James A. Morris

Postmortem bacteriology: a re-evaluation.

Aim: To assess the value of postmortem bacteriology in necropsy practice, with specific emphasis on bacterial invasion of blood and cerebrospinal fluid (CSF). Methods: A review of published articles on postmortem bacteriology. Studies were selected to cover the full range of necropsy practice including adults, the perinatal period, and infancy. The review covers over 5000 necropsies, mainly in adults, but including 1108 perinatal cases and 468 cases of sudden unexpected death in infancy. Data are available on 4992 blood cultures, 1168 specimens of CSF, and 743 cultures of spleen. Results: Studies in which careful precautions have been taken to reduce contamination show that approximately two thirds of blood cultures are negative, two in nine yield a single isolate, and one in nine have a mixed growth. The postmortem interval has only a small effect on the isolation rate. A pure growth of a known pathogen has a more than 50% likelihood of being found in association with genuine infection in adults and in the perinatal period. Conclusions: The main postmortem artefact is contamination, but this can be considerably reduced by careful technique. Agonal spread is less common than is often assumed. Postmortem translocation is not a problem if the body is appropriately stored. A pure growth of a pathogen in blood or CSF should be regarded as a possible contributing factor to death at all ages.

Lethal challenge of gnotobiotic weanling rats with bacterial isolates from cases of sudden infant death syndrome (SIDS).

An attempt was made to produce an animal model of sudden infant death syndrome (SIDS). The experimental animals (germ free weanling rats) were exposed to nasopharyngeal isolates from cases of SIDS to test the hypothesis that common bacteria may have an aetiological role in the disease. Negative results were obtained when the strains were tested in isolation, but certain combinations of organisms (specifically some Staphylococcus aureus and Escherichia coli) killed the animals rapidly (less than 18 hours) without prolonged terminal illness. Post mortem histological findings were consistent with those of SIDS. The lethal toxigenic potential of nasopharyngeal bacteria, which are regarded as harmless in adults, should be reconsidered in respect of the aetiology of SIDS.

Lethal synergy between toxins of staphylococci and enterobacteria: implications for sudden infant death syndrome.

AIM--To test the hypothesis that lethal synergy occurs between toxin preparations of nasopharyngeal staphylococci and enterobacteria from sudden infant death syndrome (SIDS) victims and matched healthy infants. METHODS--SIDS and matched healthy babies were studied if both staphylococcal and enterobacterial strains were isolated from the nasopharynx. The lethality of toxin preparations from each bacterial isolate (separately and combined) was assessed over a range of dilutions using the chick embryo assay system. RESULTS--Staphylococci and enterobacteria were isolated together from the nasopharynx of seven SIDS babies but from only one normal healthy infant. Enterobacterial toxins were lethal at high dilutions. Staphylococcal toxins were less toxic. Simultaneous testing in the chick assay of staphylococcal and enterobacterial toxins, from each baby, at non-lethal concentrations enhanced lethality levels by 177 to 1011% compared with lethality expected by an additive effect alone. CONCLUSIONS--Synergy occurs between the toxins of nasopharyngeal staphylococci and enterobacteria. This combination of strains is more likely to occur in the nasopharynx of SIDS victims than that of healthy infants.

Lethal synergistic action of toxins of bacteria isolated from sudden infant death syndrome.

AIM: To test the hypothesis that lethal toxins of bacteria associated with sudden infant death syndrome (SIDS) can act synergistically. METHODS: Bacteria occurring together in the nasopharynx of cases of cot death were studied. The lethal toxicity of crude toxin preparations was determined over a range of dilutions by injections into the chorioallantoic vein of the chick embryo. Toxin preparations of low lethality for the chick embryo SIDS model were then tested in combination. RESULTS: Staphylococcus aureus toxin preparations showed low lethality when tested alone, even at low dilution. At 1 in 100 dilution S aureus toxin was lethal to one out of 15 chick embryos. Escherichia coli toxin preparations showed high lethality except on high dilution (1 in 80) when lethality fell to two out of 15 of chick embryos. When the same toxin preparations were tested simultaneously in combination, lethality rose to 14 out of 15. Similar findings were observed over a range of toxin dilutions. This finding was highly significant (p = 0.0012). CONCLUSIONS: That synergy between toxins can enhance the lethality of toxins elaborated by bacteria associated with SIDS.

