- Email: [email protected]
INTERFERON
1022 may well include
some of these deaths. The children tend to come from the lower socioeconomic groups, and in the U.S.A. the incidence is far higher among In a the non-white than the white population. Canadian study, however, no difference was found in the educational level of the mothers. Premature babies were more susceptible than full-term babies, there was an excess of deaths in the cold season of the year, and in Canada the incidence increased with latitude. Many, and sometimes all (depending on the criteria used in the definition), died in their sleep, mainly between midnight and 8 A.M. But many of these factors apply to all postneonatal deaths. For example, in Greater London in 19662 children aged between one month and a year died more commonly in the centre of the city and during the cold months of the year, they were among the lower socioeconomic groups, and more boys died than girls. The significant difference from the cot deaths was that 65 % died in hospital. The incidence of sudden deaths in infancy varies from about 1 to 3 per 1000 live births, depending on the criteria applied. Any method of describing these deaths would be an improvement on terms such as " accidental mechanical suffocation ", with its overtones of neglect and ill-usage, or vague diagnoses, usually respiratory; but it is doubtful whether it is wise to substitute a mode of death for an inaccurate cause of death. Whether they represent a real disease or merely reflect the limitations of present knowledge of the causes of death in children is still not clear. They do account, however, for anything from 10% to as many as 40% of post-neonatal deaths, so their prevention would mean a great saving of life.
INTERFERON IT is now thirteen years since the discovery of interferon, and during the past five years many fundamentally important findings have emerged. Developments have come not only in the part played by interferon in the cell/virus interaction and its potential clinical use, but also in the synthesis of substances that may be used to induce the body to produce interferon. The latest events are recorded in a symposium3 on
interferon and host response to virus infection. The mechanism of action has been closely studied by biochemists in many countries but, although much has been clarified, it is not yet possible to say more than that interferon seems to be one of a group of biologically active peptides, others of which are polypeptide hormones and colicins. Interferon does not inactivate viruses: it acts by blocking an intracellular process concerned in virus replication. The changes that take place in interferon-treated cells and the modification of the virus growth cycle in the treated cells are both
important. The original definition of interferon as having action only against viral replication must now be extended, for many workers have shown that it has effects tumour
on
growth, chlamydia;, rickettsi2e, bacteria, fungi,
2. Chamberlain, R., Hill, G. B. Br. J. prev. 3. Archs intern. Med. 1970, 126, 49.
soc.
Med. 1970, 24, 136.
and protozoa. Interferons, therefore, may have multiple actions on cells; and their antiviral, antichlamydial, and antiprotozoal actions have different underlying mechanisms. The potential use of interferon or its inducers in the treatment of malignant neoplasms is exciting and this is the application pursued most
vigorously today. Clinical investigations of interferon begun, but most of the work so far has
have already been done in animal model systems. Local effects have been investigated by challenging with vaccinia virus an area of human skin treated with monkey interferon, or by observing the effects of interferon on herpes-simplex infection in the eyes of rabbits. The activity against respiratory viruses has been studied by spraying interferon into the respiratory tract; and intravenous and intramuscular interferon has been shown to limit the virxmia in monkeys given yellow-fever virus. The results of these experiments have been a little disappointing, but there has always been an effect sufficient to encourage further investigations. The biggest difficulties have been lack of knowledge of the effective dose and inability to get the interferon into every cell at the site of infection. Until recently further human trials have not been possible because of the lack of adequate supplies of purified and potent human interferon, but this problem has now been solved. Even though human trials are now possible, the dose remains guesswork. It
shortage of exogenous human interferon, and its potentially prohibitive cost of production, that aroused such interest in interferon inducers when they were first produced. There are many non-viral agents capable of inducing interferon and they fall into three groups: intracellular microorganisms, microbial extracts, and synthetic polyanions. Apparently the interferon inducer interacts with and penetrates the cell, triggering the production of interferon by depression of the host-cell genome, and a stable polyanionic structure appears to be essential for the activity of the inducer. One doublestranded R.N.A., which is a complex of synthetic polyriboinosinic and polyribocytidylic acids (poly i:c), has been studied extensively in the prevention of virus infections. In many trials several animal species have been given poly i :c by different routes, and their resistance to challenge with several viruses has been found to be very active. Many double-stranded ribonucleic acids of viral or synthetic origin have been shown to induce interferon and to give resistance to viral infection both in vivo and in vitro. The poly-I:C complex of synthetic homopolymers was, however, selected for trials in man because of its extremely high antiviral activity, but the toxicity for animals, which was
