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The glomerular basement membrane (GBM) is an important tissue structure in kidney function. It is the membrane through which filtrate and solutes must pass to reach the nephron tubules. This review focuses on the spatial location of the main extracellular matrix components of the GBM. It also attempts to explain this organization in terms of their synthesis, transport, and loss. The picture that emerges is that the collagen IV and laminin content of GBM are in a very slow dynamic disequilibrium, leading to GBM thickening with age, and in contrast, some heparan sulfate proteoglycans are in a dynamic equilibrium with a very rapid turnover (i.e. half-life measured in ~hours) and flow direction against the flow of filtrate. The highly rapid heparan sulfate turnover may serve several roles, including an unclogging mechanism for the GBM, compressive stiffness of the GBM fiber network, and/or enabling podocycte-endothelial crosstalk against the flow of filtrate. [ABSTRACT FROM AUTHOR]

An editorial is presented on Japanese encephalitis disease causing the outbreak being a JEV genotype IV (GIV) virus. Topics include South-East Asia associated with endemic transmission and sporadic cases of encephalitis, mainly in children; and limited distribution raising several questions about ecology, pathology and neuro-invasiveness, as well as its origin.

We have previously developed a new theory for pressure dependent outflow from the human eye, and tested the model using experimental data at intraocular pressures above normal eye pressures. In this paper, we use our model to analyze a hypotensive pressure-time dataset obtained following application of a Honan balloon. Here we show that the hypotensive pressure-time data can be successfully analyzed using our proposed pressure dependent outflow model. When the most uncertain initial data point is removed from the dataset, then parameter estimates are close to our previous parameter estimates, but clearly parameter estimates are very sensitive to assumptions. We further show that (i) for a measured intraocular pressure-time curve, the estimated model parameter for whole eye surface hydraulic conductivity is primarily a function of the ocular rigidity, and (ii) the estimated model parameter that controls the rate of decrease of outflow with increasing pressure is primarily a function of the convexity of the monotonic pressure-time curve. Reducing parameter uncertainty could be accomplished using new technologies to obtain higher quality datasets, and by gathering additional data to better define model parameter ranges for the normal eye. With additional research, we expect the pressure dependent outflow analysis described herein may find applications in the differential diagnosis, prognosis and monitoring of the glaucomatous eye. [ABSTRACT FROM AUTHOR]

Computational models have made a major contribution to the field of physiology. As the complexity of our understanding of biological systems expands, the need for computational methods only increases. But collaboration between experimental physiologists and computational modellers (ie theoretical physiologists) is not easy. One of the major challenges is to break down the barriers created by differences in vocabulary and approach between the two disciplines. In this review, we have two major aims. Firstly, we wish to contribute to the effort to break down these barriers and so encourage more interdisciplinary collaboration. So, we begin with a "primer" on the ways in which computational models can help us understand physiology and pathophysiology. Second, we aim to provide an update of recent efforts in one specific area of physiology, renal oxygenation. This work is shedding new light on the causes and consequences of renal hypoxia. But as importantly, computational modelling is providing direction for experimental physiologists working in the field of renal oxygenation by: (a) generating new hypotheses that can be tested in experimental studies, (b) allowing experiments that are technically unfeasible to be simulated in silico, or variables that cannot be measured experimentally to be estimated, and (c) providing a means by which the quality of experimental data can be assessed. Critically, based on our experience, we strongly believe that experimental and theoretical physiology should not be seen as separate exercises. Rather, they should be integrated to permit an iterative process between modelling and experimentation. [ABSTRACT FROM AUTHOR]

In this paper we set the previously reported pressure-dependent, ordinary differential equation outflow model by Smith and Gardiner for the human eye, into a new three-dimensional (3D) porous media outflow model of the eye, and calibrate model parameters using data reported in the literature. Assuming normal outflow through anterior pathways, we test the ability of 3D flow model to predict the pressure elevation with a silicone oil tamponade. Then assuming outflow across the retinal pigment epithelium is normal, we test the ability of the 3D model to predict the pressure elevation in Schwartz-Matsuo syndrome. For the first time we find the flow model can successfully model both conditions, which helps to build confidence in the validity and accuracy of the 3D pressure-dependent outflow model proposed here. We employ this flow model to estimate the translaminar pressure gradient within the optic nerve head of a normal eye in both the upright and supine postures, and during the day and at night. Based on a ratio of estimated and measured pressure gradients, we define a factor of safety against acute interruption of axonal transport at the laminar cribrosa. Using a completely independent method, based on the behaviour of dynein molecular motors, we compute the factor of safety against stalling the dynein molecule motors, and so compromising retrograde axonal transport. We show these two independent methods for estimating factors of safety agree reasonably well and appear to be consistent. Taken together, the new 3D pressure-dependent outflow model proves itself to capable of providing a useful modeling platform for analyzing eye behaviour in a variety of physiological and clinically useful contexts, including IOP elevation in Schwartz-Matsuo syndrome and with silicone oil tamponade, and potentially for risk assessment for optic glaucomatous neuropathy. [ABSTRACT FROM AUTHOR]

