The road to tuberculosis treatment in rural Nepal: A qualitative assessment of 26 journeys

BACKGROUND: The fact that tuberculosis can be treated with the DOTS strategy (Directly Observed Treatment, Short-course) is not enough to control the disease. Patients have to find their way to tuberculosis treatment first. To better understand the route to tuberculosis treatment in rural Nepal we interviewed twenty-six patients under treatment. METHODS: In semi-structured interviews patients shared their disease history and health seeking behaviour. The analysis focused on the encounters with the health care system before enrolment in the tuberculosis treatment program. RESULTS: Patient routes often started in the medical shop and led via intricate routes with multiple providers to facilities with higher qualified and more competent staff where tuberculosis was diagnosed. Several factors influenced the route to tuberculosis treatment. Besides known patients factors (such as severity of complaints, the ability to pay for services, availability of services and peer support for choosing a provider) specific health services factors were also identified. These included the perceived quality, costs and service level of a provider, and lack of provider initiated referral. Self referral because of waned trust in the provider was very common. In contrast, once tuberculosis was considered a possible diagnosis, referral to diagnostic testing and tuberculosis treatment was prompt. CONCLUSION: Patient routes towards tuberculosis treatment are characterised by self referral and include both private and public health care providers. Once tuberculosis is suspected referral for diagnosis and treatment is prompt. Given the importance of the private practitioners in the patient routes, quality improvement initiatives need to address not only the public sector but the private health care sector as well

The Urokinase Receptor (uPAR) Facilitates Clearance of Borrelia burgdorferi

The causative agent of Lyme borreliosis, the spirochete Borrelia burgdorferi, has been shown to induce expression of the urokinase receptor (uPAR); however, the role of uPAR in the immune response against Borrelia has never been investigated. uPAR not only acts as a proteinase receptor, but can also, dependently or independently of ligation to uPA, directly affect leukocyte function. We here demonstrate that uPAR is upregulated on murine and human leukocytes upon exposure to B. burgdorferi both in vitro as well as in vivo. Notably, B. burgdorferi-inoculated C57BL/6 uPAR knock-out mice harbored significantly higher Borrelia numbers compared to WT controls. This was associated with impaired phagocytotic capacity of B. burgdorferi by uPAR knock-out leukocytes in vitro. B. burgdorferi numbers in vivo, and phagocytotic capacity in vitro, were unaltered in uPA, tPA (low fibrinolytic activity) and PAI-1 (high fibrinolytic activity) knock-out mice compared to WT controls. Strikingly, in uPAR knock-out mice partially backcrossed to a B. burgdorferi susceptible C3H/HeN background, higher B. burgdorferi numbers were associated with more severe carditis and increased local TLR2 and IL-1β mRNA expression. In conclusion, in B. burgdorferi infection, uPAR is required for phagocytosis and adequate eradication of the spirochete from the heart by a mechanism that is independent of binding of uPAR to uPA or its role in the fibrinolytic system

Environmental Enrichment Induces Behavioral Recovery and Enhanced Hippocampal Cell Proliferation in an Antidepressant-Resistant Animal Model for PTSD

Background: Post traumatic stress disorder (PTSD) can be considered the result of a failure to recover after a traumatic experience. Here we studied possible protective and therapeutic aspects of environmental enrichment (with and without a running wheel) in Sprague Dawley rats exposed to an inescapable foot shock procedure (IFS). Methodology/Principal Findings: IFS induced long-lasting contextual and non-contextual anxiety, modeling some aspects of PTSD. Even 10 weeks after IFS the rats showed reduced locomotion in an open field. The antidepressants imipramine and escitalopram did not improve anxiogenic behavior following IFS. Also the histone deacetylase (HDAC) inhibitor sodium butyrate did not alleviate the IFS induced immobility. While environmental enrichment (EE) starting two weeks before IFS did not protect the animals from the behavioral effects of the shocks, exposure to EE either immediately after the shock or one week later induced complete recovery three weeks after IFS. In the next set of experiments a running wheel was added to the EE to enable voluntary exercise (EE/VE). This also led to reduced anxiety. Importantly, this behavioral recovery was not due to a loss of memory for the traumatic experience. The behavioral recovery correlated with an increase in cell proliferation in hippocampus, a decrease in the tissue levels of noradrenalin and increased turnover of 5-HT in prefrontal cortex and hippocampus. Conclusions/Significance: This animal study shows the importance of (physical) exercise in the treatment of psychiatri

Coordinated Regulation of Virulence during Systemic Infection of Salmonella enterica Serovar Typhimurium

