Numerical simulation of steady inspiratory flow through a multiply branched model of the human central airways

info:eu-repo/semantics/published

Gait and behavior in an IL1β-mediated model of rat knee arthritis and effects of an IL1 antagonist.

Interleukin-1 beta (IL1β) is a proinflammatory cytokine that mediates arthritic pathologies. Our objectives were to evaluate pain and limb dysfunction resulting from IL1β over-expression in the rat knee and to investigate the ability of local IL1 receptor antagonist (IL1Ra) delivery to reverse-associated pathology. IL1β over-expression was induced in the right knees of 30 Wistar rats via intra-articular injection of rat fibroblasts retrovirally infected with human IL1β cDNA. A subset of animals received a 30 µl intra-articular injection of saline or human IL1Ra on day 1 after cell delivery (0.65 µg/µl hIL1Ra, n = 7 per group). Joint swelling, gait, and sensitivity were investigated over 1 week. On day 8, animals were sacrificed and joints were collected for histological evaluation. Joint inflammation and elevated levels of endogenous IL1β were observed in knees receiving IL1β-infected fibroblasts. Asymmetric gaits favoring the affected limb and heightened mechanical sensitivity (allodynia) reflected a unilateral pathology. Histopathology revealed cartilage loss on the femoral groove and condyle of affected joints. Intra-articular IL1Ra injection failed to restore gait and sensitivity to preoperative levels and did not reduce cartilage degeneration observed in histopathology. Joint swelling and degeneration subsequent to IL1β over-expression is associated limb hypersensitivity and gait compensation. Intra-articular IL1Ra delivery did not result in marked improvement for this model; this may be driven by rapid clearance of administered IL1Ra from the joint space. These results motivate work to further investigate the behavioral consequences of monoarticular arthritis and sustained release drug delivery strategies for the joint space.

Quantitative model of the phase behavior of recombinant pH-responsive elastin-like polypeptides.

Quantitative models are required to engineer biomaterials with environmentally responsive properties. With this goal in mind, we developed a model that describes the pH-dependent phase behavior of a class of stimulus responsive elastin-like polypeptides (ELPs) that undergo reversible phase separation in response to their solution environment. Under isothermal conditions, charged ELPs can undergo phase separation when their charge is neutralized. Optimization of this behavior has been challenging because the pH at which they phase separate, pHt, depends on their composition, molecular weight, concentration, and temperature. To address this problem, we developed a quantitative model to describe the phase behavior of charged ELPs that uses the Henderson-Hasselbalch relationship to describe the effect of side-chain ionization on the phase-transition temperature of an ELP. The model was validated with pH-responsive ELPs that contained either acidic (Glu) or basic (His) residues. The phase separation of both ELPs fit this model across a range of pH. These results have important implications for applications of pH-responsive ELPs because they provide a quantitative model for the rational design of pH-responsive polypeptides whose transition can be triggered at a specified pH.

Altered gene expression and DNA damage in peripheral blood cells from Friedreich's ataxia patients: cellular model of pathology.

The neurodegenerative disease Friedreich's ataxia (FRDA) is the most common autosomal-recessively inherited ataxia and is caused by a GAA triplet repeat expansion in the first intron of the frataxin gene. In this disease, transcription of frataxin, a mitochondrial protein involved in iron homeostasis, is impaired, resulting in a significant reduction in mRNA and protein levels. Global gene expression analysis was performed in peripheral blood samples from FRDA patients as compared to controls, which suggested altered expression patterns pertaining to genotoxic stress. We then confirmed the presence of genotoxic DNA damage by using a gene-specific quantitative PCR assay and discovered an increase in both mitochondrial and nuclear DNA damage in the blood of these patients (p<0.0001, respectively). Additionally, frataxin mRNA levels correlated with age of onset of disease and displayed unique sets of gene alterations involved in immune response, oxidative phosphorylation, and protein synthesis. Many of the key pathways observed by transcription profiling were downregulated, and we believe these data suggest that patients with prolonged frataxin deficiency undergo a systemic survival response to chronic genotoxic stress and consequent DNA damage detectable in blood. In conclusion, our results yield insight into the nature and progression of FRDA, as well as possible therapeutic approaches. Furthermore, the identification of potential biomarkers, including the DNA damage found in peripheral blood, may have predictive value in future clinical trials.

Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure.

Chronic human heart failure is characterized by abnormalities in beta-adrenergic receptor (betaAR) signaling, including increased levels of betaAR kinase 1 (betaARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of betaARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of betaARK1 (betaARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca(2+)-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 +/- 1 weeks). In contrast, CSQ/betaARKct mice exhibited a significant increase in mean survival age (15 +/- 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/betaARKct, left ventricular end diastolic dimension 5.60 +/- 0.17 mm vs. 4.19 +/- 0.09 mm, P < 0.005; % fractional shortening, 15 +/- 2 vs. 36 +/- 2, P < 0.005). The enhancement of the survival rate in CSQ/betaARKct mice was substantially potentiated by chronic treatment with the betaAR antagonist metoprolol (CSQ/betaARKct nontreated vs. CSQ/betaARKct metoprolol treated, 15 +/- 1 weeks vs. 25 +/- 2 weeks, P < 0.0001). Thus, overexpression of the betaARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with beta-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of betaARK1 inhibition.

Changes in midbrain pain receptor expression, gait and behavioral sensitivity in a rat model of radiculopathy.

Intervertebral disc herniation may contribute to inflammatory processes that associate with radicular pain and motor deficits. Molecular changes at the affected dorsal root ganglion (DRG), spinal cord, and even midbrain, have been documented in rat models of radiculopathy or nerve injury. The objective of this study was to evaluate gait and the expression of key pain receptors in the midbrain in a rodent model of radiculopathy. Radiculopathy was induced by harvesting tail nucleus pulposus (NP) and placing upon the right L5 DRG in rats (NP-treated, n=12). Tail NP was discarded in sham-operated animals (n=12). Mechanical allodynia, weight-bearing, and gait were evaluated in all animals over time. At 1 and 4 weeks after surgery, astrocyte and microglial activation was tested in DRG sections. Midbrain sections were similarly evaluated for immunoreactivity to serotonin (5HT(2B)), mu-opioid (µ-OR), and metabotropic glutamate (mGluR4 and 5) receptor antibodies. NP-treated animals placed less weight on the affected limb 1 week after surgery and experienced mechanical hypersensitivity over the duration of the study. Astroctye activation was observed at DRGs only at 4 weeks after surgery. Findings for pain receptors in the midbrain of NP-treated rats included an increased expression of 5HT(2B) at 1, but not 4 weeks; increased expression of µ-OR and mGluR5 at 1 and 4 weeks (periaqueductal gray region only); and no changes in expression of mGluR4 at any point in this study. These observations provide support for the hypothesis that the midbrain responds to DRG injury with a transient change in receptors regulating pain responses.

Discharge competence and pattern formation in peatlands: a meta-ecosystem model of the Everglades ridge-slough landscape.

Regular landscape patterning arises from spatially-dependent feedbacks, and can undergo catastrophic loss in response to changing landscape drivers. The central Everglades (Florida, USA) historically exhibited regular, linear, flow-parallel orientation of high-elevation sawgrass ridges and low-elevation sloughs that has degraded due to hydrologic modification. In this study, we use a meta-ecosystem approach to model a mechanism for the establishment, persistence, and loss of this landscape. The discharge competence (or self-organizing canal) hypothesis assumes non-linear relationships between peat accretion and water depth, and describes flow-dependent feedbacks of microtopography on water depth. Closed-form model solutions demonstrate that 1) this mechanism can produce spontaneous divergence of local elevation; 2) divergent and homogenous states can exhibit global bi-stability; and 3) feedbacks that produce divergence act anisotropically. Thus, discharge competence and non-linear peat accretion dynamics may explain the establishment, persistence, and loss of landscape pattern, even in the absence of other spatial feedbacks. Our model provides specific, testable predictions that may allow discrimination between the self-organizing canal hypotheses and competing explanations. The potential for global bi-stability suggested by our model suggests that hydrologic restoration may not re-initiate spontaneous pattern establishment, particularly where distinct soil elevation modes have been lost. As a result, we recommend that management efforts should prioritize maintenance of historic hydroperiods in areas of conserved pattern over restoration of hydrologic regimes in degraded regions. This study illustrates the value of simple meta-ecosystem models for investigation of spatial processes.