largely
the
resembles that of
an
exotoxin in
some
respects, is
problem and will impose limitations on the use of the drug. There is hope that the toxicity/ activity ratio may be greatly improved by molecule manipulation, and this is in progress. These are exciting developments, and the enormous activity of research groups both in industry and in academic institutes must surely be approaching the answer. The reward will be a greater understanding of viral replication, host/cell interaction, and defence of the body against infections. Success will also provide proving
a
1023 weapon against many respiratory virus illnesses for which vaccines are unlikely to be successful. If the early promise of antitumour activity is fulfilled, a new series of powerful drugs will indeed be in prospect. a
TUBERCULOSIS IN THE LABORATORY THE life of the pathologist or bacteriologist is obviously less dangerous than that of a deep-sea diver Casual consideration suggests or a circus acrobat. that it is no more " nasty, brutish and short " than that of any other member of our profession. There 1 was some surprise, therefore, in 1957 when Reid pointed out that such statistics as were available to him indicated that the hospital pathologist and his assistants were about four times more likely to die of tuberculosis (and suicide) than those of comparable grades in the Post Office.I His evidence was certainly strong enough to justify concern, and an immediate result was a report2 from the Public Health Laboratory Service detailing practical measures to limit tuberculous infection in the laboratory. Since then there have been changes. There are fewer patients with tuberculosis, and fewer specimens from them reach the laboratory. Because of the range and complexity of the tests to which tubercle bacilli are now submitted, there has been a laudable tendency to concentrate this work in specialised institutions which have the experience and equipment to lessen the hazards. Nevertheless the danger still persists, and the Department of Health and Social Security has thought it wise to issue a revised edition3 of the P.H.L.S. report for general distribution. The changes are not extensive but they bring to light many details of methods which have been improved in the interval. It would be folly to offer employment in the laboratory to anyone who is tuberculin-negative. An X-ray of the chest should be taken at least annually, and this practice should include clerical as well as laboratory staff. The report might have included a word on the imperative need for the speedy reporting of accidents. The unwritten history of several laboratories holds stories of prolonged and fatal infections arising from such accidents as the slip of a hypodermic needle, not reported at the time from a sense of shame. Nowadays there can be few laboratories handling tuberculous material which do not make use of a ventilated cabinet for the operations which seem to be most dangerous. The directions for the care and maintenance of these in this report are not entirely for that matter, are the specifications of some of the models which are on the market. The essential is a continuous flow of clean air sufficient to carry any effluvia either through a filter or to the outside air under all circumstances. Since filters get clogged and electric motors fail, supervision and maintenance must get careful attention. Since such cabinets are desirable for work with many infectious parasites the Department might consider the issue of
satisfactory. Nor,
inclusive technical memorandum on their and use and offer some help in their maintendesign ance. Most of the other advice in this report is admirable, but the action to be taken when a centrifuge tube breaks while spinning seems casual. It is very well to say that " the bowl, bucket and contents " of the centrifuge are to be disinfected, but the methods are left to the imagination-and the line between disinfection and eyewash is thin. One difficulty for the authors of these reports is that the technical processes likely to disperse viable tubercle bacilli can only be guessed and have been identified by a-priori reasoning. The guesses seem sound, but they remain unproven. At the time of Reid’s inquiry there was a little evidence, numerically insufficient for serious consideration, that it was more dangerous to do a necropsy on a tuberculous patient than to examine his sputum. Experience leads to the suspicion that the postmortem-room porter has an especially dangerous job, and we hope that he is always included in the tally for an annual X-ray.