To cause a systemic infection, Salmonella must respond to many environmental cues during mouse infection and express specific subsets of genes in a temporal and spatial manner, but the regulatory pathways are poorly established. To unravel how micro-environmental signals are processed and integrated into coordinated action, we constructed in-frame non-polar deletions of 83 regulators inferred to play a role in Salmonella enteriditis Typhimurium (STM) virulence and tested them in three virulence assays (intraperitoneal [i.p.], and intragastric [i.g.] infection in BALB/c mice, and persistence in 129X1/SvJ mice). Overall, 35 regulators were identified whose absence attenuated virulence in at least one assay, and of those, 14 regulators were required for systemic mouse infection, the most stringent virulence assay. As a first step towards understanding the interplay between a pathogen and its host from a systems biology standpoint, we focused on these 14 genes. Transcriptional profiles were obtained for deletions of each of these 14 regulators grown under four different environmental conditions. These results, as well as publicly available transcriptional profiles, were analyzed using both network inference and cluster analysis algorithms. The analysis predicts a regulatory network in which all 14 regulators control the same set of genes necessary for Salmonella to cause systemic infection. We tested the regulatory model by expressing a subset of the regulators in trans and monitoring transcription of 7 known virulence factors located within Salmonella pathogenicity island 2 (SPI-2). These experiments validated the regulatory model and showed that the response regulator SsrB and the MarR type regulator, SlyA, are the terminal regulators in a cascade that integrates multiple signals. Furthermore, experiments to demonstrate epistatic relationships showed that SsrB can replace SlyA and, in some cases, SlyA can replace SsrB for expression of SPI-2 encoded virulence factors

Lipidomics Reveals Multiple Pathway Effects of a Multi-Components Preparation on Lipid Biochemistry in ApoE*3Leiden.CETP Mice

Background: Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese Medicine (CM) systems have been handed down with documented clinical features similar as metabolic syndrome, which might help developing new intervention for metabolic syndrome. The progress in systems biology and specific animal models created possibilities to assess the effects of such preparations. Here we report the plasma and liver lipidomics results of the intervention effects of a preparation SUB885C in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) mice. SUB885C was developed according to the principles of CM for treatment of metabolic syndrome. The cannabinoid receptor type 1 blocker rimonabant was included as a general control for the evaluation of weight and metabolic responses. Methodology/Principal Findings: ApoE*3Leiden.CETP mice with mild hypercholesterolemia were divided into SUB885C-, rimonabant- and non-treated control groups. SUB885C caused no weight loss, but significantly reduced plasma cholesterol (-49%, p <0.001), CETP levels (-31%,

Joint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis.

Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines

Enhancing Biological and Biomechanical Fixation of Osteochondral Scaffold: A Grand Challenge

Osteoarthritis (OA) is a degenerative joint disease, typified by degradation of cartilage and changes in the subchondral bone, resulting in pain, stiffness and reduced mobility. Current surgical treatments often fail to regenerate hyaline cartilage and result in the formation of fibrocartilage. Tissue engineering approaches have emerged for the repair of cartilage defects and damages to the subchondral bones in the early stage of OA and have shown potential in restoring the joint's function. In this approach, the use of three-dimensional scaffolds (with or without cells) provides support for tissue growth. Commercially available osteochondral (OC) scaffolds have been studied in OA patients for repair and regeneration of OC defects. However, some controversial results are often reported from both clinical trials and animal studies. The objective of this chapter is to report the scaffolds clinical requirements and performance of the currently available OC scaffolds that have been investigated both in animal studies and in clinical trials. The findings have demonstrated the importance of biological and biomechanical fixation of the OC scaffolds in achieving good cartilage fill and improved hyaline cartilage formation. It is concluded that improving cartilage fill, enhancing its integration with host tissues and achieving a strong and stable subchondral bone support for overlying cartilage are still grand challenges for the early treatment of OA

[Virological NIVEL/RIVM-surveillance of respiratory virus infection in the season 1993/94.]

Abstract niet beschikbaarIn the season 1993/94 the virological NIVEL (Netherlands institute of primary health care)/RIVM-surveillance of respiratory virus infections was continued. The sentinel general physicians participating in the NIVEL network submitted 298 samples from patients with respiratory complaints From 92 (31%) of the samples a respiratory virus was grown, 67 of which were influenza A (H3N2) viruses. The antigenic reactivity of the strains in haemagglutination inhibition tests corresponded well with the virus isolates from diagnostic laboratories. When calculated per 10,000 persons, most influenza viruses were obtained from children aged 5-14 years. This is at variance with the NIVEL registration of influenza-like illnesses, which showed the highest incidence in the age group of 0-4 years. The protective effect of influenza vaccination over the seasons 1991/92, 1992/93, and 1993/94 was estimated at 76%.GH

