Older patients are immunocompromised by cytokine depletion and loss of innate immune function after hip fracture surgery

PURPOSE/INTRODUCTION: We have examined the immune status of elderly patients who underwent surgery for a hip fracture, an injury associated with poor postoperative outcomes, to identify specific immune defects. METHODS: In a cohort observational study, 16 patients undergoing surgery for hip fractures had immune function evaluation prior to surgery, and then at 3 and 7 days postoperatively, using flow cytometry for phenotype and for monocyte and granulocyte phagocytic function and respiratory burst. Serum samples were stored and batch analyzed using a human cytokine 25-plex panel. RESULTS: We report significant loss of innate immune function, related specifically to reduced granulocyte numbers by day 7 (P < .0001, flow cytometry; P < .05 white blood cells), and although granulocyte ability to take up opsonized Escherichia coli was increased (P < .05), the ability of those cells to generate a respiratory burst was reduced at days 3 and 7 (P < .05). Monocyte respiratory burst was also significantly reduced (P < .05). Serum cytokine levels indicated very poor T-cell function. CONCLUSION: We have demonstrated that the antimicrobial immune response is profoundly reduced after surgery in elderly patients with hip fractures. The effect was sustained up to 7 days postoperatively, identifying these patients as particularly vulnerable to bacterial infections.

Effects of 60-day bed rest with and without exercise on cellular and humoral immunological parameters

Exercise at regular intervals is assumed to have a positive effect on immune functions. Conversely, after spaceflight and under simulated weightlessness (e.g., bed rest), immune functions can be suppressed. We aimed to assess the effects of simulated weightlessness (Second Berlin BedRest Study; BBR2-2) on immunological parameters and to investigate the effect of exercise (resistive exercise with and without vibration) on these changes. Twenty-four physically and mentally healthy male volunteers (20-45 years) performed resistive vibration exercise (n=7), resistance exercise without vibration (n=8) or no exercise (n=9) within 60 days of bed rest. Blood samples were taken 2 days before bed rest, on days 19 and 60 of bed rest. Composition of immune cells was analyzed by flow cytometry. Cytokines and neuroendocrine parameters were analyzed by Luminex technology and ELISA/RIA in plasma. General changes over time were identified by paired t-test, and exercise-dependent effects by pairwise repeated measurements (analysis of variance (ANOVA)). With all subjects pooled, the number of granulocytes, natural killer T cells, hematopoietic stem cells and CD45RA and CD25 co-expressing T cells increased and the number of monocytes decreased significantly during the study; the concentration of eotaxin decreased significantly. Different impacts of exercise were seen for lymphocytes, B cells, especially the IgD(+) subpopulation of B cells and the concentrations of IP-10, RANTES and DHEA-S. We conclude that prolonged bed rest significantly impacts immune cell populations and cytokine concentrations. Exercise was able to specifically influence different immunological parameters. In summary, our data fit the hypothesis of immunoprotection by exercise and may point toward even superior effects by resistive vibration exercise.Cellular & Molecular Immunology advance online publication, 10 November 2014; doi:10.1038/cmi.2014.106.

Molecular basis of copper transport: cellular and physiological functions of Menkes and Wilson disease proteins (ATP7A and ATPB)

Eukaryotic cells prevent copper-induced, free radical damage to cell components by employing copper-binding proteins and transporters that minimize the likelihood of free copper ions existing in the cell. In the cell, copper is actively transported from the cytoplasm during the biosynthesis of secreted coppercontaining proteins and, as a protective measure, when there is an excess of copper. In humans, this is accomplished by two related copper-transporting ATPases (ATP7A and ATP7B), which are the affected genes in two distinct human genetic disorders of copper transport, Menkes disease (copper deficiency) and Wilson disease (copper toxicosis). The study of these ATPases has revealed their molecular mechanisms of copper transport and their roles in physiological copper homeostasis. Both ATP7A and ATP7B are expressed in specific brain regions and neurological abnormalities are important clinical features in Menkes and Wilson disease.

