may be the etiological agent of human melioidosis, a disease with a broad spectrum of clinical manifestations ranging from fatal septicemia to chronic localized infection or asymptomatic latent infection. interferon (IFN-), interleukin-6 (IL-6), monocyte JIB-04 chemotactic protein-1 (MCP-1), and tumor necrosis factor- (TNF-) were induced during chronic infection, and histopathological analysis showed features in common with human melioidosis. Interestingly, many of these features were similar to those induced by in humans, such as development of a collagen cord that encapsulates the lesions, the presence of multinucleated giant cells, and granulomas with a caseous necrotic center, which may explain why chronic melioidosis is often misdiagnosed as tuberculosis. Our model now provides a relevant and practical tool to define the immunological features of chronic melioidosis and aid in the development of more effective treatment of this disease in humans. is a Gram-negative soil bacterium that is the causative agent of melioidosis. This pathogen is endemic in Southeast Asia and Northern Australia, but cases of melioidosis are now being reported in numerous other tropical areas, suggesting a more global distribution of the organism in the environment.1,2 The main routes of infection are believed to be via inhalation of aerosols during the rainy season or via cutaneous inoculation in people who have direct contact with wet soil.3 The consequences of infection with are remarkably diverse, ranging from an acute septicemia to a chronic localized disease or an asymptomatic latent infection. Acute infection is characterized by bacteremia, progression to septic shock with the induction of a massive but ineffective cytokine response, and a high mortality JIB-04 rate.3C5 Chronic infection is generally less severe and often characterized by persistent, localized infection that is difficult to eradicate.3,6 Recurrent disease is also common, and it is mostly due to relapse rather than reinfection. 7 The disease can also reactivate after decades of clinical latency, 8 suggesting that the bacteria may enter a dormant state where it can avoid immune surveillance.9 Despite the clear impact of this infection on public health in endemic regions, we do not understand how evades the immune response and causes a chronic infection. Chronic melioidosis is frequently misdiagnosed as tuberculosis, and the two diseases share several histological features,2,10 suggesting the possibility of common immunological mechanisms between these two infections. Animal models represent powerful tools to study immunity and virulence factors, and both outbred and inbred strains have been previously described as models to study human melioidosis.10C15 Typically, BALB/c mice, which are very susceptible, have been used to study acute melioidosis.14,16,17 In contrast, C57BL/6 mice show increased resistance to infection but are unable to clear infection, so they are better candidates to mimic chronic infection in humans.11,14 The mechanisms that regulate the development of either acute, chronic, or latent melioidosis remain unclear. However, it has been suggested that differential inflammatory responses in BALB/c mice versus C57BL/6 after infection may be responsible JIB-04 for different susceptibility to infection, suggesting that high levels of inflammatory cytokines in BALB/c may contribute JIB-04 to the immunopathogenesis.18 Other animals such as hamsters, guinea pigs, and rats have also been used,10,19 but there is little information on truly chronic models where disease progression is monitored over several months post-challenge.10,20 No licensed vaccine exists for either prophylactic or therapeutic use against 576 and investigated the histological and inflammatory responses to infection over an extended time course. Our aim was to develop a murine model of chronic disease that JIB-04 reflects chronic disease in humans. In the longer term, this model would be invaluable for evaluating pretreatments and therapeutics that might be used to treat or eliminate chronic infections. Materials and Methods Bacteria Strain strain 576 was originally isolated from a patient with a fatal case of human melioidosis in Thailand, and was kindly provided by Dr. Tyrone Pitt (Health Protection Agency, London, UK). Frozen stocks were prepared as previously described.32 All procedures involving live bacteria were performed under ACDP (Advisory Committee on Dangerous Pathogens) containment level 3 conditions. Infection of Mice and Determination of Tissue and Blood Bacterial Load Female C57BL/6 mice (6- to 8-week-old; Harlan Laboratories, Bicester, Oxon, UK) were used throughout the studies. All animal experiments were performed in accordance with the guidelines of the Animals (Scientific Procedures) Act of 1986 and were approved by the local ethical review committee at the London School of Hygiene and Tropical Medicine. A total number of 241 animals were used (191 chronically infected, 10 acutely infected, and 40 uninfected controls), distributed in 11 independent experiments. The number of animals used per experiment Rabbit polyclonal to ZNF562 and the number of experiments are shown in the figure legends. For survival curves, a total of 76 mice were used. Bacterial load and.
