Anthony Busuttil

Redistribution of HIV outside the lymphoid system with onset of AIDS

The basis for many of the symptoms and pathological changes found in patients with the acquired immunodeficiency syndrome (AIDS) remains poorly understood. We have used a quantitative polymerase chain reaction technique to investigate the extent to which direct infection with human immunodeficiency virus (HIV) produces the disease manifestations of AIDS. In five patients who died with AIDS-defining illnesses (Centers for Disease Control and Prevention class IV), we found variable, but in many cases extensive, infection by HIV at various sites, including brain, lung, colon, and liver. By contrast, in three HIV-positive subjects who died without HIV-related disease (CDC class II), we found no evidence of significant infection of any non-lymphoid organ. In both groups of patients there were high levels of infection in cells of the spleen, lymph nodes, and peripheral blood. Pathological examination of tissues from the AIDS patients revealed many abnormalities, of which some, such as giant-cell encephalitis in the brain, were specifically associated with the presence of high levels of HIV infection. These findings suggest that spread of HIV outside cells of the immune system is a late event in HIV infection and is extremely sensitive to the degree of immunosuppression in the patient.

Cytokine responses and sudden infant death syndrome: genetic, developmental, and environmental risk factors

Despite the success of the campaigns to reduce the risk of sudden infant death syndrome (SIDS), it still remains the major cause of postneonatal mortality. The incidence of SIDS is higher among ethnic groups in which there are also high incidences of serious infectious diseases. The risk factors for SIDS parallel those for susceptibility to infection, and recent data have provided evidence to support the mathematical model of the common bacterial toxin hypothesis. One current hypothesis for the etiology of SIDS is that the deaths are a result of overwhelming proinflammatory responses to bacterial toxins; as in inflammatory responses to sepsis, cytokines, induced by bacterial toxins, cause physiological changes leading to death. The genetic, developmental, and environmental risk factors for SIDS are reviewed in relation to colonization by potentially harmful bacteria and the inflammatory responses induced in the nonimmune infant to microorganisms or their products.

Upregulation of microglia in drug users with and without pre-symptomatic HIV infection

It is generally thought that infection of the central nervous system (CNS) by HIV‐1 can occur early, even around the time of seroconversion, and evidence from animal studies supports this. However, the mode and timing of viral entry remain poorly understood since there have been comparatively few studies of the early neuropathology of HIV infection. In this study, samples of frontal and temporal lobes, and basal ganglia, were selected from 12 HIV‐positive drug users who had been infected for 4–130 months before death, 10 HIV‐negative drug users and 10 non‐drug using controls, all age and sex matched. Routine and immunocytochemical staining showed that leptomeningeal and perivascular lymphocytic infiltrate was upregulated in HIV‐infected cases compared with the two control groups, and choroid plexitis was confined to the HIV‐positive subjects, suggesting an association with viral infection. In contrast, CD68‐positive microglia were enhanced in both HIV‐ positive and HIV‐negative drug users, considerably above the baseline seen in normal controls. However, there was no statistical difference between the three groups in relation to astrocytes. Screening and competitive polymerase chain reaction (PCR) undertaken on multiple samples including brain tissue, choroid plexus and leptomeninges from four of the HIV‐positive subjects and one control case showed that the pro‐viral burden was never more than 13 copies/μg DNA and was negative in multiple samples from one HIV‐positive case and one control case. All the basal ganglia samples were PCR‐negative. This study has not revealed any t spots’ of viral load in brain tissue, choroid plexus or meninges, either early or late in the course of pre‐symptomatic HIV infection. Drug use alone is associated with significant upregulation of microglia and this may predispose to HIV infection of the nervous system in drug users.

Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers

Drug abuse is a major problem worldwide. The incidence of drug‐related deaths attributed to opiate abuse is increasing annually. Apart from routine examination, little is known of the neuropathology of drug abuse. We, and others, have shown previously that drug abuse is associated with microglial activation. We hypothesised that neuroinflammation might lead to premature neurodegeneration in drug abusers. We investigated the brains of young opiate abusers (n = 34, all < 40 years) for the presence of proteins associated with neurodegenerative diseases and compared them with the brains of age‐matched, non‐drug users (n = 16) all of whom died suddenly. Detailed immunohistochemical analysis of the hippocampus, brainstem and basal ganglia for hyperphosphorylated tau, β‐amyloid, β‐amyloid precursor protein (βAPP) and ubiquitin demonstrated an excess of AT8‐positive neurofibrillary tangles (NFT) in the drug abusers. These were not only more prevalent in the drug abusers than in controls (44%vs. 19%) but also involved more brain areas. In controls NFT were confined to the entorhinal cortex whereas in drug users they were also found in the subiculum, temporal neocortex, nucleus basalis of Meynert and the locus coeruleus. Virtually no amyloid plaques were present but βAPP positivity was again much more common in drug abusers than controls (73%vs. 20% in the brainstem and 59%vs. 23% in the temporal lobe). There is no suggestion that these drug abusers had displayed major cognitive impairment although detailed neuropsychological assessment is difficult in this subject group. Likely causes of hyperphosphorylated tau deposition in drug abuse include hypoxic‐ischaemic injury, microglial‐associated cytokine release and possibly drug‐associated neurotoxicity or hepatitis. Head injury, which is another major risk factor, does not appear to have contributed to our findings. Genetic factors also merit consideration. It is unclear at present how much of the hyperphosphorylated tau detected in these young drug abusers represents a transitory phenomenon.

The role of bacterial toxins in Sudden Infant Death Syndrome (SIDS)

There is increasing evidence for the involvement of bacterial toxins in some cases of sudden infant death syndrome (SIDS), particularly the pyrogenic toxins of Staphylococcus aureus. This had led to the hypothesis that some SIDS deaths are due to induction of inflammatory mediators by infectious agents or their products during a period in which the infant is unable to control these normally protective responses. The genetic, developmental and environmental risk factors identified for SIDS are assessed in relation to frequency or density of mucosal colonisation by toxigenic bacteria and their effects on induction and control of inflammatory responses to the toxins.

The time of death after trauma

The pre-eminence of trauma as a cause of death in young adults in the United Kingdom is well established, but little is known about the temporal distribution of these deaths.1 The only complete data are from a frequently quoted paper, in which Trunkey described trauma deaths in San Francisco over two years.2 These data are nearly two decades old and come from a country where the causes of trauma and the system for dealing with it differ from those in the United Kingdom. All patients aged over 12 who died after trauma in the Lothian and Borders regions of Scotland between 1 February 1992 and 31 January 1994 were studied prospectively by the Scottish Trauma Audit Group and …

Identification in the Lockerbie Air Disaster

In the aftermath of the Lockerbie air disaster, identification of the victims (plane occupants and local residents) was established by two primary methods: odontology and dactylography. Scottish law requires corroboration of evidence of identity, so both primary methods were used whenever possible, with further evidence occasionally derived from the matching of physical characteristics, personal effects and details from past medical records. Of the 270 victims, 253 were positively identified. Of these, 209 were identified with the aid of odontology.

Fatal falls down stairs

Fatal falls down stairs in south-east Scotland were studied using prospectively collected data between 1992 and 1997. 51 individuals, comprising 27 men and 24 women with mean age 68.9 years, died following falls down stairs, 30 (59%) of which were unwitnessed. 43 (84%) individuals died following falls within their own homes. Overall, 27 (53%) fatal falls resulted in death at the scene of the accident. Analysis of injuries according to the Abbreviated Injury Scale yielded injury severity scores (ISS) of between 5 and 75, but only four individuals had injuries recognised to be unsurvivable (ISS = 75). Injury to the brain and/or spinal cord was responsible for the vast majority of most severe injuries. The results demonstrate that stairs represent a significant hazard for the elderly. Most of the deaths in the pre-hospital setting appeared to be more the result of the fact that the victim was alone and unable to summon assistance, rather than as a result of unsurvivable injuries. Consideration needs to be given to both how the safety of stairs can be improved and whether a particular elderly person can safely cope with stairs.