• Carbon dioxide (CO 2) levels are important in managing neurologic conditions. • Spreading depolarizations (SD) are a pathologic mechanism of cerebral cortex. • CO 2 levels did not impact SD characteristics in normoxic or hypoxic rat brain. • Mean arterial pressure negatively correlated with SD duration. • The role of CO 2 warrants investigation in conditions of acute focal brain injury. Patients with traumatic brain injury are typically maintained at low-normal levels of arterial partial pressure of carbon dioxide (P a CO 2) to counteract the risk of elevated intracranial pressure during intensive care. However, several studies suggest that management at hypercarbic levels may have therapeutic benefit. Here we examined the impact of CO 2 levels on spreading depolarizations (SD), a mechanism and marker of acute lesion development in stroke and brain trauma. In an acute preparation of mechanically ventilated (30/70 O 2 /N 2) female rats, SDs were evoked by cortical KCl application and monitored by electrophysiology and laser doppler flowmetry; CO 2 levels were adjusted by ventilator settings and supplemental CO 2. During 90 min of KCl application, rats were maintained at hypocapnia (end-tidal CO 2 22 ± 2 mmHg) or hypercapnia (57 ± 4 mmHg) but did not differ significantly in arterial pH (7.31 ± 0.10 vs. 7.22 ± 0.08, p = 0.31) or other variables. Surprisingly, there was no difference between groups in the number of SDs recorded (10.7 ± 4.2 vs. 11.7 ± 3.1; n = 3 rats/group; p = 0.75) nor in SD durations (64 ± 27 vs. 69 ± 37 sec, p = 0.54). In separate experiments (n = 3), hypoxia was induced by decreasing inhaled O 2 to 10% and single SDs were induced under interleaved conditions of hypo-, normo-, and hypercapnia. No differences in SD duration were observed. In both normoxia and hypoxia experiments, however, mean arterial pressures were negatively correlated with SD durations (normoxia R2 = −0.29; hypoxia R2 = −0.61, p 's < 0.001). Our results suggest that any therapeutic benefit of elevated CO 2 therapy may be dependent on an acidic shift in pH or may only be observed in conditions of focal brain injury. [ABSTRACT FROM AUTHOR]

We develop and test a new theory for pressure dependent outflow from the eye. The theory comprises three main parameters: (i) a constant hydraulic conductivity, (ii) an exponential decay constant and (iii) a no-flow intraocular pressure, from which the total pressure dependent outflow, average outflow facilities and local outflow facilities for the whole eye may be evaluated. We use a new notation to specify precisely the meaning of model parameters and so model outputs. Drawing on a range of published data, we apply the theory to animal eyes, enucleated eyes and in vivo human eyes, and demonstrate how to evaluate model parameters. It is shown that the theory can fit high quality experimental data remarkably well. The new theory predicts that outflow facilities and total pressure dependent outflow for the whole eye are more than twice as large as estimates based on the Goldman equation and fluorometric analysis of anterior aqueous outflow. It appears likely that this discrepancy can be largely explained by pseudofacility and aqueous flow through the retinal pigmented epithelium, while any residual discrepancy may be due to pathological processes in aged eyes. The model predicts that if the hydraulic conductivity is too small, or the exponential decay constant is too large, then intraocular eye pressure may become unstable when subjected to normal circadian changes in aqueous production. The model also predicts relationships between variables that may be helpful when planning future experiments, and the model generates many novel testable hypotheses. With additional research, the analysis described here may find application in the differential diagnosis, prognosis and monitoring of glaucoma. [ABSTRACT FROM AUTHOR]

Inflammatory cytokines are key drivers of cartilage degradation in post-traumatic osteoarthritis. Cartilage degradation mediated by these inflammatory cytokines has been extensively investigated using in vitro experimental systems. Based on one such study, we have developed a computational model to quantitatively assess the impact of charged small molecules intended to inhibit IL-1 mediated cartilage degradation. We primarily focus on the simplest possible computational model of small molecular interaction with the IL-1 system—direct binding of the small molecule to the active site on the IL-1 molecule itself. We first use the model to explore the uptake and release kinetics of the small molecule inhibitor by cartilage tissue. Our results show that negatively charged small molecules are excluded from the negatively charged cartilage tissue and have uptake kinetics in the order of hours. In contrast, the positively charged small molecules are drawn into the cartilage with uptake and release timescales ranging from hours to days. Using our calibrated computational model, we subsequently explore the effect of small molecule charge and binding constant on the rate of cartilage degradation. The results from this analysis indicate that the small molecules are most effective in inhibiting cartilage degradation if they are either positively charged and/or bind strongly to IL-1α, or both. Furthermore, our results showed that the cartilage structural homeostasis can be restored by the small molecule if administered within six days following initial tissue exposure to IL-1α. We finally extended the scope of the computational model by simulating the competitive inhibition of cartilage degradation by the small molecule. Results from this model show that small molecules are more efficient in inhibiting cartilage degradation by binding directly to IL-1α rather than binding to IL-1α receptors. The results from this study can be used as a template for the design and development of more pharmacologically effective osteoarthritis drugs, and to investigate possible therapeutic options. [ABSTRACT FROM AUTHOR]

Although dogs are widely trained and deployed for odor detection work, relatively little research has investigated procedures that may more efficiently train or increase detection performance. Prior research in rodents and humans suggests that odorant exposure may enhance sensitivity to that odorant; however, other research has suggested that exposure may have the opposite effect. Our aim was to assess whether exposure to odorants influences dogs’ sensitivity to those odorants on a subsequent operant task. We specifically tested whether simply being non-contingently exposed to an odorant or being exposed to an odorant in an appetitive Pavlovian conditioning paradigm influenced dogs’ sensitivity to that odorant. In a pre- post-test design we assessed changes in dogs’ sensitivity to two odorants. In the first phase, dogs’ sensitivity to both odorants was assessed using a descending series of half (binary) dilutions presented using a liquid-dilution olfactometer. Then half the dogs were non-contingently exposed or Pavlovian conditioned to one odorant while the second odorant remained an unexposed control. Sensitivity to both odorants was then re-assessed using the same procedures as during baseline. Dogs showed a significant increase in sensitivity to the Pavlovian conditioned odorant compared to both the control odorant ( p < 0.01) and compared to the non-contingently exposed odorant ( p < 0.01). These results suggest that Pavlovian conditioning may be a simple procedure to enhance olfactory sensitivity to a target odorant. [ABSTRACT FROM AUTHOR]

