- Email: [email protected]
The rising cost of independence
206
no
technique has been available for reliable diagnosis
of the disease in the acute stages, there have been few case-reports of "mild" forms ofHSE18 and most cases will go unrecognised. An association between subclinical (possibly recurrent) HSE and subsequent psychiatric or psychotic illness has long been suggested ;19 perhaps prospective longitudinal studies will now settle this issue. Another area in which PCR may prove valuable is in investigation of treatment "failures". A complete course of treatment with either vidarabine2° or acyclovir21 has occasionally been followed by readmission with encephalitis. The differential diagnosis includes incomplete treatment of the initial encephalitic episode (necessitating further acyclovir therapy), drug resistant HSE (necessitating an alternative
herpes simplex encephalitis after conventional acyclovir therapy. JAMA 1988; 259: 1051-53. 22. Rotbart HA. Enzymatic RNA amplification of enteroviruses. J Clin Microbiol 1990; 28: 438-42. 23. Shankar P, Manjunath N. Mohan KK, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991; 337: 5-7.
antiviral
agent), or a perivenous leucoencephalopathy (not requiring antiviral therapy but perhaps improved by anti-inflammatory corticosteroids). PCR techniques for the identification of enterovirus infection of the central nervous system22 and Mycobacterium tuberculosisZ3 have also been developed. The application of these and other virusspecific PCR methods should lead to accurate diagnosis of the 60-70% of cases of acute encephalitis of presumed viral origin.
1.
16. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz C. Establishment of PCR for the early diagnosis of herpes simplex encephalitis. J Med Virol 1990; 32: 77-82. 17. Klapper PE, Cleator GM, Dennett C, Lewis AG. Diagnosis of herpes encephalitis via Southern blotting of CSF DNA amplified by polymerase chain reaction. J Med Virol 1990; 32: 261-64. 18. Klapper PE, Cleator GM, Longson M. Mild forms of herpes encephalitis. J Neurol Neurosurg Psychiatry 1984; 47: 1247-50. 19. Cleobury JF, Skinner GRB, Thonless ME, Wildy MP. Association between psychopathic disorders and serum antibody to herpes simplex (type 1). Br Med J 1971; i: 438-41. 20. Dix RD, Baringer JR, Panitch HS, et al. Recurrent herpes simplex encephalitis: recovery of virus after Ara-A treatment. Ann Neurol 1983; 13: 196-200. 21. Van Landingham KE, Marsteller HB, Ross GW, Hayden FG. Relapse of
Whitley RJ, Soong SJ, Dolin R, et al. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 1977; 297: 289-94.
Sköldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitits. Lancet 1984; ii: 707-11. 3. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitits. N Engl J Med 1986: 314: 2.
144-49. 4. Editorial. Herpes simplex encephalitis. Lancet 1986; i: 535-36. 5. Brick JF, Brick JE, Morgan JJ, Gutierrez AR. EEG and pathologic findings in patients undergoing brain biopsy for suspected encephalitis. Electroencephalographr Clin Neurophysiol 1990; 76: 86-89. 6. Greenberg SB, Taber L, Septimus E, et al. Computerized tomography in brain biopsy proven herpes simplex encephalitits. Arch Neurol 1981; 38: 58-59. 7. Whitley RJ, Cobbs CG, Alford CA, et al. Diseases that mimic herpes simplex encephalitits. JAMA 1989; 262: 234-39. 8. Kahlon J, Chatterjee S, Lakeman FD, Lee F, Nahmias AJ, Whitley RJ. Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 38-44. 9. Lakeman FD, Koga J, Whitley RJ. Detection of antigen to herpes simplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 1172-78. 10. Klapper PE, Cleator GM, Lewis AG. Obstacle to early diagnosis of herpex simples encephalitis via CSF. Lancet 1990; 336: 385-86. 11. Price RW, Saito Y, Fox JJ. Prospects for the use of radiolabelled antiviral drugs in the diagnosis of herpes simplex encephalitis. Biochem Pharmacol 1983; 32: 2455-61. 12. Cleator GM, Klapper PE, Lewis AG, Sharma HL, Longson M. Specific neuro-radiological diagnosis of herpes encephalitis in an animal model. Arch Virol 1988; 101: 1-12. 13. Tovell DR, Samuel J, Mercer JR, et al. The in vitro evaluation of nucleoside analogues as probes for use in the non-invasive diagnosis of herpes simplex encephalitis. Drug Des Deliv 1988; 3: 213-21. 14. Powell KF, Anderson NE, Fnth RW, Croxson MC. Non-invasive diagnosis of herpes simplex encephalitis. Lancet 1990; 335: 357-58. 15. Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 1990; 335: 440-41.