Sleeping position and upper airways bacterial flora: relevance to cot death.

The hypothesis that the prone sleeping position is associated with accumulation of upper airways secretions and increased bacterial growth was investigated in adults. Ten subjects with upper respiratory tract infection lay prone for one hour and then supine for one hour. Nasal swabs after the prone period yielded higher bacterial counts than swabs obtained after the supine period. This result could be relevant to sudden infant death syndrome (SIDS), as infants who sleep in the prone position are at increased risk of SIDS and one theory is that death is caused by toxins produced by bacterial overgrowth in the upper respiratory tract following a viral infection.

Bacterial toxins: a possible cause of cot death.

AIM: To test the hypothesis that sudden infant death syndrome (SIDS) may be caused by toxins of commonly occurring bacteria in infants lacking developed immunity. METHODS: Nasopharyngeal microbial isolates from 22 pairs of SIDS cases and healthy infants matched for age (by month), sex, and sampling time (by month) were compared for lethal toxigenicity. Crude toxin preparations were made from isolates cultured on dialysis membrane overlaid on agar, and these preparations were then tested for lethality by intravenous injection into 11 day old chick embryos. RESULTS: Fifteen (68%) of the SIDS cases were each found to have at least one lethally toxigenic organism in their nasopharyngeal flora; only eight (36%) of the flora of normal infants included a lethally toxigenic species. CONCLUSION: Infants who have died of SIDS have a significantly higher (p less than 0.05) probability than matched healthy infants of having a lethally toxigenic bacterial species in their nasopharyngeal flora.

Significance of endotoxin in lethal synergy between bacteria associated with sudden infant death syndrome: follow up study.

AIM: To investigate the role of endotoxin in synergy between bacterial toxins associated with sudden infant death syndrome (SIDS). METHODS: Extracellular toxins of 13 isolates of Staphylococcus from SIDS victims and matched healthy infants were tested for lethal toxicity in chick embryos with and without standard endotoxin (used at 1.00 ng/embryo). Endotoxin and toxins from staphylococci were used at dilutions with negligible lethality. RESULTS: Simultaneous injection of non-lethal levels of endotoxin and toxins from 11 of the 13 staphylococcal isolates tested produced lethal toxicity that was 111 to 613% greater than expected by an additive effect alone. This was highly significant and occurred even in the absence of staphylococcal enterotoxins or toxic shock syndrome toxin-1. CONCLUSION: Endotoxin enhancement of staphylococcal toxin lethality could be partly responsible for the clinical outcome in SIDS.

Genetic control of redundant systems

Concepts from information theory are used to develop a model in which genes control highly redundant systems. One consequence is that mutations interact synergistically and there will be selection against zygotes which have several mutations in any one system. This could explain why total mutational load in the human genome remains constant even though there are several new mutations per generation. This model has implications for fertility, polygenic disease and cancer. It also explains a fundamental biological problem concerning the advantage of sexual over asexual reproduction.

Hypothesis: increased male mortality caused by infection is due to a decrease in heterozygous loci as a result of a single X chromosome.

Inbreeding in experimental animals leads to loss of heterozygous loci and a marked increase in morbidity and mortality. Males have fewer heterozygous loci than females because of a single X chromosome. It is suggested that heterozygous loci protect against infection and that increased male mortality in humans at all ages is secondary to infection. The specific testable hypothesis is that episodes of bacteraemia occur throughout life leading to toxin secretion causing sudden death in infancy (SUDI), accelerating the development of atherosclerosis and precipitating sudden death in old age.

Fetal origin of maturity-onset diabetes mellitus : genetic or environmental cause?

Low birthweight is a risk factor for a number of diseases of adult life including non-insulin-dependent diabetes mellitus (NIDDM). This implies that either genetic constitution or factors operating during intrauterine development have a causal role in NIDDM. One reason for rejecting a genetic cause, however, is that there is a rapidly changing prevalence of NIDDM with the onset and establishment of affluence, which does not fit with conventional models of multifactorial genetic disease. But in this article a new model of genetic disease based on the concept of redundancy is explored. The idea is that mutant genes interact synergistically in highly redundant systems to degrade performance and increase the risk of disease. The mutational load is in turn determined by the pre-conceptual environment. This model can explain a rapidly changing prevalence of NIDDM.