Virological NIVEL/RIVM-surveillance of respiratory virus infection in the season 1994/95

Sinds het seizoen 1992/93 sturen de NIVEL (Nederlands Instituut voor Onderzoek van de Gezondheidszorg) peilstationartsen neus-/keelwatten op van door hen behandelde patienten met acute luchtwegklachten naar het RIVM. Aldaar worden deze monsters m.b.v. de kweek in celcultuur op virussen onderzocht. In het seizoen 1994/95 werden de monsters tevens m.b.v. de polymerase chain reactie (PCR) onderzocht op Mycoplasma pneumoniae, Chlamydia pneumoniae, rhinovirus, enterovirus, RS-virus, coronavirus OC43 en coronavirus 229E. Deze surveillance verschaft een beter inzicht in de etiologie en de incidenties van minder ernstig verlopende luchtweginfecties dan de virusisoleringen voor diagnostische doeleinden. In het seizoen 1994/95 stuurden de peilstationartsen 557 monsters van patienten met respiratoire aandoeningen naar het RIVM. In 189 (34%) werd een respiratoir virus en/of bacterie aangetoond. Influenza B-virus (9%) en rhinovirus (9%) waren de meest voorkomende verwekkers gevolgd door coronavirus OC43 (4%), influenza A-virus (3%), RS-virus (3%) en adenovirus (2%). In 8 (4%) van de positieve monsters werden twee verwekkers aangetoond. In 70 (37%) van de positieve monsters werd alleen m.b.v. de PCR een micro-organisme aangetoond. Worden deze resultaten vergeleken met die uit de diagnostische laboratoria, dan zijn de belangrijkste verschillen het relatief hogere aantal influenzavirus-isolaten en het relatief lagere aantal RS-virus-isolaten in het NIVEL/RIVM-surveillance netwerk. Tevens is influenza B-virus de meest voorkomende verwekker in het NIVEL/RIVM-surveillance netwerk in tegenstelling tot de diagnostische laboratoria, waar het type A(H3N2) domineerde. Van 68 PCR-positieve patienten werden 72 vervolgmonsters afgenomen na gemiddeld 24 dagen. Drie patienten bleken PCR-positief te blijven voor hetzelfde agens ; in twee gevallen betrof het Chlamydia pneumoniae. De klinische relevantie van de PCR lijkt daarom goed te zijn voor de onderzochte respiratoire virussen en voor Mycoplasma pneumoniae.The Netherlands institute of primary health care (NIVEL) is running a surveillance network of 46 sentinel general practices (GP) stations, spread over the country in proportion to the population density. The GP of this network sent nose/throat swabs from the part of their patients with respiratory illnesses to the RIVM. In the season 1994/95 557 respiratory specimens were examined by virus isolation and PCR. In 189 (34%) of the samples a respiratory virus or bacterium was detected by either technique. Influenza B (9%) and rhinovirus (9%) were the predominant viruses followed by coronavirus OC43 (4%), influenza A virus (3%), RS virus (3%), and adenovirus (2%). In 8 (4%) of the positive samples two etiologic agents were detected. In 70 (37%) of the causative agents were only recognized by PCR. When comparing the results of the surveillance among patients in the GP network with those of the examinations of virus diagnostic laboratories, the main differences were the higher proportion of influenza virus isolations and the lower proportion of RS virus isolations in the GP system. Among the isolated influenza viruses, type B prevailed in the GP system and type A(H3N2) in the virus diagnostic laboratories. From 68 PCR-positive patients 72 follow-up samples could be obtained, taken on an average 24 days after the first specimen. In only three patients the agent could still be demonstrated in the follow-up sample ; in two of these the agent was Chlamydia pneumoniae. Conclusions: The proportions of at least part of the viruses isolated from patients with respiratory complaints in a GP network differ considerably from those isolated in virus diagnostic laboratories, the samples of which are mainly derived from hospitalised patients. Surveillance of respiratory infections among patients of GP is therefore essential for the insight in the epidemiology of respiratory diseases. On the average, illness from infection with influenza B-virus appears to be less severe compared to influenza A(H3N2) virus. Application of the PCR-technique enhances considerably the rate of positive results of the examination of respiratory specimens. Important respiratory pathogens as coronavirus, Mycoplasma pneumoniae, and Chlamydia pneumoniae even can only be detected by PCR. The clinical relevance of the PCR-technique appears to be high for the tested respiratory viruses and for Mycoplasma pneumoniae. The rhinovirus PCR and the virus culture technique should be improved, whereas the bacterial surveillance should be extended to important cultivable respiratory bacteria.IG