Ross River virus disease in Australia, 1886-1998, with analysis of risk factors associated with outbreaks

Ross River virus (RE) is a mosquito-borne arbovirus responsible for outbreaks of polyarthritic disease throughout Australia. To better understand human and environmental factors driving such events, 57 historical reports oil RR Outbreaks between 1896 and 1998 were examined collectively. The magnitude, regularity, seasonality, and locality of outbreaks were found to be wide ranging; however, analysis of climatic and tidal data highlighted that environmental conditions let differently ill tropical, arid, and temperate regions. Overall, rainfall seems to be the single most important risk factor, with over 90% of major outbreak locations receiving higher than average rainfall in preceding mouths. Many temperatures were close to average, particularly in tropical populations; however, in arid regions, below average maximum temperatures predominated, and ill southeast temperate regions, above average minimum temperatures predominated. High spring tides preceded coastal Outbreaks, both in the presence and absence of rainfall, and the relationship between rainfall and the Southern Oscillation Index and Lit Nina episodes suggest they may be useful predictive tools, but only ill southeast temperate regions. Such heterogeneity predisposing outbreaks supports the notion that there are different RE epidemiologies throughout Australia but also Suggests that generic parameters for the prediction and control of outbreaks are of limited use at a local level.

Lineage replacement accompanying duplication and rapid fixation of an RNA element in the nsP3 gene in a species of alphavirus

A sequence of thirty-six nucleotides in the nsP3 gene of Ross River virus (RRV), coding for the amino acid sequence HADTVSLDSTVS, was duplicated some time between 1969 and 1979 coinciding with the appearance of a new lineage of this virus and with a major outbreak of Epidemic Polyarthritis among residents of the Pacific Islands. This lineage of RRV continues to circulate throughout Australia and both earlier lineages, which lacked the duplicated element, now are extinct. Multiple copies of several other elements also were observed in this region of the nsP3 gene in all lineages of RRV. Multiple copies of one of these, coding for the amino acid sequence P*P*PR, were detected in the C-terminal region of the nsP3 protein of all alphaviruses except those of African origin. The fixation of duplications and insertions in 3' region of nsP3 genes from all lineages of alphaviruses, suggests they provide some fitness advantage

Molecular evolutionary dynamics of Ross River virus and implications for vaccine efficacy

Ross River virus (RRV) is a mosquito-borne member of the genus Alphavirus that causes epidemic polyarthritis in humans, costing the Australian health system at least US$10 million annually. Recent progress in RRV vaccine development requires accurate assessment of RRV genetic diversity and evolution, particularly as they may affect the utility of future vaccination. In this study, we provide novel RRV genome sequences and investigate the evolutionary dynamics of RRV from time-structured E2 gene datasets. Our analysis indicates that, although RRV evolves at a similar rate to other alphaviruses (mean evolutionary rate of approx. 8x10(-4) nucleotide substitutions per site year(-1)), the relative genetic diversity of RRV has been continuously low through time, possibly as a result of purifying selection imposed by replication in a wide range of natural host and vector species. Together, these findings suggest that vaccination against RRV is unlikely to result in the rapid antigenic evolution that could compromise the future efficacy of current RRV vaccines.

Evaluation of an inactivated Ross River virus vaccine in active and passive mouse immunization models and establishment of a correlate of protection

Ross River Virus has caused reported outbreaks of epidemic polyarthritis, a chronic debilitating disease associated with significant long-term morbidity in Australia and the Pacific region since the 1920s. To address this public health concern, a formalin- and UV-inactivated whole virus vaccine grown in animal protein-free cell culture was developed and tested in preclinical studies to evaluate immunogenicity and efficacy in animal models. After active immunizations, the vaccine dose-dependently induced antibodies and protected adult mice from viremia and interferon α/β receptor knock-out (IFN-α/βR(-/-)) mice from death and disease. In passive transfer studies, administration of human vaccinee sera followed by RRV challenge protected adult mice from viremia and young mice from development of arthritic signs similar to human RRV-induced disease. Based on the good correlation between antibody titers in human sera and protection of animals, a correlate of protection was defined. This is of particular importance for the evaluation of the vaccine because of the comparatively low annual incidence of RRV disease, which renders a classical efficacy trial impractical. Antibody-dependent enhancement of infection, did not occur in mice even at low to undetectable concentrations of vaccine-induced antibodies. Also, RRV vaccine-induced antibodies were partially cross-protective against infection with a related alphavirus, Chikungunya virus, and did not enhance infection. Based on these findings, the inactivated RRV vaccine is expected to be efficacious and protect humans from RRV disease