The
rising
cost
of independence
One morning last November a group of British doctors enjoyed a rare and possibly unique experience. Unrestrained by budgetary restriction, overdrained resources, or government "cuts" they were able to estimate the needs of their institution then vote themselves the funds required. Members of the General Medical Council (GMC) could do this because their activities are funded entirely by an annual fee levied on doctors, because the Council itself determines the size of the fee, and because all doctors have to pay it if they wish to work in the National Health Service or indeed in most private hospitals. In the November debate, the GMC justified the near trebling of the fee (from 30 to 80) by saying that it needed the money to meet its statutory obligation to maintain professional standards-though one member did ask acerbicly what standard of performance should be demanded, say, of psychiatrists by a society that chooses to treat the mentally ill by sending them to prison or accommodating them in cardboard boxes. There is no doubt that without this year’s increase the GMC would be headed for the rocks. Its existing deficit is about 1million and, as became clear in November, the Council’s financial management has been far too amateurish for an organisation with an estimated expenditure this year of 8-5 million. About 30% of that sum will be spent on running the Council’s disciplinary procedures and this percentage is likely to increase. Despite the fact that the Professional Conduct Committee now sits for a record number of days each year, the Council is accumulating an undesirable "waiting list" and most cases now last longer and cost more (in one case recently, nearly 1 million). Over the next few years those costs are likely to accelerate way beyond the rate of inflation. And that is before the GMC launches its new, and probably expensive, scheme to monitor professional
performance.
207
The reasons for the rising cost of discipline are clear. As with other forms of medical litigation, lawyers representing doctors before the GMC are fighting more aggressively than they used to, and this aggression involves not only representation by more expensive legal retinues but also more frequent demands for expensive procedures such as judicial review. (Add the amounts doctors contribute to defence costs through their medical defence organisations and one finds that UK doctors, like those in other countries, now make a substantial contribution to maintaining lawyers in the style to which they would like to become accustomed.) In the existing political climate, British doctors are prepared to pay the increased GMC fees to protect their profession’s right to regulate its own standards. But as demands for more rigorous monitoring increase, and the costs of meeting those demands accelerate, could a time come when doctors will say that the burden is too great and that at least part of it should be shouldered by the society that makes the demands? Such a point may well be reached within the next decade. Meanwhile, there would seem to be a ready British market for those US bumper stickers that read: "Support your local lawyer; send your son to medical school".
Gamma/delta T-cell receptors Why should clinicians take an interest in yò T-cell receptors? Most T cells in the thymus and periphery express T-cell receptors (TcRs) in the form of disulphide-linked alpha and beta chains (ap TcR). Genes for the a and [3 chains are on chromosomes 14 and 7, respectively. Each chain has multiple variable (V) and joining (J) region genes and a single constant region (C). The p chain also has diversity (D) region genes between the V andJ regions. Variability in TcR specificity is brought about by the different V(D)J combinations and also by insertion and deletion of random (N) sequences into specific sites in the V and V(D)J junctional regions. When expressed on the cell surface, the TcR is non-covalently linked with the invariant CD3 complex of proteins. TcRs recognise antigenic peptides bound to class I or class II major histocompatibility (MHC) molecules rather than native antigen. TcRs with high affinity for self-MHC, or self-antigens on self-MHC, are deleted in the thymus. A second TcR associated with CD3 has been identified.This receptor consists oftand ò chains (y8 TcR) encoded by genes on chromosomes 7 and 14, respectively (the § chain genes are located within the a chain gene locus). The y and ò chain genes also have multiple V and J regions and the 8 chain, like the (3 chain, includes D region genes. These segments rearrange themselves and diversify when the V(D)J and C regions align. There are two Cys-Cyl and Cy2. Cyl proteins can form disulphide bridges with the ò chain, so the y8