This paper reviews basic methods and recent applications of length-based fiber bundle analysis of cerebral white matter using diffusion magnetic resonance imaging (dMRI). improving the methodology through more complex anatomical models and potential areas of new application for qtDTI. Keywords: Diffusion tensor imaging, White matter, Quantitative tractography, Aging INTRODUCTION Advances in diffusion Moxonidine HCl weighted imaging (DWI) technology have allowed researchers to characterize the structural integrity of white matter tissue. Diffusion tensor imaging (DTI) is an extension of DWI utilized to non-invasively examine neuronal tracts to quantitatively measure white matter integrity (1,22,34,37,46). Highly advanced DTI methods have been developed in recent years and have significantly improved the utility of diffusion tensor measurements to detect subtle Rabbit polyclonal to ISOC2 white matter changes in both healthy and diseased populations (13C14,17,39C41). One example includes the integration of quantitative tractography based on diffusion tensor imaging (qtDTI) technology that has enhanced our ability to examine specific detail about the direction and curvature Moxonidine HCl of white matter pathways using in vivo imaging (17). This method is usually highly sensitive to white matter changes within entire tracts and, therefore, may be more advantageous than methods that involve placing regions of interest on two-dimensional scalar DTI parameter maps (17). In this review, we Moxonidine HCl describe the fundamentals of the diffusion tensor model and qtDTI technology. We then Moxonidine HCl review the existing literature on length-based metrics using qtDTI, followed by a discussion of the strengths and limitations of qtDTI. Finally, a brief review of future applications is provided. DIFFUSION MR TECHNIQUES DTI Physical Basis DTI is usually a noninvasive magnetic resonance imaging (MRI) technology that measures water diffusion at each voxel in the brain. Water molecules diffuse differently along tissues depending on tissue microstructure and the presence of anatomical barriers. One simple and useful way to characterize diffusion at a location in the brain is usually along a spectrum between isotropic and anisotropic. Diffusion that is highly similar in all directions (i.e., isotropic diffusion) is typically observed in grey matter and cerebrospinal fluid. By contrast, directionally dependent diffusion (i.e., anisotropic diffusion) is usually observed in white matter due to the linear organization of the fiber tracts. Water within these tracts preferentially diffuses in one direction because physical barriers such as axonal walls and myelin restrict water movement in other directions (5,24,47,48). Neuropathological mechanisms associated with multiple conditions, including subcortical ischemia, neurodegeneration, and traumatic brain injury, cause reductions in the linear organization of white matter pathways with corresponding reductions in linear anisotropy (5,19,48,52). DTI is usually sensitive to these changes in linear anisotropy even when white matter integrity appears healthy based on structural neuroimaging methods (referenced as normal appearing white matter) (4,30), making DTI a powerful in vivo imaging method for the examination of the microstructural integrity of white matter. DTI Scalar Metrics A symmetric 33 diffusion tensor characterizes water diffusion in brain tissues. This model represents the diffusion pattern with a second-order tensor that can be decomposed into three non-negative eigenvalues and three eigenvectors that describe the magnitude and orientation of water diffusion in each voxel (Physique 1). Eigenvalues describe the shape and size of the tensor, impartial of orientation, while eigenvectors describe the orientation of the tensor, impartial of shape and size. The tensor model parameterizes the diffusion in each voxel with Moxonidine HCl an ellipsoid whose diameter in any direction estimates the diffusivity in that direction and whose major principle axis is usually oriented in the direction of maximum diffusivity The major.