In vivo luminescence imaging of NF-κB activity and serum cytokine levels predict pain sensitivities in a rodent model of osteoarthritis.

OBJECTIVE: To investigate the relationship between NF-κB activity, cytokine levels, and pain sensitivities in a rodent model of osteoarthritis (OA). METHODS: OA was induced in transgenic NF-κB-luciferase reporter mice via intraarticular injection of monosodium iodoacetate (MIA). Using luminescence imaging we evaluated the temporal kinetics of NF-κB activity and its relationship to the development of pain sensitivities and serum cytokine levels in this model. RESULTS: MIA induced a transient increase in joint-related NF-κB activity at early time points (day 3 after injection) and an associated biphasic pain response (mechanical allodynia). NF-κB activity, serum interleukin-6 (IL-6), IL-1β, and IL-10 levels accounted for ∼75% of the variability in pain-related mechanical sensitivities in this model. Specifically, NF-κB activity was strongly correlated with mechanical allodynia and serum IL-6 levels in the inflammatory pain phase of this model (day 3), while serum IL-1β was strongly correlated with pain sensitivities in the chronic pain phase of the model (day 28). CONCLUSION: Our findings suggest that NF-κB activity, IL-6, and IL-1β may play distinct roles in pain sensitivity development in this model of arthritis and may distinguish the acute pain phase from the chronic pain phase. This study establishes luminescence imaging of NF-κB activity as a novel imaging biomarker of pain sensitivities in this model of OA.

A memory-based model of posttraumatic stress disorder: evaluating basic assumptions underlying the PTSD diagnosis.

In the mnemonic model of posttraumatic stress disorder (PTSD), the current memory of a negative event, not the event itself, determines symptoms. The model is an alternative to the current event-based etiology of PTSD represented in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). The model accounts for important and reliable findings that are often inconsistent with the current diagnostic view and that have been neglected by theoretical accounts of the disorder, including the following observations. The diagnosis needs objective information about the trauma and peritraumatic emotions but uses retrospective memory reports that can have substantial biases. Negative events and emotions that do not satisfy the current diagnostic criteria for a trauma can be followed by symptoms that would otherwise qualify for PTSD. Predisposing factors that affect the current memory have large effects on symptoms. The inability-to-recall-an-important-aspect-of-the-trauma symptom does not correlate with other symptoms. Loss or enhancement of the trauma memory affects PTSD symptoms in predictable ways. Special mechanisms that apply only to traumatic memories are not needed, increasing parsimony and the knowledge that can be applied to understanding PTSD.

The Basic-Systems Model of Episodic Memory.

Behavior, neuropsychology, and neuroimaging suggest that episodic memories are constructed from interactions among the following basic systems: vision, audition, olfaction, other senses, spatial imagery, language, emotion, narrative, motor output, explicit memory, and search and retrieval. Each system has its own well-documented functions, neural substrates, processes, structures, and kinds of schemata. However, the systems have not been considered as interacting components of episodic memory, as is proposed here. Autobiographical memory and oral traditions are used to demonstrate the usefulness of the basic-systems model in accounting for existing data and predicting novel findings, and to argue that the model, or one similar to it, is the only way to understand episodic memory for complex stimuli routinely encountered outside the laboratory.

Telescoping is not time compression: a model of the dating of autobiographical events.

A model of telescoping is proposed that assumes no systematic errors in dating. Rather, the overestimation of recent occurrences of events is based on the combination of three factors: (1) Retention is greater for recent events; (2) errors in dating, though unbiased, increase linearly with the time since the dated event; and (3) intrusions often occur from events outside the period being asked about, but such intrusions do not come from events that have not yet occurred. In Experiment 1, we found that recall for colloquia fell markedly over a 2-year interval, the magnitude of errors in psychologists' dating of the colloquia increased at a rate of .4 days per day of delay, and the direction of the dating error was toward the middle of the interval. In Experiment 2, the model used the retention function and dating errors from the first study to predict the distribution of the actual dates of colloquia recalled as being within a 5-month period. In Experiment 3, the findings of the first study were replicated with colloquia given by, instead of for, the subjects.