TcR may or may not be disulphide linked. Unlike a(3 TcR-positive T cells, most y8 TcR-positive cells do not express CD4 or CD8 and there is no consensus about their recognition elements. Clones and lines have been generated that recognise nominal antigen in the context of class II MHC; some recognise antigen in a non-MHC-restricted fashion. Many y8 TcRpositive T-cell lines or clones show non-MHC restricted cytotoxicity in vitro but it is unclear whether they have this function in vivo.2 In rodents, y8 TcR-positive T cells are uncommon spleen and lymph nodes but are abundant in epithelium. A special feature of these cells in the skin and reproductive tract of mice is that they represent separate waves of thymic emigrants which appear during thymic ontogeny and colonise different epithelia. Most murine y8 TcR-positive T cells are in the gut epithelium and are thymus independent.3In man, only about 10% of intestinal intraepithelial T cells express yo TcR, the same proportion as in the blood. yo TcR-positive T cells in the epithelium mostly use the Vol gene segment whereas those in the blood mostly use the Vo2 segment.2,4Human V82 y8 TcR-positive T cells may be thymus independent, unlike T cells expressing Vol, which are probably thymic emigrants2°
in
Monoclonal antibodies to the constant and variable regions of the human 8 chain are now widely available and changes in expression of y8 TcR can be determined in various diseases. Thus it has been observed that in untreated coeliac disease an increase in the proportion of gut epithelial T cells that express y8 TcR accompanies the general increase in intraepithelial lymphocyte density; all these cells use the V81 segment. By contrast, in a small study of patients with high intraepithelial lymphocyte counts and partial villous atrophy due to giardiasis or tropical sprue, the numbers of yb TcR-positive intraepithelial lymphocytes were not increased. More studies are needed in patients with food-sensitive enteropathies to determine whether an increased percentage of intraepithelial lymphocytes expressing y8 TcR could be used as the basis for a diagnostic test for coeliac disease.4 y8 T cells are also increased in some infectious diseases--eg, localised cutaneous leishmaniasis (but not mucocutaneous leishmaniasis); reversal reactions in leprosy;7 the area surrounding zones of necrosis in tuberculous lymphadenitis;8 and the peripheral blood of patients with measles.2 In mice, y8 T cells are increased in the peritoneal cavity of animals infected with Listeria monocytogenes9 and in the lungs of those infected with influenza virus. 10 Although the role of y6 T cells in disease may be to eliminate infectious agents, they are also prominent in immunological disorders such as rheumatoid arthritis2 and pulmonary sarcoidosis," as well as coeliac disease.4 Whether this increase in y8 T cells is a causal factor or a consequence of disease remains to be established.
no
technique has been available for reliable diagnosis
of the disease in the acute stages, there have been few case-reports of "mild" forms ofHSE18 and most cases will go unrecognised. An association between subclinical (possibly recurrent) HSE and subsequent psychiatric or psychotic illness has long been suggested ;19 perhaps prospective longitudinal studies will now settle this issue. Another area in which PCR may prove valuable is in investigation of treatment "failures". A complete course of treatment with either vidarabine2° or acyclovir21 has occasionally been followed by readmission with encephalitis. The differential diagnosis includes incomplete treatment of the initial encephalitic episode (necessitating further acyclovir therapy), drug resistant HSE (necessitating an alternative
herpes simplex encephalitis after conventional acyclovir therapy. JAMA 1988; 259: 1051-53. 22. Rotbart HA. Enzymatic RNA amplification of enteroviruses. J Clin Microbiol 1990; 28: 438-42. 23. Shankar P, Manjunath N. Mohan KK, et al. Rapid diagnosis of tuberculous meningitis by polymerase chain reaction. Lancet 1991; 337: 5-7.
antiviral
agent), or a perivenous leucoencephalopathy (not requiring antiviral therapy but perhaps improved by anti-inflammatory corticosteroids). PCR techniques for the identification of enterovirus infection of the central nervous system22 and Mycobacterium tuberculosisZ3 have also been developed. The application of these and other virusspecific PCR methods should lead to accurate diagnosis of the 60-70% of cases of acute encephalitis of presumed viral origin.
1.
16. Puchhammer-Stockl E, Popow-Kraupp T, Heinz FX, Mandl CW, Kunz C. Establishment of PCR for the early diagnosis of herpes simplex encephalitis. J Med Virol 1990; 32: 77-82. 17. Klapper PE, Cleator GM, Dennett C, Lewis AG. Diagnosis of herpes encephalitis via Southern blotting of CSF DNA amplified by polymerase chain reaction. J Med Virol 1990; 32: 261-64. 18. Klapper PE, Cleator GM, Longson M. Mild forms of herpes encephalitis. J Neurol Neurosurg Psychiatry 1984; 47: 1247-50. 19. Cleobury JF, Skinner GRB, Thonless ME, Wildy MP. Association between psychopathic disorders and serum antibody to herpes simplex (type 1). Br Med J 1971; i: 438-41. 20. Dix RD, Baringer JR, Panitch HS, et al. Recurrent herpes simplex encephalitis: recovery of virus after Ara-A treatment. Ann Neurol 1983; 13: 196-200. 21. Van Landingham KE, Marsteller HB, Ross GW, Hayden FG. Relapse of
Whitley RJ, Soong SJ, Dolin R, et al. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med 1977; 297: 289-94.
Sköldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitits. Lancet 1984; ii: 707-11. 3. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitits. N Engl J Med 1986: 314: 2.
144-49. 4. Editorial. Herpes simplex encephalitis. Lancet 1986; i: 535-36. 5. Brick JF, Brick JE, Morgan JJ, Gutierrez AR. EEG and pathologic findings in patients undergoing brain biopsy for suspected encephalitis. Electroencephalographr Clin Neurophysiol 1990; 76: 86-89. 6. Greenberg SB, Taber L, Septimus E, et al. Computerized tomography in brain biopsy proven herpes simplex encephalitits. Arch Neurol 1981; 38: 58-59. 7. Whitley RJ, Cobbs CG, Alford CA, et al. Diseases that mimic herpes simplex encephalitits. JAMA 1989; 262: 234-39. 8. Kahlon J, Chatterjee S, Lakeman FD, Lee F, Nahmias AJ, Whitley RJ. Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 38-44. 9. Lakeman FD, Koga J, Whitley RJ. Detection of antigen to herpes simplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 1172-78. 10. Klapper PE, Cleator GM, Lewis AG. Obstacle to early diagnosis of herpex simples encephalitis via CSF. Lancet 1990; 336: 385-86. 11. Price RW, Saito Y, Fox JJ. Prospects for the use of radiolabelled antiviral drugs in the diagnosis of herpes simplex encephalitis. Biochem Pharmacol 1983; 32: 2455-61. 12. Cleator GM, Klapper PE, Lewis AG, Sharma HL, Longson M. Specific neuro-radiological diagnosis of herpes encephalitis in an animal model. Arch Virol 1988; 101: 1-12. 13. Tovell DR, Samuel J, Mercer JR, et al. The in vitro evaluation of nucleoside analogues as probes for use in the non-invasive diagnosis of herpes simplex encephalitis. Drug Des Deliv 1988; 3: 213-21. 14. Powell KF, Anderson NE, Fnth RW, Croxson MC. Non-invasive diagnosis of herpes simplex encephalitis. Lancet 1990; 335: 357-58. 15. Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 1990; 335: 440-41.
The
rising
cost
of independence
One morning last November a group of British doctors enjoyed a rare and possibly unique experience. Unrestrained by budgetary restriction, overdrained resources, or government "cuts" they were able to estimate the needs of their institution then vote themselves the funds required. Members of the General Medical Council (GMC) could do this because their activities are funded entirely by an annual fee levied on doctors, because the Council itself determines the size of the fee, and because all doctors have to pay it if they wish to work in the National Health Service or indeed in most private hospitals. In the November debate, the GMC justified the near trebling of the fee (from 30 to 80) by saying that it needed the money to meet its statutory obligation to maintain professional standards-though one member did ask acerbicly what standard of performance should be demanded, say, of psychiatrists by a society that chooses to treat the mentally ill by sending them to prison or accommodating them in cardboard boxes. There is no doubt that without this year’s increase the GMC would be headed for the rocks. Its existing deficit is about 1million and, as became clear in November, the Council’s financial management has been far too amateurish for an organisation with an estimated expenditure this year of 8-5 million. About 30% of that sum will be spent on running the Council’s disciplinary procedures and this percentage is likely to increase. Despite the fact that the Professional Conduct Committee now sits for a record number of days each year, the Council is accumulating an undesirable "waiting list" and most cases now last longer and cost more (in one case recently, nearly 1 million). Over the next few years those costs are likely to accelerate way beyond the rate of inflation. And that is before the GMC launches its new, and probably expensive, scheme to monitor professional
performance.
207
The reasons for the rising cost of discipline are clear. As with other forms of medical litigation, lawyers representing doctors before the GMC are fighting more aggressively than they used to, and this aggression involves not only representation by more expensive legal retinues but also more frequent demands for expensive procedures such as judicial review. (Add the amounts doctors contribute to defence costs through their medical defence organisations and one finds that UK doctors, like those in other countries, now make a substantial contribution to maintaining lawyers in the style to which they would like to become accustomed.) In the existing political climate, British doctors are prepared to pay the increased GMC fees to protect their profession’s right to regulate its own standards. But as demands for more rigorous monitoring increase, and the costs of meeting those demands accelerate, could a time come when doctors will say that the burden is too great and that at least part of it should be shouldered by the society that makes the demands? Such a point may well be reached within the next decade. Meanwhile, there would seem to be a ready British market for those US bumper stickers that read: "Support your local lawyer; send your son to medical school".