In this study, we develop a computational model to simulate the in vitro biochemical degradation of articular cartilage explants sourced from the femoropatellar grooves of bovine calves. Cartilage explants were incubated in culture medium with and without the inflammatory cytokine IL-1α. The spatio-temporal evolution of the cartilage explant's extracellular matrix components is modelled. Key variables in the model include chondrocytes, aggrecan, collagen, aggrecanase, collagenase and IL-1α. The model is first calibrated for aggrecan homeostasis of cartilage in vivo , then for data on (explant) controls, and finally for data on the IL-1α driven proteolysis of aggrecan and collagen over a 4-week period. The model was found to fit the experimental data best when: (i) chondrocytes continue to synthesize aggrecan during the cytokine challenge, (ii) a one to two day delay is introduced between the addition of IL-1α to the culture medium and subsequent aggrecanolysis, (iii) collagen degradation does not commence until the total concentration of aggrecan (i.e. both intact and degraded aggrecan) at any specific location within the explant becomes ≤1.5 mg/ml and (iv) degraded aggrecan formed due to the IL-1α induced proteolysis of intact aggrecan protects the collagen network while collagen degrades in a two-step process which, together, significantly modulate the collagen network degradation. Under simulated in vivo conditions, the model predicts increased aggrecan turnover rates in the presence of synovial IL-1α, consistent with experimental observations. Such models may help to infer the course of events in vivo following traumatic joint injury, and may also prove useful in quantitatively evaluating the efficiency of various therapeutic molecules that could be employed to avoid or modify the course of cartilage disease states. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Renal oxygenation: pre-glomerular vasculature is an unlikely contributor to renal oxygen shunting" by U. Olgac and V. Kurtcuoglu, in the 2015 issue of the periodical.

Domestic dogs are used to aid in the detection of a variety of substances such as narcotics and explosives. Under real-world detection situations there are many variables that may disrupt the dog's performance. Prior research on behavioral momentum theory suggests that higher rates of reinforcement produce greater resistance to disruption, and that this is heavily influenced by the stimulus-reinforcer relationship. The present study tests the Pavlovian interpretation of resistance to change using dogs engaged in an odor discrimination task. Dogs were trained on two odor discriminations that alternated every six trials akin to a multiple schedule in which the reinforcement probability for a correct response was always 1. Dogs then received several sessions of either odor Pavlovian conditioning to the S+ of one odor discrimination (Pavlovian group) or explicitly unpaired exposure to the S+ of one odor discrimination (Unpaired group). The remaining odor discrimination pair for each dog always remained an unexposed control. Resistance to disruption was assessed under presession feeding, a food-odor disruptor condition, and extinction, with baseline sessions intervening between disruption conditions. Equivalent baseline detection rates were observed across experimental groups and odorant pairs. Under disruption conditions, Pavlovian conditioning led to enhanced resistance to disruption of detection performance compared to the unexposed control odor discrimination. Unpaired odor conditioning did not influence resistance to disruption. These results suggest that changes in Pavlovian contingencies are sufficient to influence resistance to change. [ABSTRACT FROM AUTHOR]

Background: The abomasal helminth Teladorsagia circumcincta is one of the most economically important parasites affecting sheep in temperate regions. Infection is particularly detrimental to lambs, in which it can cause pronounced morbidity and severe production losses. Due to the spreading resistance of this parasite to all classes of anthelmintic drugs, teladorsagiosis is having an increasingly severe impact on the sheep industry with significant implications for sheep welfare. Protective immunity develops slowly, wanes rapidly and does not appear to be as effective in young lambs. To investigate the development of immunity to T. circumcincta in sheep and lambs, we used cytokine transcript profiling to examine differences in the abomasal mucosa and gastric lymph node of naïve and previously infected sheep and lambs following challenge. Results: The results of these experiments demonstrated that the abomasal mucosa is a major source of cytokines during abomasal helminth infection. A local Th2-type cytokine response was observed in the abomasal mucosa and gastric lymph node of the previously infected sheep and lambs when compared with those of the naïve during the early stages of infection. In contrast, a pro-inflammatory component more was evident in the abomasal mucosa and gastric lymph node of the naïve sheep when compared with those of the previously infected, which was not observed in the lambs. Conclusions: The greater levels of Th2-type cytokine transcripts in both the abomasum and gastric lymph node of the previously infected compared with naïve sheep and lambs emphasises the importance of these mechanisms in the immune response to T. circumcincta infection. Younger lambs appear to be able to generate similar Th2-type responses in the abomasum suggesting that the increased morbidity and apparent lack of resistance in younger lambs following continuous or repeated exposure to T. circumcincta is unlikely to be due to a lack of appropriate Th2-type cytokine production. [ABSTRACT FROM AUTHOR]

On 14 June 2012, the Asia-Pacific Alliance for the Control of Influenza ( APACI) convened the first Antiviral Forum jointly with the Influenza Foundation of Thailand and the Thailand Department of Disease Control. The goals of the meeting were to improve pandemic planning in the region from lessons learned during the 2009 pandemic, particularly with regard to the safety and efficacy of antiviral use; gain a better understanding of the therapeutic use of antivirals in seasonal influenza; review and analyse the official influenza control policies of Asia-Pacific countries and evidence gaps to support policy development; and to establish collaborative relationships to promote best practices in the use of antivirals for the treatment of influenza. The urgent need for education highlighting the importance of influenza and the benefits of antiviral drug use in the Asia-Pacific region was identified. [ABSTRACT FROM AUTHOR]

On June 12-13, 2012, the Asia- Pacific Alliance for the Control of Influenza ( APACI) convened jointly with the Influenza Foundation of Thailand and the Thailand Department of Disease Control, the First Asia- Pacific Influenza Summit. The objectives of the meeting were to review the current state of official influenza control policies in Asia- Pacific countries; identify, summarize and communicate influenza control strategies that have successfully increased vaccine uptake in the region; develop policy and advocacy approaches to improve influenza vaccine uptake in high-risk groups and healthcare workers in the region; and establish collaborative relationships to promote best practices for the control of influenza. In moving forward, the challenge for the region will be establishing collaborations able to effectively communicate risk and key messages about influenza vaccination. [ABSTRACT FROM AUTHOR]

Highlights: [•] We developed a rapid discrete-trials procedure to train an odor-detection in dogs. [•] We show dogs can rapidly acquire an odor-detection in a few sessions and that the present procedure can be used to identify individual differences. [•] Dogs learned the odor-detection faster if the experimenter delivered food by hand instead of burying it with the odor. [•] Dogs learned an odor discrimination faster than a visual discrimination. [Copyright &y& Elsevier]