Ross River virus evolution : implications for vaccine development

Ross River virus is a mosquito-borne alphavirus that causes approximately 5000 cases of epidemic polyarthritis in Australia each year and has direct medical-associated costs of approximately US$15 million annually. While mosquito control programs are able, at best, to contain rather than prevent this disease, natural infection with Ross River virus confers lifelong protection against subsequent clinical infection. A killed-virus vaccine has been developed, which is in Phase III clinical trials. Analyses of intra-host genetic diversity and of long-term evolutionary changes in Ross River virus populations suggest that antigenic variation is unlikely to pose a threat to the efficacy of this vaccine.

Ross River virus arthritis

“Epidemics” of a benign disease causing polyarthralgia and rash were first described in Australia in 1927.63 Following the recovery of the causative agent and the advent of serologic tests able to diagnose Ross River virus infection, epidemic polyarthritis has been recognized as endemic in Australia and has occurred as epidemics in numerous Pacific nations. Approximately 4000 cases of epidemic polyarthritis are reported in Australia each year, with a peak of 7800 cases in 1996. Some confusion has been generated recently by use of the term Ross River fever to describe clinical Ross River virus infections because fever does not develop in more than half of those with clinical disease.59 Additional confusion has been generated by efforts to describe any polyarthritis caused by an Australian arbovirus as epidemic polyarthritis. The term epidemic polyarthritis should be used to describe only clinical disease caused by Ross River virus.

An arthritogenic alphavirus uses the α1β1 integrin collagen receptor

Ross River (RR) virus is an alphavirus endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis or RR virus disease. Here we provide evidence that RR virus uses the collagen-binding α1β1 integrin as a cellular receptor. Infection could be inhibited by collagen IV and antibodies specific for the β1 and α1 integrin proteins, and fibroblasts from α1-integrin-/- mice were less efficiently infected than wild-type fibroblasts. Soluble α1β1 integrin bound immobilized RR virus, and peptides representing the α1β1 integrin binding-site on collagen IV inhibited virus binding to cells. We speculate that two highly conserved regions within the cell-receptor binding domain of E2 mimic collagen and provide access to cellular collagen-binding receptors.

Characterization of epitopes for virus-neutralizing monoclonal antibodies to Ross River virus E2 using phage-displayed random peptide libraries

Ross River virus (RRV) is the predominant cause of epidemic polyarthritis in Australia, yet the antigenic determinants are not well defined. We aimed to characterize epitope(s) on RRV-E2 for a panel of monoclonal antibodies (MAbs) that recognize overlapping conformational epitopes on the E2 envelope protein of RRV and that neutralize virus infection of cells in vitro. Phage-displayed random peptide libraries were probed with the MAbs T1E7, NB3C4, and T10C9 using solution-phase and solid-phase biopanning methods. The peptides VSIFPPA and KTAISPT were selected 15 and 6 times, respectively, by all three of the MAbs using solution-phase biopanning. The peptide LRLPPAP was selected 8 times by NB3C4 using solid-phase biopanning; this peptide shares a trio of amino acids with the peptide VSIFPPA. Phage that expressed the peptides VSIFPPA and LRLPPAP were reactive with T1E7 and/or NB3C4, and phage that expressed the peptides VSIFPPA, LRLPPAP, and KTAISPT partially inhibited the reactivity of T1E7 with RRV. The selected peptides resemble regions of RRV-E2 adjacent to sites mutated in neutralization escape variants of RRV derived by culture in the presence of these MAbs (E2 210-219 and 238-245) and an additional region of E2 172-182. Together these sites represent a conformational epitope of E2 that is informative of cellular contact sites on RRV.

Epitope-blocking enzyme-linked immunosorbent assay for detection of antibodies to Ross River virus in vertebrate sera

We describe the development of an epitope-blocking enzyme-linked immunosorbent assay (ELISA) for the sensitive and rapid detection of antibodies to Ross River virus (RRV) in human sera and known vertebrate host species. This ELISA provides an alternative method for the serodiagnosis of RRV infections.