Background We have previously reported the effects of age and diet about nutrient digestibility, intestinal morphology, and large intestinal fermentation patterns in healthy young adult and senior dogs. with apoptosis and defensive mechanisms were decreased in older vs. young adult dogs. No consistent diet-induced alterations in gene manifestation existed in both age groups, with the effects of diet becoming more pronounced in older dogs than in young adult dogs. Summary Our results provide molecular insight pertaining to the aged canine colon and 1186486-62-3 IC50 its predisposition to dysfunction and disease. Consequently, our data may aid in long term research pertaining to age-associated gastrointestinal physiological changes and spotlight potential focuses on for dietary treatment to limit 1186486-62-3 IC50 their progression. Introduction The primary role of the colon has been known for years to maintain water and electrolyte balance and to excrete undigested food materials. Currently, FBL1 the colon is definitely appreciated like a metabolically active organ and, therefore, colonic health is definitely closely linked with overall health of humans and animals . Until recently, however, the physiology of the colon has received little attention in biological studies as compared to additional body organs. Diet composition may be the most important factor influencing colonic health because of its direct effects on microbial fermentation, morphology, and rate of metabolism. Ageing also takes on a significant part in colon health. It is well known that 1186486-62-3 IC50 age is highly associated with an increased risk of colonic diseases in humans , . Similarly, dogs become more susceptible to gastrointestinal disorders with age . Our earlier experiment reported significant variations in colonic butyrate concentrations and morphology (e.g., crypt depth) between older and young adult dogs . However, the molecular mechanisms underlying the effects of age and diet on colonic physiology remain unstudied. Gene manifestation profiling may improve our understanding of colonic physiology and metabolic alterations like a function of age and diet. The PCR and Northern-blotting assays have been widely used for measuring gene expression changes in humans and animals for years; however, they are only capable of monitoring a limited quantity of genes at a time. As a powerful alternative to those classical methods, DNA microarrays can analyze thousands of genes simultaneously, providing a global look at of gene manifestation . In recent years, microarrays have been used to investigate how genes are differentially indicated in diseased individuals , in response to diet treatments , and relating 1186486-62-3 IC50 to physiological stage , . Consequently, microarrays may be used to link molecular events with physiological response and determine crucial genes and biological pathways. Previously, we reported the effects of diet (APB; animal protein-based vs. PPB; flower protein-based) and age (young adult vs. older dogs) on gene manifestation profiles of cerebral cortex , skeletal muscle mass , and abdominal adipose cells . To our knowledge, no large-scale molecular analysis of colonic mucosa in young adult vs. older dogs is available. Consequently, we isolated RNA from colonic mucosa that was collected from the experiment of Kuzmuk et al.  and measured gene expression profiles using commercial microarrays. The objective of this experiment, consequently, was to compare colonic mucosal gene manifestation in healthy young adult vs. older dogs fed two distinct diet programs. Results and Conversation The characteristics of undigested food residue, microbial populations, and their fermentation play a key part in colonic health and physiology . In our earlier experiments , , it was shown that age and diet affected nutrient digestibility, intestinal morphology, and colonic fermentation patterns in dogs. In short, older dogs had higher (P<0.05) apparent total tract digestibility of organic matter and fat as compared to young growing dogs, while these variations were undetectable as young dogs became mature (12 month old). Dogs consuming PPB experienced a lower (P<0.01) fat digestibility, tended to have decreased (P<0.10) organic matter (OM) digestibility, but had increased (P<0.01) crude protein (CP) digestibility than dogs consuming APB. Older dogs experienced deeper (P<0.01) colonic crypt depth and higher (P<0.05) colonic concentrations of butyrate compared with young adult dogs regardless of diet programs. Dogs consuming APB had higher (P<0.05) colonic concentrations of ammonia and butyrate than dogs consuming PPB. These observations bring to question the relationship between physiological response and colonic transcriptional activity like a function of age and diet. To address this question, we used DNA microarray technology to provide a global look at of gene manifestation and advance our.