Dissociation between mitogenicity and immunogenicity of TNP- lipopolysaccharide, a T-independent antigen

Two models have been proposed to explain triggering of B cells by so-called “T-independent antigen.” Feldmann and Basten (1) proposed that the interaction of multiple repeating determinants on polymeric antigens with specific Ig receptors on the B-cell surface is sufficient to provide the signals for division of these cells and differentiation to antibody-forming cells. In contrast, coutinho et al. (2, and see review, 3) have claimed that there is only one signal, a mitogenic signal, receptors acting merely as passive focusing devices to localize the antigen on specific cells where it delivers a mitogenic signal resulting in differentiation to an antibody-producing cell. This model rests primarily on the demonstration that at high concentration all T-independent antigens they have tested are mitogenic for B cells (4-6). Compatible with this hypothesis are the observations that hydrolysis of lipopolysaccharide (LPS) to remove the ester- linked fatty acids of the mitogenic lipid A component abrogates its mitogenic (7,8) activity as well as its ability, when substituted with the TNP hapten, to induce a T-independent anti- TNP response (9). However, alkali treatment of LPS, although not changing its antigenic component (8), may also modify the molecule physically or chemically which could account for loss of immunogenic properties (10). We therefore investigated other reagents which interact with LPS in a more chemically defined manner in an effort to clarify the relationship between the mitogenic and immunogenic properties of this molecule. Polymyxin B (PB) is one of a family of cyclic peptide antibiotics which are bactericidal for most gram-negative bacteria. It prevents the lethal endotoxic activity of LPS (11, 12) and changes the physical structure of LPS (13). We report here that low doses of PB added to cultures of mouse spleen cells inhibit the mitogenic activity of TNP-LPS, a T- independent antigen, and native LPS, but do not suppress the immune response to TNP-LPS. PB interacts with TNP-LPS and LPS causing a physical change in the molecule. In addition, polymyxin-treated LPS is no longer mitogenic. These results suggest a dissociation between the mitogenic and immunogenic properties of TNP-LPS

A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma

PURPOSE: We determine if several hours of controlled elevation of IOP (CEI) will produce the optic nerve head (ONH) gene expression changes and optic nerve (ON) damage pattern associated with early experimental glaucoma in rats. METHODS: The anterior chambers of anesthetized rats were cannulated and connected to a reservoir to elevate IOP. Physiologic parameters were monitored. Following CEI at various recovery times, ON cross-sections were graded for axonal injury. Anterior ONHs were collected at 0 hours to 10 days following CEI and RNA extracted for quantitative PCR measurement of selected messages. The functional impact of CEI was assessed by electroretinography (ERG). RESULTS: During CEI, mean arterial pressure (99 ± 6 mm Hg) and other physiologic parameters remained stable. An 8-hour CEI at 60 mm Hg produced significant focal axonal degeneration 10 days after exposure, with superior lesions in 83% of ON. Message analysis in CEI ONH demonstrated expression responses previously identified in minimally injured ONH following chronic IOP elevation, as well as their sequential patterns. Anesthesia with cannulation at 20 mm Hg did not alter these message levels. Electroretinographic A- and B-waves, following a significant reduction at 2 days after CEI, were fully recovered at 2 weeks, while peak scotopic threshold response (pSTR) remained mildly but significantly depressed. CONCLUSIONS: A single CEI reproduces ONH message changes and patterns of ON injury previously observed with chronic IOP elevation. Controlled elevation of IOP can allow detailed determination of ONH cellular and functional responses to an injurious IOP insult and provide a platform for developing future therapeutic interventions

Comparison and Mapping Facilitate Relation Discovery and Predication

Relational concepts play a central role in human perception and cognition, but little is known about how they are acquired. For example, how do we come to understand that physical force is a higher-order multiplicative relation between mass and acceleration, or that two circles are the same-shape in the same way that two squares are? A recent model of relational learning, DORA (Discovery of Relations by Analogy; Doumas, Hummel & Sandhofer, 2008), predicts that comparison and analogical mapping play a central role in the discovery and predication of novel higher-order relations. We report two experiments testing and confirming this prediction

The modified Glasgow prognostic score in prostate cancer: results from a retrospective clinical series of 744 patients

<p>Background: As the incidence of prostate cancer continues to rise steeply, there is an increasing need to identify more accurate prognostic markers for the disease. There is some evidence that a higher modified Glasgow Prognostic Score (mGPS) may be associated with poorer survival in patients with prostate cancer but it is not known whether this is independent of other established prognostic factors. Therefore the aim of this study was to describe the relationship between mGPS and survival in patients with prostate cancer after adjustment for other prognostic factors.</p> <p>Methods: Retrospective clinical series on patients in Glasgow, Scotland, for whom data from the Scottish Cancer Registry, including Gleason score, Prostate Specific Antigen (PSA), C-reactive protein (CRP) and albumin, six months prior to or following the diagnosis, were included in this study.</p> <p>The mGPS was constructed by combining CRP and albumin. Five-year and ten-year relative survival and relative excess risk of death were estimated by mGPS categories after adjusting for age, socioeconomic circumstances, Gleason score, PSA and previous in-patient bed days.</p> <p>Results: Seven hundred and forty four prostate cancer patients were identified; of these, 497 (66.8%) died during a maximum follow up of 11.9 years. Patients with mGPS of 2 had poorest 5-year and 10-year relative survival, of 32.6% and 18.8%, respectively. Raised mGPS also had a significant association with excess risk of death at five years (mGPS 2: Relative Excess Risk = 3.57, 95% CI 2.31-5.52) and ten years (mGPS 2: Relative Excess Risk = 3.42, 95% CI 2.25-5.21) after adjusting for age, socioeconomic circumstances, Gleason score, PSA and previous in-patient bed days.</p> <p>Conclusions: The mGPS is an independent and objective prognostic indicator for survival of patients with prostate cancer. It may be useful in determining the clinical management of patients with prostate cancer in addition to established prognostic markers.</p&gt