The potential role of bacterial toxins in Sudden Infant Death Syndrome (SIDS)

SummaryToxigenic bacteria have been implicated in some cases of Sudden Infant Death Syndrome (SIDS). Although there is not much evidence thatClostridia spp. are associated with SIDS in Britain, strains ofStaphylococcus aureus producing pyrogenic toxins have been isolated from significant numbers of these infants at autopsy. The pyrogenic toxins, produced by some strains of group AStreptococcus pyogenes as well as staphylococci, are powerful “superantigens” that have significant physiological effects including induction of fever > 38°C. In this article, interactions between genetic and environmental factors that might enhance colonization of epithelial surfaces by toxigenic staphylococci are analyzed: infants expression of Lewisa antigen which acts as a receptor for some microorganisms; viral infections; the effect of mothers smoking on susceptibility to respiratory infection. Based on epidemiological findings and laboratory investigations, a hypothesis is proposed to explain how bacteria producing pyrogenic toxins might contribute to some cot deaths.ZusammenfassungIn einigen Fällen des Sudden Infant Death Syndrom (SIDS) wurde die Rolle Toxin bildender Bakterien diskutiert. Obwohl es keinen Beweis gibt, daß Clostridia spp. mit SIDS in Großbritanien assoziiert sind, sind von signifikanter Anzahl dieser Kinder bei der Autopsie Stämme von Stapylokkokus aureus isoliert worden, welche Fieber erzeugende Toxine produzieren. Die Fieber erzeugenden Toxine, welche von einigen Stämmen der Gruppe A Streptokkokus pyogenes produziert werden, wie auch von Staphylokkoken, sind mächtige „Superantigene”, welche signifikante physiologische Effekte haben unter Einbeziehung der Induktion von Fieber mit mehr als 38°C. In diesem Artikel werden Interaktionen zwischen genetischen und Umgebungsfaktoren erörtert, welche die Kolonisierung epithelialer Oberflächen durch Toxin bildende Staphylokkoken steigern könnten: die Expression des Lewisa Antigens des Kindes, welches als Rezeptor für einige Mikroorganismen wirksam ist; virale Infektionen; die Auswirkung des mütterlichen Rauchens auf die Empfänglichkeit für Atemwegsinfektionen. Basierend auf epidemiologischen Befunden und Laboratoriumsuntersuchungen wird eine Hypothese vorgeschlagen, wie Bakterien; welche pyrogene Toxine produzieren, zu einigen plötzlichen Kindstodesfällen beitragen könnten.

Immunocytochemical detection of the microsomal glucose‐6‐phosphatase in human brain astrocytes

Using an antibody raised against the catalytic subunit of glucose‐6‐phosphatase, this enzyme was immuno‐localized in many astrocytes in 20 normal human brains. Double immunofluorescence studies showed co‐localization of glial fibrillary acidic protein (GFAP) with glucose‐6‐phosphatase in astrocytes. However, not all GFAP‐positive cells were also glucose‐6‐phosphatase positive, indicating that some astrocytes do not contain demonstrable expression of this enzyme. Reactive astrocytes in a variety of abnormal brains were strongly glucose‐6‐phosphatase positive, but neoplastic astrocytes were often only weakly positive. Expression of the enzyme could not be demonstrated in radial glia, neurons or oligodendroglia. Astrocytes normally contain glycogen and the demonstration that some astrocytes also contain glucose‐6‐phosphatase indicates that they are competent for both glycogenolysis and gluconeogenesis, which may be critical for neuronal welfare.