Background and objective Interferon alpha ( IFNα) is a known antiviral agent. A double-blind, placebo-controlled clinical trial was conducted investigating the use of low-dose oral interferon alpha for preventing acute viral respiratory illnesses. Methods Two hundred healthy adults aged 18-75 years were enrolled and completed weekly health data questionnaires to monitor for symptoms and impact of respiratory illness. Serum samples were tested for antibodies against influenza and other common respiratory viruses. Results Low-dose oral IFNα prophylaxis did not reduce the incidence or impact of acute respiratory illness ( ARI) or the impact of illness on daily activities. Post hoc analysis of participant subgroups, however, identified significant reductions in the incidence of ARI reported by males, those aged 50 years or more and those who received the 2009 seasonal influenza vaccine. Interferon alpha prophylaxis had a significant impact on the reporting of moderate-to-severe feverishness by the study population. Seropositive participants in the IFN group were more likely to report asymptomatic or mild symptoms compared with those in the placebo group who were more likely to report stronger symptoms. Conclusions Low-dose oral IFNα prophylaxis was not effective in limiting the overall incidence of ARI in our study population. However, there was evidence that prophylaxis reduced the severity of symptoms and had a beneficial effect in some subpopulations, including those who received the 2009 seasonal trivalent influenza vaccination. [ABSTRACT FROM AUTHOR]

IGF signaling is involved in cell proliferation, differentiation and apoptosis in a wide range of tissues, both normal and diseased, and so IGF-IR has been the focus of intense interest as a promising drug target. In this computational study on cartilage, we focus on two questions: (i) what are the key factors influencing IGF-IR complex formation, and (ii) how might cells regulate IGF-IR complex formation? We develop a reaction-diffusion computational model of the IGF system involving twenty three parameters. A series of parametric and sensitivity studies are used to identify the key factors influencing IGF signaling. From the model we predict the free IGF and IGF-IR complex concentrations throughout the tissue. We estimate the degradation half-lives of free IGF-I and IGFBPs in normal cartilage to be 20 and 100 mins respectively, and conclude that regulation of the IGF half-life, either directly or indirectly via extracellular matrix IGF-BP protease concentrations, are two critical factors governing the IGF-IR complex formation in the cartilage. Further we find that cellular regulation of IGF-II production, the IGF-IIR concentration and its clearance rate, all significantly influence IGF signaling. It is likely that negative feedback processes via regulation of these factors tune IGF signaling within a tissue, which may help explain the recent failures of single target drug therapies aimed at modifying IGF signaling. [ABSTRACT FROM AUTHOR]

Maintaining bone volume during bone turnover by a BMU is known as bone balance. Balance is required to maintain structural integrity of the bone and is often dysregulated in disease. Consequently, understanding how a BMU controls bone balance is of considerable interest. This paper develops a methodology for identifying potential balance controls within a single cortical BMU. The theoretical framework developed offers the possibility of a directed search for biological processes compatible with the constraints of balance control. We first derive general control constraint equations and then introduce constitutive equations to identify potential control processes that link key variables that describe the state of the BMU. The paper describes specific local bone volume balance controls that may be associated with bone resorption and bone formation. Because bone resorption and formation both involve averaging over time, short-term fluctuations in the environment are removed, leaving the control systems to manage deviations in longer-term trends back towards their desired values. The length of time for averaging is much greater for bone formation than for bone resorption, which enables more filtering of variability in the bone formation environment. Remarkably, the duration for averaging of bone formation may also grow to control deviations in long-term trends of bone formation. Providing there is sufficient bone formation capacity by osteoblasts, this leads to an extraordinarily robust control mechanism that is independent of either osteoblast number or the cellular osteoid formation rate. A complex picture begins to emerge for the control of bone volume. Different control relationships may achieve the same objective, and the 'integration of information' occurring within a BMU may be interpreted as different sets of BMU control systems coming to the fore as different information is supplied to the BMU, which in turn leads to different observable BMU behaviors. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: The design, testing and clinical implementation of a simple quality assurance tool which allows quick and accurate identification of regions of data loss and data interpolation in 4DCT data sets is reported. Materials and methods: A 4DCT model, dependent on gantry rotation time and pitch, was developed to allow an understanding of the data collection and reconstruction processes. To test this model, 4DCT scans of a phantom were acquired using a Siemens SOMATOM Sensation 40 slice CT scanner. A radio-opaque rod mounted under the couch top was present during the phantom scans. Results: The model predicts that periodic regions of data loss occur when the respiration rate drops below a critical value. These results are verified by experimental data. Regions of data loss result in breaks in the imaged radio-opaque rod. Conclusions: Regions of data loss in 4DCT data sets can be difficult to detect. Mounting a radio-opaque rod under the couch top allows regions of data loss and data interpolation to be quickly assessed on a patient by patient basis. This quality assurance tool has been successfully implemented into clinical use. The results of this work have implications for quality assurance programmes for 4DCT scanning. [Copyright &y& Elsevier]

A set of 'soil columns was constructed to simulate discharge of disinfected tertiary treated wastewater to a river via nearby land application or indirect discharge. The system was primarily designed to observe the fate of metal ions and nutrients. The following three experiments were conducted: (1) flow through saturated soils only, which simulates indirect discharge where water is directly applied to groundwater; (2) flow through unsaturated soil followed by saturated flow, which simulates vadose then saturated zone transport; and (3) saturated flow only using ethylene diamine tetraacetic acid-metal chelates, which determined effects of metal organic complexes on metal mobility through the soil. Metal ion attenuation was substantial but not complete in experiments 1 and 2 (removal: 68% Cu2~, 43% Ni2~, 98% Pb2', and 96% Hg21), which was somewhat contrary to modeling results. Cyanide attenuation was also monitored (92% removal). In experiment 3, lead attenuation was somewhat reduced (92% removal) and delayed (requiring additional residence time); copper attenuation was significantly reduced (38% removal) and delayed; and nickel concentrations were higher in the 28-day sample (>80 μg/L) than in the column feed water (58 μg/L). Near-complete denitrification and total phosphorus attenuation were observed. For the water quality constituents studied, unsaturated (vadose zone) transport did not appear to add additional benefit. [ABSTRACT FROM AUTHOR]

