Delineating neuroinflammation, parasite CNS invasion, and blood-brain barrier dysfunction in an experimental murine model of human African trypanosomiasis

Although Trypanosoma brucei spp. was first detected by Aldo Castellani in CSF samples taken from sleeping sickness patients over a century ago there is still a great deal of debate surrounding the timing, route and effects of transmigration of the parasite from the blood to the CNS. In this investigation, we have applied contrast-enhance magnetic resonance imaging (MRI) to study the effects of trypanosome infection on the blood-brain barrier (BBB) in the well-established GVR35 mouse model of sleeping sickness. In addition, we have measured the trypanosome load present in the brain using quantitative Taqman PCR and assessed the severity of the neuroinflammatory reaction at specific time points over the course of the infection. Contrast enhanced – MRI detected a significant degree of BBB impairment in mice at 14 days following trypanosome infection, which increased in a step-wise fashion as the disease progressed. Parasite DNA was present in the brain tissue on day 7 after infection. This increased significantly in quantity by day 14 post-infection and continued to rise as the infection advanced. A progressive increase in neuroinflammation was detected following trypanosome infection, reaching a significant level of severity on day 14 post-infection and rising further at later time-points. In this model stage-2 disease presents at 21 days post-infection. The combination of the three methodologies indicates that changes in the CNS become apparent prior to the onset of established stage-2 disease. This could in part account for the difficulties associated with defining specific criteria to distinguish stage-1 and stage-2 infections and highlights the need for improved staging diagnostics

Stereo optical guidance system for control of industrial robots

A device for the generation of basic electrical signals which are supplied to a computerized processing complex for the operation of industrial robots. The system includes a stereo mirror arrangement for the projection of views from opposite sides of a visible indicia formed on a workpiece. The views are projected onto independent halves of the retina of a single camera. The camera retina is of the CCD (charge-coupled-device) type and is therefore capable of providing signals in response to the image projected thereupon. These signals are then processed for control of industrial robots or similar devices

Trypanosoma brucei brucei invasion and T-cell infiltration of the brain parenchyma in experimental sleeping sickness: timing and correlation with functional changes

Background: The timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications. Methodology: Using a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis, were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses. Principal findings: Trypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion. Conclusion: These findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging

The blood–brain barrier significantly limits eflornithine entry into Trypanosoma brucei brucei infected mouse brain1

Drugs to treat African trypanosomiasis are toxic, expensive and subject to parasite resistance. New drugs are urgently being sought. Although the existing drug, eflornithine, is assumed to reach the brain in high concentrations, little is known about how it crosses the healthy and infected blood–brain barrier. This information is essential for the design of drug combinations and new drugs. This study used novel combinations of animal models to address these omissions. Eflornithine crossed the healthy blood–CNS interfaces poorly, but this could be improved by co-administering suramin, but not nifurtimox, pentamidine or melarsoprol. Work using a murine model of sleeping sickness demonstrated that Trypanosoma brucei brucei crossed the blood–CNS interfaces, which remained functional, early in the course of infection. Concentrations of brain parasites increased during the infection and this resulted in detectable blood–brain barrier, but not choroid plexus, dysfunction at day 28 post-infection with resultant increases in eflornithine brain delivery. Barrier integrity was never restored and the animals died at day 37.9 ± 1.2. This study indicates why an intensive treatment regimen of eflornithine is required (poor blood–brain barrier penetration) and suggests a possible remedy (combining eflornithine with suramin). The blood–brain barrier retains functionality until a late, possibly terminal stage, of trypanosoma infection

Longitudinal impact of demographic and clinical variables on Health-Related Quality of Life in Cystic Fibrosis

Objectives: The insights that people with cystic fibrosis have concerning their health are important given that aspects of health-related quality of life (HRQoL) are independent predictors of survival and a decrease in lung function is associated with a decrease in HRQoL over time. Cross-sectional data suggest that key variables, other than lung function, are also associated with HRQoL - although study results are equivocal. This work evaluates the relationship between these key demographic and clinical variables and HRQoL longitudinally. Design: Longitudinal observational study. Observations were obtained at seven time points: approximately every two years over a twelve year period. Setting: Large Adult Cystic Fibrosis Centre in the UK. Participants: 234 participants aged 14-48 years at recruitment. Outcome measure: Nine domains of HRQoL (Cystic Fibrosis Quality of Life Questionnaire) in relation to demographic (age, gender) and clinical measures (FEV1% predicted, BMI, cystic fibrosis related diabetes, B. cepacia complex, totally implantable vascular access device, nutritional and transplant status). Results: A total of 770 patient assessments were obtained for 234 patients. The results of random coefficients modelling indicated that demographic and clinical variables were identified as being significant for HRQoL over time. In addition to lung function, transplant status, age, having a totally implantable vascular access device, cystic fibrosis related diabetes, BMI and B. cepacia complex impacted on many HRQoL domains longitudinally. Gender was important for the domain of Body image. Conclusion: Demographic and changes in clinical variables were independently associated with a change in health-related quality of life over time. Compared with these longitudinal data, cross-sectional data are inadequate when evaluating the relationships between HRQoL domains and key demographic and clinical variables, as they fail to recognise the full impact of the CF disease trajectory and its treatments on quality of life