An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow Inflammation Outcome Study

INTRODUCTION: A selective combination of C-reactive protein and albumin (termed the modified Glasgow Prognostic Score, mGPS) has been shown to have prognostic value, independent of tumour stage, in lung, gastrointestinal and renal cancers. It is also of interest that liver function tests such as bilirubin, alkaline phosphatase and gamma-glutamyl transferase, as well as serum calcium, have also been reported to predict cancer survival. The aim of the present study was to examine the relationship between an inflammation-based prognostic score (mGPS), biochemical parameters, tumour site and survival in a large cohort of patients with cancer. METHODS: Patients (n = 21 669) who had an incidental blood sample taken between 2000 and 2006 for C-reactive protein, albumin and calcium (and liver function tests where available) and a diagnosis of cancer were identified. Of this group 9608 patients who had an ongoing malignant process were studied (sampled within 2 years before diagnosis). Also a subgroup of 5397 sampled at the time of diagnosis (sampled within 2 months prior to diagnosis) were examined. Cancers were grouped by tumour site in accordance with International Classification of Diseases 10 (ICD 10). RESULTS: On follow up, there were 6005 (63%) deaths of which 5122 (53%) were cancer deaths. The median time from blood sampling to diagnosis was 1.4 months. Increasing age, male gender and increasing deprivation was associated with a reduced 5-year overall and cancer-specific survival (all P < 0.001). An elevated mGPS, adjusted calcium, bilirubin, alkaline phosphatase, aspartate transaminase, alanine transaminase and gamma-glutamyl transferase were associated with a reduced 5-year overall and cancer-specific survival (independent of age, sex and deprivation in all patients sampled), as well as within the time of diagnosis subgroup (all P < 0.001). An increasing mGPS was predictive of a reduced cancer-specific survival in all cancers (all P < 0.001). CONCLUSION: The results of the present study indicate that the mGPS is a powerful prognostic factor when compared with other biochemical parameters and independent of tumour site in patients with cancer

The increase of the functional entropy of the human brain with age

We use entropy to characterize intrinsic ageing properties of the human brain. Analysis of fMRI data from a large dataset of individuals, using resting state BOLD signals, demonstrated that a functional entropy associated with brain activity increases with age. During an average lifespan, the entropy, which was calculated from a population of individuals, increased by approximately 0.1 bits, due to correlations in BOLD activity becoming more widely distributed. We attribute this to the number of excitatory neurons and the excitatory conductance decreasing with age. Incorporating these properties into a computational model leads to quantitatively similar results to the fMRI data. Our dataset involved males and females and we found significant differences between them. The entropy of males at birth was lower than that of females. However, the entropies of the two sexes increase at different rates, and intersect at approximately 50 years; after this age, males have a larger entropy

Effect of Dietary Components on Larval Life History Characteristics in the Medfly (Ceratitis capitata: Diptera, Tephritidae)

Background: The ability to respond to heterogenous nutritional resources is an important factor in the adaptive radiation of insects such as the highly polyphagous Medfly. Here we examined the breadth of the Medfly’s capacity to respond to different developmental conditions, by experimentally altering diet components as a proxy for host quality and novelty. Methodology/Principal Findings: We tested responses of larval life history to diets containing protein and carbohydrate components found in and outside the natural host range of this species. A 40% reduction in the quantity of protein caused a significant increase in egg to adult mortality by 26.5%±6% in comparison to the standard baseline diet. Proteins and carbohydrates had differential effects on larval versus pupal development and survival. Addition of a novel protein source, casein (i.e. milk protein), to the diet increased larval mortality by 19.4%±3% and also lengthened the duration of larval development by 1.93±0.5 days in comparison to the standard diet. Alteration of dietary carbohydrate, by replacing the baseline starch with simple sugars, increased mortality specifically within the pupal stage (by 28.2%±8% and 26.2%±9% for glucose and maltose diets, respectively). Development in the presence of the novel carbohydrate lactose (milk sugar) was successful, though on this diet there was a decrease of 29.8±1.6 µg in mean pupal weight in comparison to pupae reared on the baseline diet. Conclusions: The results confirm that laboratory reared Medfly retain the ability to survive development through a wide range of fluctuations in the nutritional environment. We highlight new facets of the responses of different stages of holometabolous life histories to key dietary components. The results are relevant to colonisation scenarios and key to the biology of this highly invasive species

New Mechanics of Traumatic Brain Injury

The prediction and prevention of traumatic brain injury is a very important aspect of preventive medical science. This paper proposes a new coupled loading-rate hypothesis for the traumatic brain injury (TBI), which states that the main cause of the TBI is an external Euclidean jolt, or SE(3)-jolt, an impulsive loading that strikes the head in several coupled degrees-of-freedom simultaneously. To show this, based on the previously defined covariant force law, we formulate the coupled Newton-Euler dynamics of brain's micro-motions within the cerebrospinal fluid and derive from it the coupled SE(3)-jolt dynamics. The SE(3)-jolt is a cause of the TBI in two forms of brain's rapid discontinuous deformations: translational dislocations and rotational disclinations. Brain's dislocations and disclinations, caused by the SE(3)-jolt, are described using the Cosserat multipolar viscoelastic continuum brain model. Keywords: Traumatic brain injuries, coupled loading-rate hypothesis, Euclidean jolt, coupled Newton-Euler dynamics, brain's dislocations and disclinationsComment: 18 pages, 1 figure, Late

Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al