To understand how arterial-to-venous (AV) oxygen shunting influences kidney oxygenation, a mathematical model of oxygen transport in the renal cortex was created. The model consists of a multiscale hierarchy of 11 countercurrent systems representing the various branch levels of the cortical vasculature. At each level, equations describing the reactive- advection-diffusion of oxygen are solved. Factors critical in renal oxygen transport incorporated into the model include the parallel geometry of arteries and veins and their respective sizes, variation in blood velocity in each vessel, oxygen transport (along the vessels, between the vessels and between vessel and parenchyma), nonlinear binding of oxygen to hemoglobin, and the consumption of oxygen by renal tissue. The model is calibrated using published measurements of cortical vascular geometry and microvascular Po2. The model predicts that AV oxygen shunting is quantitatively significant and estimates how much kidney V̇o2 must change, in the face of altered renal blood flow, to maintain cortical tissue Po2 at a stable level. It is demonstrated that oxygen shunting increases as renal V̇o2 or arterial Po2 increases. Oxygen shunting also increases as renal blood flow is reduced within the physiological range or during mild hemodilution. In severe ischemia or anemia, or when kidney V̇o2 increases, AV oxygen shunting in proximal vascular elements may reduce the oxygen content of blood destined for the medullary circulation, thereby exacerbating the development of tissue hypoxia. That is, cortical ischemia could cause medullary hypoxia even when medullary perfusion is maintained. Cortical AV oxygen shunting limits the change in oxygen delivery to cortical tissue and stabilizes tissue Po2 when arterial Po2 changes, but renders the cortex and perhaps also the medulla susceptible to hypoxia when oxygen delivery falls or consumption increases. [ABSTRACT FROM AUTHOR]

T-wave abnormalities are gaining significance in the realm of electrocardiogram diagnostics. In particular, T-wave alternans are proving to be powerful predictive indicators of potentially fatal arrhythmias. T-wave morphology monitoring and analysis are the means by which alternans and other abnormalities are detected. We have presented a preliminary design of an analog T-wave monitor to provide a characteristic description of the beat-to-beat T-wave morphology in terms of its maximum leading edge and trailing edge slopes, and its area. Experimental results showed that data from the analog T-wave monitor compared well with those predicted theoretically. Current design of the T-wave monitor, once improved, can find use in the screening, diagnosis, and early detection of T-wave abnormalities in clinical settings. [ABSTRACT FROM AUTHOR]

Background: Glaucoma surgery is the most effective means for lowering intraocular pressure by providing a new route for fluid to exit the eye. This new pathway is through the sclera of the eye into sub-conjunctival tissue, where a fluid filled bleb typically forms under the conjunctiva. The long-term success of the procedure relies on the capacity of the sub-conjunctival tissue to absorb the excess fluid presented to it, without generating excessive scar tissue during tissue remodeling that will shut-down fluid flow. The role of inflammatory factors that promote scarring are well researched yet little is known regarding the impact of physical forces on the healing response. Methodology: To help elucidate the interplay of physical factors controlling the distribution and absorption of aqueous humor in sub-conjunctival tissue, and tissue remodeling, we have developed a computational model of fluid production in the eye and removal via the trabecular/uveoscleral pathways and the surgical pathway. This surgical pathway is then linked to a porous media computational model of a fluid bleb positioned within the sub-conjunctival tissue. The computational analysis is centered on typical functioning bleb geometry found in a human eye following glaucoma surgery. A parametric study is conducted of changes in fluid absorption by the sub-conjunctival blood vessels, changes in hydraulic conductivity due to scarring, and changes in bleb size and shape, and eye outflow facility. Conclusions: This study is motivated by the fact that some blebs are known to have 'successful' characteristics that are generally described by clinicians as being low, diffuse and large without the formation of a distinct sub-conjunctival encapsulation. The model predictions are shown to accord with clinical observations in a number of key ways, specifically the variation of intra-ocular pressure with bleb size and shape and the correspondence between sites of predicted maximum interstitial fluid pressure and key features observed in blebs, which gives validity to the model described here. This model should contribute to a more complete explanation of the physical processes behind successful bleb characteristics and provide a new basis for clinically grading blebs. [ABSTRACT FROM AUTHOR]

Purpose: This study characterizes the dosimetric properties of the iBEAM evo carbon fiber couch manufactured by Medical Intelligence and examines the accuracy of the CMS XiO and Nucletron Oncentra Masterplan (OMP) treatment planning systems for calculating beam attenuation due to the presence of the couch. Methods: To assess the homogeneity of the couch, it was CT scanned at isocentric height and a number of signal intensity profiles were generated and analyzed. To simplify experimental procedures, surface dose and central axis depth dose measurements were performed in a solid water slab phantom using Gafchromic film for 6 and 10 MV photon beams at gantry angles of 0° (normal incidence), 30°, and 60° with an inverted iBEAM couch placed on top of the phantom. Attenuation measurements were performed in a cylindrical solid water phantom with an ionization chamber positioned at the isocenter. Measurements were taken for gantry angles from 0° to 90° in 10° increments for both 6 and 10 MV photon beams. This setup was replicated in the XiO and OMP treatment planning systems. Dose was calculated using the pencil beam, collapsed cone, convolution, and superposition algorithms. Results: The CT scan of the couch showed that it was uniformly constructed. Surface dose increased by (510±30)% for a 6 MV beam and (600±20)% for a 10 MV beam passing through the couch at normal incidence. Obliquely incident beams resulted in a higher surface dose compared to normally incident beams for both open fields and fields with the couch present. Depth dose curves showed that the presence of the couch resulted in an increase in dose in the build up region. For 6 and 10 MV beams incident at 60°, nearly all skin sparing was lost. Attenuation measurements derived using the ionization chamber varied from 2.7% (0°) to a maximum of 4.6% (50°) for a 6 MV beam and from 1.9% (0°) to a maximum of 4.0% (50°) for a 10 MV beam. The pencil beam and convolution algorithms failed to accurately calculate couch attenuation. The collapsed cone and superposition algorithms calculated attenuation within an absolute error of ±1.2% for 6 MV and ±0.8% for 10 MV for gantry angles from 0° to 40°. Some differences in attenuation were observed dependent on how the couch was contoured. Conclusions: These results demonstrate that the presence of the iBEAM evo carbon fiber couch increases the surface dose and dose in the build up region. The inclusion of the couch in the planning scan is limited by the field of view employed and the couch height at the time of CT scanning. [ABSTRACT FROM AUTHOR]

The author reflects regarding the outbreak of Guillain-Barré syndrome and Zika virus in sub-Saharan Africa. Topics discussed include the role of Aedes aegypti mosquitoes as carrier of diseases, various symptoms of the illness such as joint pain, rash, and fever, and the implication of other flaviviruses for the disease.