The relative importance of training volume and coach autonomy support for preventing youth swimming attrition

There are hypothesized associations between high training volume in youth sport and negative psychological and behavioral outcomes such as decreased enjoyment, and increased burnout and dropout. Autonomy support, however, is associated with positive motivational and behavioral outcomes. The purpose of this study was to concurrently explore the relationships of training volume and perceived coach autonomy support with enjoyment, commitment, burnout symptoms, and dropout from swimming. Survey data were collected from 265 swimmers (Mage = 13.78 ± 1.60) representing more than 50 clubs across Canada. Their parents provided training volume data. Several months later, at the start of the next swimming season, a follow-up survey identified which swimmers dropped out. Structural equation modeling did not show a significant relationship between training volume and enjoyment, but there was a significant pathway from autonomy support to enjoyment, which predominantly predicted functional commitment. Obligatory and functional commitment differentially predicted burnout and intentions to continue swimming. Swimmers who dropped out had significantly lower training volume, enjoyment, functional commitment, and intentions to continue swimming, and higher sport devaluation, compared to those who continued swimming in the following season. Perceptions of an enjoyable, autonomy-supportive training context in adolescent swimming seem to have greater associations than training volume with several psychological and behavioral outcomes, including burnout symptoms and dropout

Weld analysis and control system

The invention is a Weld Analysis and Control System developed for active weld system control through real time weld data acquisition. Closed-loop control is based on analysis of weld system parameters and weld geometry. The system is adapted for use with automated welding apparatus having a weld controller which is capable of active electronic control of all aspects of a welding operation. Enhanced graphics and data displays are provided for post-weld analysis. The system provides parameter acquisition, including seam location which is acquired for active torch cross-seam positioning. Torch stand-off is also monitored for control. Weld bead and parent surface geometrical parameters are acquired as an indication of weld quality. These parameters include mismatch, peaking, undercut, underfill, crown height, weld width, puddle diameter, and other measurable information about the weld puddle regions, such as puddle symmetry, etc. These parameters provide a basis for active control as well as post-weld quality analysis and verification. Weld system parameters, such as voltage, current and wire feed rate, are also monitored and archived for correlation with quality parameters

Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice

Peer reviewedPublisher PD

Microarray profiling predicts early neurological and immune phenotypic traits in advance of CNS disease during disease progression in Trypanosoma.b.brucei infected CD1 mouse brains

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. We hypothesised that recent findings of neurological features and parasite brain infiltration occurring at much earlier stages in HAT than previously thought could be explained by early activation of host genetic programmes controlling CNS disease. Accordingly, a transcriptomal analysis was performed on brain tissue at 0, 7, 14, 21 and 28dpi from the HAT CD1/GVR35 mouse model. Up to 21dpi, most parasites are restricted to the blood and lymphatic system. Thereafter the trypanosomes enter the brain initiating the encephalitic stage. Analysis of ten different time point Comparison pairings, revealed a dynamic transcriptome comprising four message populations. All 7dpi Comparisons had by far more differentially expressed genes compared to all others. Prior to invasion of the parenchyma, by 7dpi, ~2,000 genes were up-regulated, denoted [7dpi↑] in contrast to a down regulated population [7dpi↓] also numbering ~2,000. However, by 14dpi both patterns had returned to around the pre-infected levels. The third, [28dpi↑] featured over three hundred transcripts which had increased modestly up to14dpi, thereafter were significantly up-regulated and peaked at 28dpi. The fourth, a minor population, [7dpi↑-28dpi↑], had similar elevated levels at 7dpi and 28dpi. KEGG and GO enrichment analysis predicted a diverse phenotype by 7dpi with changes to innate and adaptive immunity, a Type I interferon response, neurotransmission, synaptic plasticity, pleiotropic signalling, circadian activity and vascular permeability without disruption of the blood brain barrier. This key observation is consistent with recent rodent model neuroinvasion studies and clinical reports of Stage 1 HAT patients exhibiting CNS symptoms. Together, these findings challenge the strict Stage1/Stage2 phenotypic demarcation in HAT and show that that significant neurological, and immune changes can be detected prior to the onset of CNS disease