a
more
SEQUESTERING AGENTS AND BILE SALTS BILE salts are sterols of great physiological importance. They have both hydrophilic and hydrophobic groups which confer detergent properties, so they play a key part in fat absorption. They are excreted into the bile as glycine or taurine conjugates and in both man and laboratory animals the conjugated bile salts are actively reabsorbed in the ileum 1; but significant amounts of unconjugated bile acids are reabsorbed by passive diffusion in the human jejunum.2 The reabsorbed bile salts return via the portal blood to the liver whence, together with newly synthesised bile salts, they are re-excreted. This enterohepatic circulation is remarkably efficient. The normal bile-salt pool is about 4 g. and the total pool probably circulates about six times a day.Such bile salts as do escape to the colon undergo bacterial deconjugation and dehydroxylation and are reabsorbed to contribute to the bile-salt pool. Thus less than 5 % of the bile salts is lost in the faeces per cycle.4 Bile-acid synthesis is increased when there is interruption of the enterohepatic circulation, but the capacity of the liver to improve the bile-acid synthesis-rate is limited and is incapable of increasing beyond four to six fold.55 Loss of function in the terminal ileum, either through disease or surgical resection, causes a break in the enterohepatic circulation of the bile salts and a corresponding increase in bile-salt synthesis and turnover. Another result is the passage of large amounts of bile salts into the colon. For reasons which are not understood, bile salts in excess in the colon have a cathartic action, inhibiting water transport, stimulating mucus Thus severe secretion, and influencing motility. diarrhoea may result, cholegenic diarrhoea ", and the "
3.
Borgström, B., Lundh, G., Hofmann, A. F. Gastroenterology, 1963, 45, 229. Hislop, I. G., Hofmann, A. F., Schoenfield, L. J. J. clin. Invest. 1967, 46, 1070. Borgström, B., Dahlquist, A., Lundh, G., Sjovall, J. ibid. 1957, 36,
4. 5.
Meihoff, W. E., Kern, F. Jr. ibid. 1968, 47, 261. Hofmann, A. F. Gastroenterology, 1966, 50, 56.
1. 2.
1. Reid, D. D. Br. med. J. 1957, ii, 10. 2. Mon. Bull. Minist. Hlth Lab. Serv. 1957, 16, 64. 3. Precautions against Tuberculous Infection in the Diagnostic Labcratory. October, 1970. Department of Health and Social Security.
H.M.(70)60.
1521.
some of these deaths. The children tend to come from the lower socioeconomic groups, and in the U.S.A. the incidence is far higher among In a the non-white than the white population. Canadian study, however, no difference was found in the educational level of the mothers. Premature babies were more susceptible than full-term babies, there was an excess of deaths in the cold season of the year, and in Canada the incidence increased with latitude. Many, and sometimes all (depending on the criteria used in the definition), died in their sleep, mainly between midnight and 8 A.M. But many of these factors apply to all postneonatal deaths. For example, in Greater London in 19662 children aged between one month and a year died more commonly in the centre of the city and during the cold months of the year, they were among the lower socioeconomic groups, and more boys died than girls. The significant difference from the cot deaths was that 65 % died in hospital. The incidence of sudden deaths in infancy varies from about 1 to 3 per 1000 live births, depending on the criteria applied. Any method of describing these deaths would be an improvement on terms such as " accidental mechanical suffocation ", with its overtones of neglect and ill-usage, or vague diagnoses, usually respiratory; but it is doubtful whether it is wise to substitute a mode of death for an inaccurate cause of death. Whether they represent a real disease or merely reflect the limitations of present knowledge of the causes of death in children is still not clear. They do account, however, for anything from 10% to as many as 40% of post-neonatal deaths, so their prevention would mean a great saving of life.
INTERFERON IT is now thirteen years since the discovery of interferon, and during the past five years many fundamentally important findings have emerged. Developments have come not only in the part played by interferon in the cell/virus interaction and its potential clinical use, but also in the synthesis of substances that may be used to induce the body to produce interferon. The latest events are recorded in a symposium3 on
interferon and host response to virus infection. The mechanism of action has been closely studied by biochemists in many countries but, although much has been clarified, it is not yet possible to say more than that interferon seems to be one of a group of biologically active peptides, others of which are polypeptide hormones and colicins. Interferon does not inactivate viruses: it acts by blocking an intracellular process concerned in virus replication. The changes that take place in interferon-treated cells and the modification of the virus growth cycle in the treated cells are both
important. The original definition of interferon as having action only against viral replication must now be extended, for many workers have shown that it has effects tumour
on
growth, chlamydia;, rickettsi2e, bacteria, fungi,
2. Chamberlain, R., Hill, G. B. Br. J. prev. 3. Archs intern. Med. 1970, 126, 49.
soc.