Odorant diluents are generally chosen because of their odorless qualities, allowing them to dilute a target odorant without otherwise altering its perception. Unpublished observations from our laboratory, however, suggest that mineral oil (MO), a common diluent for oil-based odorants, may possess a distinct odor when used in the behavioral testing of mice. To test this, mice were trained to discriminate between 4 brands of MO, using a commercial, liquid-dilution olfactometer and a 2-odorant discrimination task. The results demonstrate that mice were able to detect MOs and to discriminate between MO pairs obtained from different sources. Additionally, we sought to determine if mice could discriminate different MOs when used as a diluent for suprathreshold levels of cineole. Mice were required to discriminate between bottles containing identical concentrations of cineole diluted in different brands of MO. The results showed that the mice readily discriminated each cineole/MO pairing. These data demonstrate that mice are able to detect and discriminate MOs obtained from different sources, both when presented alone and in mixtures. The results also indicate that MO is not an odorless diluent and should be used with caution in olfactory experiments, as the perception of odors being diluted may be unintentionally altered. [ABSTRACT FROM PUBLISHER]

Objectives. We obtained population estimates of the prevalence of lack of diagnostic follow-up after an abnormal prostate-specific antigen (PSA) result and assessed the role of sociodemographic, access, and risk perception factors on follow-up of abnormal tests. Methods. We used data from the 2000 National Health Interview Survey cancer control supplement. For 3,310 men aged 40 or older with a PSA test, 463 men reported an abnormal PSA test. Outcomes were abnormal PSA and lack of diagnostic follow-up in the latter group. Covariates for logistic regression included sociodemographic variables (age, race/ethnicity, and education), access to care (health insurance and usual source), and risk of cancer (family history and perceived risk). Survey analysis procedures accounted for the complex survey design. Results. Abnormal PSA results were associated with age, family history, and perceived risk of cancer. Approximately 15% of men with abnormal PSA tests reported no follow-up. The estimated number was 423,549 (95% confidence interval [Cl] 317,755, 529,343). No follow-up was more likely in Hispanic men (odds ratio [OR] = 2.21, 95% Cl 1.04, 4.70) and men without insurance (OR=6.56, 95% Cl 2.02, 21 .29), but less likely in men with a family history of prostate cancer or higher perceived risk of cancer. Conclusions. Substantial numbers of men had no follow-up of abnormal PSA tests. Primary care physicians should assess continuity of care following abnormal PSA results. Data about prostate cancer screening and follow-up are needed to support clinical and policy decisions. [ABSTRACT FROM AUTHOR]

The article presents a response by Benjamin S. Bradshaw, David W, Smith and Stephen Blanchard to the analysis of Andrew Noymer to their paper "A Cohort Study of Tuberculosis and Influenza Mortality in the Twentieth Century." According to them, Noymer sees their paper in contrast to his work regarding a change in the sex difference in life expectancy following the 1918-19 influenza pandemic in the U.S. Moreover, they argue that the alteration in tuberculosis death rate that occurred in 1945 support the theory that the rise in tuberculosis mortality in 1918 was promoted by wartime mobilization.

Abstract: A dysregulated hypothalamic-pituitary-adrenal axis (HPA) has been implicated in major depressive disorder and most commonly used animal models of depression have been shown to elevate circulating levels of plasma corticosterone. We have compared the effects of chronic and acute corticosterone administration on hippocampal cell proliferation (as measured by BrdU immunohistochemistry), hippocampal volume and the appearance of anxiety (light dark box) and depression (forced swim test) like behaviours in CD1 mice. We have also examined the effects of chronic administration of fluoxetine and imipramine on these parameters. Chronic (14 days) but not acute treatment with corticosterone resulted in reduced hippocampal cell proliferation and granule cell layer volume, these changes were prevented by co-administration of imipramine and fluoxetine. In contrast, acute and 7 day but not 14 or 21 day treatment with corticosterone gave rise to a “depressed” phenotype in the forced swim test. Mice treated for 14 days with corticosterone also developed an anxious phenotype in the light dark box but only upon repeated testing. The results presented here demonstrate that moderately elevated corticosterone for a prolonged period is sufficient to induce cellular changes in the hippocampus that are prevented by chronic administration of antidepressants. [Copyright &y& Elsevier]

We reviewed period and cohort mortality for tuberculosis and influenza and pneumonia over the twentieth century and data on the roles of influenza and tuberculosis as underlying and contributory causes of death. As would be consistent with long-term trends, each cohort had lower tuberculosis mortality but there was no decisive downturn in age specific tuberculosis mortality for any male cohort until after 1945. Tuberculosis mortality among females fell steadily from cohort to cohort as well as within each cohort. In every cohort born from around 1890 to around 1930, tuberculosis mortality was higher among women than among men at ages under 30, suggesting that prevalence in women was also higher, but death rates of females crossed under those of males at about age 30. Tuberculosis death rates rose more for males than females around 1918; however, any unusual increase that could be attributable to the 1918 influenza pandemic must have been brief. Contrary to expectations in the medical community, tuberculosis mortality did not rise following the 1918 influenza pandemic. Some portion of the rise in death rates around 1918 may have been associated with the influenza, but a comparison of the increase in male tuberculosis mortality during and after World War II, when there was no influenza pandemic, with male mortality in a similar period during and after World War I suggests that any excess in tuberculosis mortality among males in both periods may have been due to wartime mobilization rather than influenza. [ABSTRACT FROM AUTHOR]

