Neuroinflammation in Alzheimer's disease and prion disease

Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Abeta and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Abeta and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Abeta plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders.     

Malaria exoantigens induce TNF, are toxic and are blocked by T-independent antibody

The production of cytokines, including tumour necrosis factor (TNF), may be involved in the pathology of malaria, as well as in protection against the parasite. We have shown that parasite exoantigens induce the secretion of TNF in vitro and in vivo and kill mice made hypersensitive to TNF. They elicit T-independent antibody that inhibits their capacity to stimulate TNF production and protects against toxicity in vivo, and those of human and rodent parasites are serologically related. Their active component does not appear to be protein. Here we review their properties and consider the epidemiological significance of our findings and their possible contribution to the development of an "anti-disease" vaccine.     

Developing Crowdsourced Training Data Sets for Pharmacovigilance Intelligent Automation

Drug Safety - Machine learning offers an alluring solution to developing automated approaches to the increasing individual case safety report burden being placed upon pharmacovigilance. Leveraging...     

Extending epidural analgesia for emergency Caesarean section: a meta-analysis

There is no high-level evidence supporting an optimal top-up solution to convert labour epidural analgesia to surgical anaesthesia for Caesarean section. The aim of this meta-analysis was to identify the best epidural solutions for emergency Caesarean section anaesthesia, with respect to rapid onset and low supplementation of intraoperative block. Eleven randomized controlled trials, involving 779 parturients, were identified for inclusion after a systematic literature search and risk of bias assessment. 'Top-up' boluses were classified into three groups: 0.5% bupivacaine or levobupivacaine (Bup/Levo); lidocaine and epinephrine, with or without fentanyl (LE ± F); and 0.75% ropivacaine (Ropi). Pooled analysis using the fixed-effects method was used to calculate the mean difference (MD) for continuous outcomes and risk ratio (RR) for dichotomous outcomes. Lidocaine and epinephrine, with or without fentanyl, resulted in a significantly faster onset of sensory block [MD -4.51 min, 95% confidence interval (CI) -5.89 to -3.13 min, P < 0.00001]. Bup/Levo was associated with a significantly increased risk of intraoperative supplementation compared with the other groups (RR 2.03; 95% CI 1.22-3.39; P = 0.007), especially compared with Ropi (RR 3.24, 95% CI 1.26-8.33, P=0.01). Adding fentanyl to a local anaesthetic resulted in a significantly faster onset but did not affect the need for intraoperative supplementation. Bupivacaine or levobupivacaine 0.5% was the least effective solution. If the speed of onset is important, then a lidocaine and epinephrine solution, with or without fentanyl, appears optimal. If the quality of epidural block is paramount, then 0.75% ropivacaine is suggested.     

Short stature caused by obstructive apnoea during sleep.

A 5 year old girl presented to a growth clinic with short stature. Obstructive sleep apnoea was diagnosed. After tonsillectomy her symptoms were alleviated and her rate of growth increased from 4.0 cm/year to 13.6 cm/year.     

The malaria vaccine: anti-parasite or anti-disease?

There are three major difficulties hindering the development of a vaccine for malaria. First, for all three stages of the parasite life cycle there is an incomplete understanding of the precise type of immune response to aim for. Second, only a handful of the many hundreds of parasite-derived antigens have been explored, and though several have been shown to be protective in animal models, it is not known if they are the most potent. Third, there is strong evidence that the parasite can evade host immunity, for example by antigenic variation. In this brief article, John Playfair and his colleagues address mainly the first issue and suggest that complete resistance to infection is probably not feasible, and that attention should be directed not so much at vaccines designed to eliminate one or other stage of the parasite, but rather towards the possibility of an 'antitoxic' vaccine that prevents the serious pathological complications of the disease.