Med. 1970, 24, 136.
and protozoa. Interferons, therefore, may have multiple actions on cells; and their antiviral, antichlamydial, and antiprotozoal actions have different underlying mechanisms. The potential use of interferon or its inducers in the treatment of malignant neoplasms is exciting and this is the application pursued most
vigorously today. Clinical investigations of interferon begun, but most of the work so far has
have already been done in animal model systems. Local effects have been investigated by challenging with vaccinia virus an area of human skin treated with monkey interferon, or by observing the effects of interferon on herpes-simplex infection in the eyes of rabbits. The activity against respiratory viruses has been studied by spraying interferon into the respiratory tract; and intravenous and intramuscular interferon has been shown to limit the virxmia in monkeys given yellow-fever virus. The results of these experiments have been a little disappointing, but there has always been an effect sufficient to encourage further investigations. The biggest difficulties have been lack of knowledge of the effective dose and inability to get the interferon into every cell at the site of infection. Until recently further human trials have not been possible because of the lack of adequate supplies of purified and potent human interferon, but this problem has now been solved. Even though human trials are now possible, the dose remains guesswork. It
shortage of exogenous human interferon, and its potentially prohibitive cost of production, that aroused such interest in interferon inducers when they were first produced. There are many non-viral agents capable of inducing interferon and they fall into three groups: intracellular microorganisms, microbial extracts, and synthetic polyanions. Apparently the interferon inducer interacts with and penetrates the cell, triggering the production of interferon by depression of the host-cell genome, and a stable polyanionic structure appears to be essential for the activity of the inducer. One doublestranded R.N.A., which is a complex of synthetic polyriboinosinic and polyribocytidylic acids (poly i:c), has been studied extensively in the prevention of virus infections. In many trials several animal species have been given poly i :c by different routes, and their resistance to challenge with several viruses has been found to be very active. Many double-stranded ribonucleic acids of viral or synthetic origin have been shown to induce interferon and to give resistance to viral infection both in vivo and in vitro. The poly-I:C complex of synthetic homopolymers was, however, selected for trials in man because of its extremely high antiviral activity, but the toxicity for animals, which was
largely
the
resembles that of
an
exotoxin in
some
respects, is
problem and will impose limitations on the use of the drug. There is hope that the toxicity/ activity ratio may be greatly improved by molecule manipulation, and this is in progress. These are exciting developments, and the enormous activity of research groups both in industry and in academic institutes must surely be approaching the answer. The reward will be a greater understanding of viral replication, host/cell interaction, and defence of the body against infections. Success will also provide proving
a
1023 weapon against many respiratory virus illnesses for which vaccines are unlikely to be successful. If the early promise of antitumour activity is fulfilled, a new series of powerful drugs will indeed be in prospect. a
TUBERCULOSIS IN THE LABORATORY THE life of the pathologist or bacteriologist is obviously less dangerous than that of a deep-sea diver Casual consideration suggests or a circus acrobat. that it is no more " nasty, brutish and short " than that of any other member of our profession. There 1 was some surprise, therefore, in 1957 when Reid pointed out that such statistics as were available to him indicated that the hospital pathologist and his assistants were about four times more likely to die of tuberculosis (and suicide) than those of comparable grades in the Post Office.I His evidence was certainly strong enough to justify concern, and an immediate result was a report2 from the Public Health Laboratory Service detailing practical measures to limit tuberculous infection in the laboratory. Since then there have been changes. There are fewer patients with tuberculosis, and fewer specimens from them reach the laboratory. Because of the range and complexity of the tests to which tubercle bacilli are now submitted, there has been a laudable tendency to concentrate this work in specialised institutions which have the experience and equipment to lessen the hazards. Nevertheless the danger still persists, and the Department of Health and Social Security has thought it wise to issue a revised