Abstract: When olfactory receptor neurons respond to odors, a depolarizing Cl− efflux is a substantial part of the response. This requires that the resting neuron accumulate Cl− against an electrochemical gradient. In isolated olfactory receptor neurons, the Na ++K+ +2Cl− cotransporter NKCC1 is essential for Cl− accumulation. However, in intact epithelium, a robust electrical olfactory response persists in mice lacking NKCC1. To determine whether NKCC1 is required for normal olfactory sensitivity, olfactory sensitivity was compared between knockout (KO) mice carrying a null mutation for NKCC1 and wild-type (WT) littermates. Using operant behavioral techniques, olfactory sensitivity was measured using a commercial liquid-dilution olfactometer. Detection thresholds for the simple odorants cineole, 1-heptanol, and 1-propanol were compared in KO and WT animals. Regardless of the stimulus conditions employed, no systematic differences in behavioral thresholds were evident between KO and WT animals. We conclude that NKCC1 is not required for normal olfactory sensitivity. [Copyright &y& Elsevier]

Abstract: Double-blinding is an important and widely implemented feature of clinical trials although its success is rarely assessed. In a randomized, placebo-controlled trial of tea tree oil, an aromatic essential oil, for the treatment of recurrent herpes labialis (RHL), or cold sores, deception was used to prevent volunteers from identifying their treatment allocation. Volunteers received placebo (n =102) or tea tree oil (n =112) ointment in preparation for their next episode of RHL and were told, falsely, that the aroma of the ointments had been changed to prevent identification of the treatment group. At the trial''s end, of the volunteers who had used their ointment and presented for treatment assessment (n =100), approximately 50% correctly guessed their treatment allocation (P =0.774). Amongst volunteers that had not presented for treatment assessment (n =114), 12 volunteers did not provide blinding data and 46 did not open their tube. For the 56 volunteers who opened their tube, less than half of those receiving tea tree oil (44.4%) and only a small proportion of those on placebo (17.2%) were able to correctly identify their treatment allocation. Among the volunteers that were not treated, the P-value was 0.083. This study showed that the ethical use of deception may provide effective blinding in challenging circumstances. [Copyright &y& Elsevier]

Abstract: Purpose: To compare the visibility of different manufacturers I-125, seeds, and to investigate the effect of differences in dosimetry on treatment planning. Materials and methods: Oncura Oncoseed, Oncura Echoseed, IBT Intersource, Bebig Isoseed and Nucletron Selectseed were investigated. The point dose at increasing distances from each seed type was calculated for three different angles; θ =0°, 45° and 90° (where θ =0° lies parallel to seed length). 10 patient plans were used to assess the effect of a change in dosimetry on treatment planning and quality of prostate and rectum implant indices such as Vp100, Vp200, Dp90, Vr100 and Vr69. All implant indices and dosimetry data were compared to Oncoseed. Visibility under X-ray, fluoroscopy, CT and MRI was investigated using prostate phantoms created in-house. Statistical significance was calculated using paired two-tailed t-tests. Results: Dosimetric analysis was carried out for seeds of the same source strength. Differences in dose increase closer to the centre of each source, with the largest changes occurring for the angle θ =0°. Selectseed and Isoseed seed types provide a consistently lower dose in all three directions. Changes to Vp100 are small and statistically insignificant for all seeds except Selectseed which shows a statistically significant decrease of 0.04% (p =0.02). Changes to Vp150 and Vp200 are statistically significant (p <0.01), with Intersource showing the greatest increase in both values. Selectseed shows a decrease in both Vp150 and Vp200. Echoseed shows an increase in both Vp150 and Vp200. Changes to D90 are statistically significant (p <0.01), with Intersource showing the greatest increase, followed by Isoseed then Echoseed. Selectseed shows a decrease in D90. For Vr100 there is no statistically significant change for any seed type. However, all seeds except Selectseed show a statistically significant increase in the value of Vr69, with Intersource showing the greatest increase. On fluoroscopy and X-ray images, Intersource seeds appear least visible, Echoseed and Oncoseed are similar, and Isoseed and Selectseed are most visible. Ultrasound greyscale beam profiles show that all seed images have a FWHM larger than the Oncoseed image. The CT greyscale beam profiles are similar for all seed images. The MRI signal voids are similar for all seed images except Intersource which shows a larger signal void. Conclusions: The greatest changes to point dose occur at very close distances to the seeds. Changing seed type may require a treatment replan to maintain satisfactory DVH criteria. Visibility on US and CT is similar, though it may vary on MRI, X-ray and fluoroscopy. [Copyright &y& Elsevier]

The National Center for Health Statistics (NCHS) reports life expectancy at birth (LE) for each year in the United States. Censal year estimates of LE use complete life tables. From 1900 through 1947, LEs for intercensal years were interpolated from decennial life tables and annual crude death rates. Since 1948, estimates have been computed from annual life tables. A substantial drop in variation in LE occurred in the 1940s. To evaluate these methods and examine variation without artifacts of different methods, we estimated a consistent series of both annual abridged life tables and LEs from official NCHS age-specific death rates and also LEs using the interpolation method for 1900-1998. Interpolated LEs are several times as variable as life table estimates, about 2 times as variable before 1940 and about 6.5 times as variable after 1950. Estimates of LE from annual life tables are better measures than those based on the mixed methods detailed in NCHS reports. Estimates from life tables show that the impact of the 1918 influenza pandemic on LE was much smaller than indicated by official statistics. We conclude that NCHS should report official estimates of intercensal LE for 1900-1948 computed from life tables in place of the existing LEs that were computed by interpolation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The demanding behavioral changes for weight control to manage diabetes might contribute to lower quality of life (QOL). This research examines whether the demands of diet and exercise contribute to lower QOL among persons with diabetes. Methods: Data were from the Behavioral Risk Factor Surveillance System (BRFSS), which measures days in the last month for poor physical health, poor mental health, limited activity, pain, depression, stress, poor sleep, and high energy, as well as weight control efforts. Results: Respondents with diabetes averaged more impaired days on every measure of QOL. Neither efforts to control weight nor dieting were related to any measure. Exercise was associated with reductions in impaired days on all measures. Conclusions: Exercising to control weight had a powerful effect on reducing QOL differences while attempting to maintain or reduce weight, and dieting to do so had no effect. [Copyright &y& Elsevier]