Gamma/delta T-cell receptors Why should clinicians take an interest in yò T-cell receptors? Most T cells in the thymus and periphery express T-cell receptors (TcRs) in the form of disulphide-linked alpha and beta chains (ap TcR). Genes for the a and [3 chains are on chromosomes 14 and 7, respectively. Each chain has multiple variable (V) and joining (J) region genes and a single constant region (C). The p chain also has diversity (D) region genes between the V andJ regions. Variability in TcR specificity is brought about by the different V(D)J combinations and also by insertion and deletion of random (N) sequences into specific sites in the V and V(D)J junctional regions. When expressed on the cell surface, the TcR is non-covalently linked with the invariant CD3 complex of proteins. TcRs recognise antigenic peptides bound to class I or class II major histocompatibility (MHC) molecules rather than native antigen. TcRs with high affinity for self-MHC, or self-antigens on self-MHC, are deleted in the thymus. A second TcR associated with CD3 has been identified.This receptor consists oftand ò chains (y8 TcR) encoded by genes on chromosomes 7 and 14, respectively (the § chain genes are located within the a chain gene locus). The y and ò chain genes also have multiple V and J regions and the 8 chain, like the (3 chain, includes D region genes. These segments rearrange themselves and diversify when the V(D)J and C regions align. There are two Cys-Cyl and Cy2. Cyl proteins can form disulphide bridges with the ò chain, so the y8
TcR may or may not be disulphide linked. Unlike a(3 TcR-positive T cells, most y8 TcR-positive cells do not express CD4 or CD8 and there is no consensus about their recognition elements. Clones and lines have been generated that recognise nominal antigen in the context of class II MHC; some recognise antigen in a non-MHC-restricted fashion. Many y8 TcRpositive T-cell lines or clones show non-MHC restricted cytotoxicity in vitro but it is unclear whether they have this function in vivo.2 In rodents, y8 TcR-positive T cells are uncommon spleen and lymph nodes but are abundant in epithelium. A special feature of these cells in the skin and reproductive tract of mice is that they represent separate waves of thymic emigrants which appear during thymic ontogeny and colonise different epithelia. Most murine y8 TcR-positive T cells are in the gut epithelium and are thymus independent.3In man, only about 10% of intestinal intraepithelial T cells express yo TcR, the same proportion as in the blood. yo TcR-positive T cells in the epithelium mostly use the Vol gene segment whereas those in the blood mostly use the Vo2 segment.2,4Human V82 y8 TcR-positive T cells may be thymus independent, unlike T cells expressing Vol, which are probably thymic emigrants2°
in
Monoclonal antibodies to the constant and variable regions of the human 8 chain are now widely available and changes in expression of y8 TcR can be determined in various diseases. Thus it has been observed that in untreated coeliac disease an increase in the proportion of gut epithelial T cells that express y8 TcR accompanies the general increase in intraepithelial lymphocyte density; all these cells use the V81 segment. By contrast, in a small study of patients with high intraepithelial lymphocyte counts and partial villous atrophy due to giardiasis or tropical sprue, the numbers of yb TcR-positive intraepithelial lymphocytes were not increased. More studies are needed in patients with food-sensitive enteropathies to determine whether an increased percentage of intraepithelial lymphocytes expressing y8 TcR could be used as the basis for a diagnostic test for coeliac disease.4 y8 T cells are also increased in some infectious diseases--eg, localised cutaneous leishmaniasis (but not mucocutaneous leishmaniasis); reversal reactions in leprosy;7 the area surrounding zones of necrosis in tuberculous lymphadenitis;8 and the peripheral blood of patients with measles.2 In mice, y8 T cells are increased in the peritoneal cavity of animals infected with Listeria monocytogenes9 and in the lungs of those infected with influenza virus. 10 Although the role of y6 T cells in disease may be to eliminate infectious agents, they are also prominent in immunological disorders such as rheumatoid arthritis2 and pulmonary sarcoidosis," as well as coeliac disease.4 Whether this increase in y8 T cells is a causal factor or a consequence of disease remains to be established.