic acute-phase-protein synthesis, are also induced by IL-1. Increased synthesis of IL-1 occurs during sepsis, flares of rheumatoid arthritis, transplant rejection, haemodialysis, and experimental