Quality of life (QOL) among Americans with diabetes was compared to Americans without diabetes using the Behavioral Risk Factor Surveillance System for 1996 through 2000. QOL was measured in terms of days in the last month of limited activity, poor physical health, poor mental health, pain, depression, stress, poor sleep, and high energy and perceived general health. Each of 42,154 diabetics was matched with one non-diabetic (control) respondent on age, sex, race, and ethnicity. Additional statistical adjustments were made for socio-economic status, marital status, and access to health care. Respondents with diabetes averaged more statistically adjusted impaired days than controls: 3.11 days (SE = 0.07) for physical health, 0.92 (SE = 0.06) for mental health, 1.69 (SE = 0.06) for limited activity, 1.86 (SE = 0.16) for pain, 1.14 (SE = 0.14) for depression, 1.11 (SE = 0.16) for stress, 1.47 (SE = 0.18) for inadequate rest or sleep, and 3.54 (SE = 0.21) fewer for high energy. General health was also lower. Diabetes compromised QOL a substantial proportion of time on every dimension tested. Across the board, lower education, being unable to work, unemployed, or retired and lacking funds to pay for needed medical care were associated with greater impairments among persons with diabetes. [ABSTRACT FROM AUTHOR]

Chemical consolidation may occur when a salt solution infiltrates into a clay soil. To date, most studies have considered solute diffusion alone, ignoring advective transport processes. This may be justified for some clays, however for other clays osmotic flows can be significant, and so require a careful analysis of solute advection. This paper considers the influence of solute advection on coupled chemical and mechanical consolidation of clays. The theoretical and numerical study considers both transient and steady-state solutions. It is found that solute advection can have a large effect on computed solute concentrations, excess pore water pressures, and settlements. The effects of including solute advection become increasingly important for osmotic efficiencies greater than 0.005 and when the ratio of chemical to mechanical coefficients of volume change become greater than 0.005. The differences in estimated responses of the clay, based on models with and without solute advection, can be as large as one order of magnitude. [Copyright &y& Elsevier]

The neutron probe has proven to be an effective means for monitoring long term in situ soil moisture variations. However, it is difficult to experimentally correlate neutron probe data ~i.e., neutron counts! with accurate estimates of absolute soil moisture content, particularly for unsaturated clay soils. In this paper, a numerical model based on multigroup neutron diffusion theory is employed to predict the distribution of neutron flux in a neutron probe system. The model discretizes the neutron energy spectrum into seven intervals, with energy-dependent diffusion coefficients and parameters for each energy interval. The finite element method is employed to solve the coupled seven-group neutron diffusion equations. It is demonstrated that the numerical results compare very well with both laboratory experimental results and field measurements. The theoretical approach to neutron probe calibration described herein offers significant time and cost savings over traditional calibration methods, and potentially opens up new applications for neutron probe monitoring. [ABSTRACT FROM AUTHOR]

Inhibitors of amyloid-β (Aβ) protein production have been widely pursued as a potential treatment for Alzheimer''s disease. Following the identification of a 5 μM screening hit, SAR was initiated using solid-phase synthetic techniques. Two series of α-hydroxy esters and ketones which are sub-micromolar inhibitors of Aβ production were identified. The most potent α-hydroxyketone identified is approximately 30-fold more potent than the initial lead. [Copyright &y& Elsevier]

Presents a two-dimensional finite element method for the solution of the advection-dispersion transport equation for multicomponent contaminants through soils. Application of the Petrov-Galerkin method for the transport equation; Iteration between the transport and equilibrium equations; Overview of initial and feed concentrations and equilibrium parameters.

Provides information on a study that investigates the effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament. Materials and methods of the study; Study results; Discussion on the use of growth factors to promote soft tissue healing.

An alternative model useful for addressing the problem of negative variance component estimators is proposed. Specifically, it is possible to view certain of the parameters as covariances rather than as variances. Thus, the problems of the negative variance component estimator may be resolved by using a different model. Distributional results relating to both estimation and tests of hypotheses are also given. [ABSTRACT FROM AUTHOR]

The goal of this study was to measure behavioral auditory thresholds in four Japanese macaques. Animals were trained using food as a reward in an operant reinforcement paradigm. Stimuli were 1-s sinusoids with 10-ms rise/fall times delivered through insert earphones (Etymotic ER-1) having expandable foam eartips. The animals generally produced threshold contours similar in shape to those reported for other macaques species, except that the low-frequency thresholds may have been slightly higher in the present studies. At middle and high frequencies, thresholds fell at the lower extreme of the range previously reported in other macaque species. The possible difference in low-frequency thresholds may have been a result of either transducer and calibration differences between studies or true species variations, or both. Though somewhat limited at high frequencies, the insert earphones used in these studies offer more reliable calibrations, less susceptibility to changes in positioning with movement of the animal, and greater interaural attenuation. Am. J. Primatol. 41:323–329, 1997. © 1997 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Causes of death have changed greatly in the United States during the 20th century.Objective: To detail these changes in elderly people during 1950-1990.Methods: The source of data was 'Vital Statistics of the United States' for the years discussed. Mortality rates for several causes were calculated for the 85-89 age group, and the percentage of deaths attributed to several causes was calculated.Results: There are large peaks about 1970 in both the mortality rate of ischemic heart disease and the percentage of total deaths attributed to this cause. The peaks have been followed by declines. Death rates from cancer and the percent of deaths attributed to cancer have increased during 1950-1990.Conclusions: The above changes coincide with major changes in medical science and care, the identification of the risk factors predisposing to ischemic heart disease and cerebrovascular diseases, and the implementation of Medicare, a program of health care benefits to all people 65 and over that is supported by the United States government. [ABSTRACT FROM AUTHOR]