A Methodological Framework for the Evaluation of Syndromic Surveillance Systems: A Case Study of England

Background: Syndromic surveillance complements traditional public health surveillance by collecting and analysing health indicators in near real time. The rationale of syndromic surveillance is that it may detect health threats faster than traditional surveillance systems permitting more timely, and hence potentially more effective public health action. The effectiveness of syndromic surveillance largely relies on the methods used to detect aberrations. Very few studies have evaluated the performance of syndromic surveillance systems and consequently little is known about the types of events that such systems can and cannot detect. Methods: We introduce a framework for the evaluation of syndromic surveillance systems that can be used in any setting based upon the use of simulated scenarios. For a range of scenarios this allows the time and probability of to be determined and uncertainty is fully incorporated. In addition, we demonstrate how such a framework can model the benefits of increases in the number of centres reporting syndromic data and also determine the minimum size of outbreaks that can or cannot be detected. Here, we demonstrate its utility using simulations of national influenza outbreaks and localised outbreaks of cryptosporidiosis. Results: Influenza outbreaks are consistently detected with larger outbreaks being detected in a more timely manner. Small cryptosporidiosis outbreaks (<1000 symptomatic individuals) are unlikely to be detected. We also demonstrate the advantages of having multiple syndromic data streams (e.g. emergency attendance data, telephone helpline data, general practice consultation data) as different streams are able to detect different types outbreaks with different efficacy (e.g. emergency attendance data are useful for the detection of pandemic influenza but not for outbreaks of cryptosporidiosis). We also highlight that for any one disease, the utility of data streams may vary geographically, and that the detection ability of syndromic surveillance varies seasonally (e.g. an influenza outbreak starting in July is detected sooner than one starting later in the year). We argue that our framework constitutes a useful tool for public health emergency preparedness in multiple settings. Conclusions: The proposed framework allows the exhaustive evaluation of any syndromic surveillance system and constitutes a useful tool for emergency preparedness and response

Circadian Integration of Glutamatergic Signals by Little SAAS in Novel Suprachiasmatic Circuits

Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood.Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS-expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS.Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock

Thermal Stability of the Human Immunodeficiency Virus Type 1 (HIV-1) Receptors, CD4 and CXCR4, Reconstituted in Proteoliposomes

BACKGROUND: The entry of human immunodeficiency virus (HIV-1) into host cells involves the interaction of the viral exterior envelope glycoprotein, gp120, and receptors on the target cell. The HIV-1 receptors are CD4 and one of two chemokine receptors, CCR5 or CXCR4. METHODOLOGY/PRINCIPAL FINDINGS: We created proteoliposomes that contain CD4, the primary HIV-1 receptor, and one of the coreceptors, CXCR4. Antibodies against CD4 and CXCR4 specifically bound the proteoliposomes. CXCL12, the natural ligand for CXCR4, and the small-molecule CXCR4 antagonist, AMD3100, bound the proteoliposomes with affinities close to those associated with the binding of these molecules to cells expressing CXCR4 and CD4. The HIV-1 gp120 exterior envelope glycoprotein bound tightly to proteoliposomes expressing only CD4 and, in the presence of soluble CD4, bound weakly to proteoliposomes expressing only CXCR4. The thermal stability of CD4 and CXCR4 inserted into liposomes was examined. Thermal denaturation of CXCR4 followed second-order kinetics, with an activation energy (E(a)) of 269 kJ/mol (64.3 kcal/mol) and an inactivation temperature (T(i)) of 56°C. Thermal inactivation of CD4 exhibited a reaction order of 1.3, an E(a) of 278 kJ/mol (66.5 kcal/mol), and a T(i) of 52.2°C. The second-order denaturation kinetics of CXCR4 is unusual among G protein-coupled receptors, and may result from dimeric interactions between CXCR4 molecules. CONCLUSIONS/SIGNIFICANCE: Our studies with proteoliposomes containing the native HIV-1 receptors allowed an examination of the binding of biologically important ligands and revealed the higher-order denaturation kinetics of these receptors. CD4/CXCR4-proteoliposomes may be useful for the study of virus-target cell interactions and for the identification of inhibitors

An overview of tissue engineering approaches for management of spinal cord injuries