Bowel-associated dermatosis-arthritis syndrome in an adolescent with short bowel syndrome

Bowel-associated dermatosis-arthritis syndrome (BADAS) is a neutrophilic dermatosis, characterized by the occurrence of arthritis and skin lesions related to bowel disease with or without bowel bypass. We report an unusual case of BADAS in a 15-year-old white male with congenital aganglionosis of the colon and hypoganglionosis of the small intestine and multiple bowel surgeries in childhood complicated by short bowel syndrome. He presented with recurrent peripheral polyarthritis, tenosynovitis, and painful erythematous subcutaneous nodules located on the dorsolateral regions of the legs and on the dorsa of the feet. Histological examination disclosed a neutrophilic dermatosis confirming the diagnosis of BADAS.Although an uncommon disease, especially at pediatric age, it is important to evoke the diagnosis of BADAS in children and adolescents with bowel disease, because treatment options and prognosis are distinct from other rheumatologic conditions.

Bowel-associated dermatosis-arthritis syndrome in an adolescent with short bowel syndrome

Bowel-associated dermatosis-arthritis syndrome (BADAS) is a neutrophilic dermatosis, characterized by the occurrence of arthritis and skin lesions related to bowel disease with or without bowel bypass. We report an unusual case of BADAS in a 15-year-old white male with congenital aganglionosis of the colon and hypoganglionosis of the small intestine and multiple bowel surgeries in childhood complicated by short bowel syndrome. He presented with recurrent peripheral polyarthritis, tenosynovitis, and painful erythematous subcutaneous nodules located on the dorsolateral regions of the legs and on the dorsa of the feet. Histological examination disclosed a neutrophilic dermatosis confirming the diagnosis of BADAS.Although an uncommon disease, especially at pediatric age, it is important to evoke the diagnosis of BADAS in children and adolescents with bowel disease, because treatment options and prognosis are distinct from other rheumatologic conditions.

Predicting epidemic outbreak from individual features of the spreaders

Knowing which individuals can be more efficient in spreading a pathogen throughout a determinate environment is a fundamental question in disease control. Indeed, over recent years the spread of epidemic diseases and its relationship with the topology of the involved system have been a recurrent topic in complex network theory, taking into account both network models and real-world data. In this paper we explore possible correlations between the heterogeneous spread of an epidemic disease governed by the susceptible-infected-recovered (SIR) model, and several attributes of the originating vertices, considering Erdos-Renyi (ER), Barabasi-Albert (BA) and random geometric graphs (RGG), as well as a real case study, the US air transportation network, which comprises the 500 busiest airports in the US along with inter-connections. Initially, the heterogeneity of the spreading is achieved by considering the RGG networks, in which we analytically derive an expression for the distribution of the spreading rates among the established contacts, by assuming that such rates decay exponentially with the distance that separates the individuals. Such a distribution is also considered for the ER and BA models, where we observe topological effects on the correlations. In the case of the airport network, the spreading rates are empirically defined, assumed to be directly proportional to the seat availability. Among both the theoretical and real networks considered, we observe a high correlation between the total epidemic prevalence and the degree, as well as the strength and the accessibility of the epidemic sources. For attributes such as the betweenness centrality and the k-shell index, however, the correlation depends on the topology considered.

On the time to reach a critical number of infections in epidemic models with infective and susceptible immigrants.

In this paper we examine the time T to reach a critical number K0 of infections during an outbreak in an epidemic model with infective and susceptible immigrants. The underlying process X, which was first introduced by Ridler-Rowe (1967), is related to recurrent diseases and it appears to be analytically intractable. We present an approximating model inspired from the use of extreme values, and we derive formulae for the Laplace-Stieltjes transform of T and its moments, which are evaluated by using an iterative procedure. Numerical examples are presented to illustrate the effects of the contact and removal rates on the expected values of T and the threshold K0, when the initial time instant corresponds to an invasion time. We also study the exact reproduction number Rexact,0 and the population transmission number Rp, which are random versions of the basic reproduction number R0.

Different cognitive profiles for single compared with recurrent fallers without Dementia

Relationships between self-reported retrospective falls and cognitive measures (executive function, reaction time, processing speed, working memory, visual attention) were examined in a population based sample of older adults (n = 658). Two of the choice reaction time tests involved inhibiting responses to either targets of a specific color or location with hand and foot responses. Potentially confounding demographic variables, medical conditions and postural sway were controlled for in logistic regression models, excluding participants with possible cognitive impairment. A factor analysis of cognitive measures extracted factors measuring reaction time, accuracy and inhibition, and visual search. Single fallers did not differ from non-fallers in terms of health, sway or cognitive function, except that they performed worse on accuracy and inhibition. In contrast, recurrent fallers performed worse than non-fallers on all measures. Results suggest that occasional falls in late life may be associated with subtle age-related changes in the pre-frontal cortex leading to failures of executive control, whereas recurrent falling may result from more advanced brain ageing that is associated with generalized cognitive decline.