edition3 of the P.H.L.S. report for general distribution. The changes are not extensive but they bring to light many details of methods which have been improved in the interval. It would be folly to offer employment in the laboratory to anyone who is tuberculin-negative. An X-ray of the chest should be taken at least annually, and this practice should include clerical as well as laboratory staff. The report might have included a word on the imperative need for the speedy reporting of accidents. The unwritten history of several laboratories holds stories of prolonged and fatal infections arising from such accidents as the slip of a hypodermic needle, not reported at the time from a sense of shame. Nowadays there can be few laboratories handling tuberculous material which do not make use of a ventilated cabinet for the operations which seem to be most dangerous. The directions for the care and maintenance of these in this report are not entirely for that matter, are the specifications of some of the models which are on the market. The essential is a continuous flow of clean air sufficient to carry any effluvia either through a filter or to the outside air under all circumstances. Since filters get clogged and electric motors fail, supervision and maintenance must get careful attention. Since such cabinets are desirable for work with many infectious parasites the Department might consider the issue of
satisfactory. Nor,
inclusive technical memorandum on their and use and offer some help in their maintendesign ance. Most of the other advice in this report is admirable, but the action to be taken when a centrifuge tube breaks while spinning seems casual. It is very well to say that " the bowl, bucket and contents " of the centrifuge are to be disinfected, but the methods are left to the imagination-and the line between disinfection and eyewash is thin. One difficulty for the authors of these reports is that the technical processes likely to disperse viable tubercle bacilli can only be guessed and have been identified by a-priori reasoning. The guesses seem sound, but they remain unproven. At the time of Reid’s inquiry there was a little evidence, numerically insufficient for serious consideration, that it was more dangerous to do a necropsy on a tuberculous patient than to examine his sputum. Experience leads to the suspicion that the postmortem-room porter has an especially dangerous job, and we hope that he is always included in the tally for an annual X-ray.
a
more
SEQUESTERING AGENTS AND BILE SALTS BILE salts are sterols of great physiological importance. They have both hydrophilic and hydrophobic groups which confer detergent properties, so they play a key part in fat absorption. They are excreted into the bile as glycine or taurine conjugates and in both man and laboratory animals the conjugated bile salts are actively reabsorbed in the ileum 1; but significant amounts of unconjugated bile acids are reabsorbed by passive diffusion in the human jejunum.2 The reabsorbed bile salts return via the portal blood to the liver whence, together with newly synthesised bile salts, they are re-excreted. This enterohepatic circulation is remarkably efficient. The normal bile-salt pool is about 4 g. and the total pool probably circulates about six times a day.Such bile salts as do escape to the colon undergo bacterial deconjugation and dehydroxylation and are reabsorbed to contribute to the bile-salt pool. Thus less than 5 % of the bile salts is lost in the faeces per cycle.4 Bile-acid synthesis is increased when there is interruption of the enterohepatic circulation, but the capacity of the liver to improve the bile-acid synthesis-rate is limited and is incapable of increasing beyond four to six fold.55 Loss of function in the terminal ileum, either through disease or surgical resection, causes a break in the enterohepatic circulation of the bile salts and a corresponding increase in bile-salt synthesis and turnover. Another result is the passage of large amounts of bile salts into the colon. For reasons which are not understood, bile salts in excess in the colon have a cathartic action, inhibiting water transport, stimulating mucus Thus severe secretion, and influencing motility. diarrhoea may result, cholegenic diarrhoea ", and the "
3.
Borgström, B., Lundh, G., Hofmann, A. F. Gastroenterology, 1963, 45, 229. Hislop, I. G., Hofmann, A. F., Schoenfield, L. J. J. clin. Invest. 1967, 46, 1070. Borgström, B., Dahlquist, A., Lundh, G., Sjovall, J. ibid. 1957, 36,
4. 5.
Meihoff, W. E., Kern, F. Jr. ibid. 1968, 47, 261. Hofmann, A. F. Gastroenterology, 1966, 50, 56.
1. 2.
1. Reid, D. D. Br. med. J. 1957, ii, 10. 2. Mon. Bull. Minist. Hlth Lab. Serv. 1957, 16, 64. 3. Precautions against Tuberculous Infection in the Diagnostic Labcratory. October, 1970. Department of Health and Social Security.
H.M.(70)60.
1521.