Severe spinal cord injury (SCI) leads to devastating neurological deficits and disabilities, which necessitates spending a great deal of health budget for psychological and healthcare problems of these patients and their relatives. This justifies the cost of research into the new modalities for treatment of spinal cord injuries, even in developing countries. Apart from surgical management and nerve grafting, several other approaches have been adopted for management of this condition including pharmacologic and gene therapy, cell therapy, and use of different cell-free or cell-seeded bioscaffolds. In current paper, the recent developments for therapeutic delivery of stem and non-stem cells to the site of injury, and application of cell-free and cell-seeded natural and synthetic scaffolds have been reviewed

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Orthotopic transplantation of immortalized mesencephalic progenitors (CSM14.1 cells) into the substantia nigra of hemiparkinsonian rats induces neuronal differentiation and motoric improvement

Neural progenitor cell grafting is a promising therapeutic option in the treatment of Parkinson's disease. In previous experiments we grafted temperature-sensitive immortalized CSM14.1 cells, derived from the ventral mesencephalon of E14-rats, bilaterally in the caudate putamen of adult hemiparkinsonian rats. In these studies we were not able to demonstrate either a therapeutic improvement or neuronal differentiation of transplanted cells. Here we examined whether CSM14.1 cells grafted bilaterally orthotopically in the substantia nigra of hemiparkinsonian rats have the potential to differentiate into dopaminergic neurons. Adult male rats received 6-hydroxydopamine into the right medial forebrain bundle, and successful lesions were evaluated with apomorphine-induced rotations 12 days after surgery. Two weeks after a successful lesion the animals received bilateral intranigral grafts consisting of either about 50 000 PKH26-labelled undifferentiated CSM14.1 cells (n = 16) or a sham-graft (n = 9). Rotations were evaluated 3, 6, 9 and 12 weeks post-grafting. Animals were finally perfused with 4% paraformaldehyde. Cryoprotected brain slices were prepared for immunohistochemistry using the freeze-thaw technique to preserve PKH26-labelling. Slices were immunostained against neuronal epitopes (NeuN, tyrosine hydroxylase) or glial fibrillary acidic protein. The CSM14.1-cell grafts significantly reduced the apomorphine-induced rotations 12 weeks post-grafting compared to the sham-grafts (P < 0.05). There was an extensive mediolateral migration (400–700 µm) of the PKH26-labelled cells within the host substantia nigra. Colocalization with NeuN or glial fibrillary acidic protein in transplanted cells was confirmed with confocal microscopy. No tyrosine hydroxylase-immunoreactive grafted cells were detectable. The therapeutic effect of the CSM14.1 cells could be explained either by their glial cell-derived neurotrophic factor-expression or their neural differentiation with positive effects on the basal ganglia neuronal networks

Quantitative Detection of Shiga Toxin-Producing and Enteropathogenic Escherichia coli Serotypes O157 and O26 in Bulk Raw Milk

The presence of pathogens must be adequately monitored in raw milk and dairy products to assess their safety. With this aim, sampling plans and analytical methods should be evaluated for their appropriateness. Five incremental samples were collected from 40 milk tankers and overall 200 individual samples were analysed to assess the number and distribution of Escherichia coli O157 and O26. Enriched samples were screened by PCR for the presence of the serogroup-specific genes rfbEO157 and wzxO26, and the positive cultures were analysed by reverse transcriptase-PCR to detect mRNA sequences encoded by these genes, which are indicative of the presence of viable bacteria. In addition, the numbers of E. coli O157 and O26 in milk were estimated by most-probable-number–PCR method. The results of PCR screening targeting the rfbEO157 and wzxO26 genes were positive in 34 samples (representing 15 batches) and complementary mRNA sequences were detected in 27 of these (80 %). Isolation from the enriched cultures resulted in detection of E. coli O157 in 100% of the enriched samples positive for the O157 RNA marker, whereas E. coli O26 was isolated from only 37.5 % of the enriched cultures positive for O26 RNA marker. E. coli strains that produce Shiga toxins O26:H11 was isolated from one batch (2.5 %), while typical enteropathogenic E. coli O26 and non-pathogenic strains of E. coli O157 were isolated from four other batches. Estimated by most-probable-number (MPN), the number of E. coli O157 or O26 was below 0.3 MPN ml−1 in all the milk samples, except two that had MPN equal to 1.4 ml−1 (CI95% 0.36–4.2). The distribution of E. coli O157 and O26 within the milk batches was not uniform. Seven (47 %) of the 15 batches with positive results for either the O157 or O26 gene had only one incremental sample positive out of five samples analysed. In the presence of very low concentrations of pathogens, the sampling method used may affect the probability of detection of ‘defective’ batches