Molecular and cellular aspects of copper transport in developing mammals

Copper is an essential trace element that requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects because of the ability of the metal ion to catalyze the formation of free radicals. The Cu-ATPases, ATP7A and ATP7B, play an important role in the physiological regulation of copper. Adequate supplies of copper are particularly important in developing animals, and in humans this is illustrated by mutations of ATP7A that cause the copper deficiency condition Menkes disease, which is fatal in early childhood. In contrast, mutations in ATP7B result in the genetic toxicosis, Wilson disease. We propose that the physiological regulation of copper is accomplished mainly by the intracellular copper-regulated trafficking of the Cu-ATPases. This process allows the overall copper status in the body to be maintained when levels of copper in the diet alter. A study of the defects in mouse models of Menkes and Wilson diseases has demonstrated that both ATPases play an important role in supplying copper to the developing fetus and neonate

Effects of the density on compressive properties in cellular aluminum produced by the sintering method

The cellular aluminum materials with relative densities of 0.1"-'0.25 were fabricated by the sintering method and effects of the density on mechanical properties of the cellular aluminum were investigated by compressive tests. The cellular aluminum exhibited a plateau region with a nearly constant flow stress. The stress in the plateau region increased with increasing relative density, on the other hand, the densification strain decreased with increasing relative density. Observation of the deformed cells revealed that the cell walls were bent. Besides, the stress in the plateau region was proportional to 1.9 power of the density. These suggest that plastic collapse is dominated by bending of the cell walls for the cellular aluminum produced by the sintering method.

Speed control and policing in a cellular mobile network: speedNet

In this paper, we describe SpeedNet, a GSM network variant which resembles an ad hoc wireless mobile network where base stations keep track of the velocities of mobile users (cars). SpeedNet is intended to track mobile users and their speed passively for both speed policing and control of traffic. The speed of the vehicle is controlled in a speed critical zone by means of an electro-mechanical control system, suitably referred to as VVLS (Vehicular Velocity Limiting System). VVLS is mounted on the vehicle and responds to the command signals generated by the base station. It also determines the next base station to handoff, in order to improve the connection reliability and bandwidth efficiency of the underlying network. Robust Extended Kalman Filter (REKF) is used as a passive velocity estimator of the mobile user with the widely used proportional and integral controller speed control. We demonstrate through simulation and analysis that our prediction algorithm can successfully estimate the mobile user’s velocity with low system complexity as it requires two closest mobile base station measurements and also it is robust against system uncertainties due to the inherent deterministic nature in the mobility model.

Apoptosis may underlie the pathology of zinc-deficient skin

The trace element zinc is essential for the survival and function of all cells. Zinc deficiency, whether nutritional or genetic, is fatal if left untreated. The effects of zinc deficiency are particularly obvious in the skin, seen as an erythematous rash, scaly plaques, and ulcers. Electron microscopy reveals degenerative changes within keratinocytes. Despite the well-documented association between zinc deficiency and skin pathology, it is not clear which cellular processes are most sensitive to zinc deficiency and could account for the typical pathological features. We used the cultured HaCaT keratinocyte line to obtain insight into the cellular effects of zinc deficiency, as these cells show many characteristics of normal skin keratinocytes. Zinc deficiency was induced by growing cells in the presence of the zinc chelator, TPEN, or by growth in zinc-deficient medium. Growth of cells in zinc-deficient medium resulted in a 44% reduction of intracellular zinc levels and a 75% reduction in the activity of the zinc-dependent enzyme, 5'-nucleotidase, relative to the control cells. Over a period of 7 days of exposure to zinc-deficient conditions, no changes in cell viability and growth, or in the cytoskeletal and cell adhesion systems, were found in HaCaT cells. At 7 days, however, induction of apoptosis was indicated by the presence of DNA fragmentation and expression of active caspase-3 in cells. These results demonstrate that apoptosis is the earliest detectable cellular change induced by zinc deficiency in HaCaT keratinocytes. Our observations account for many of the features of zinc deficiency, including the presence of degenerate nuclei, chromatin aggregates and abnormal organization of keratin, that may represent the later stages of apoptosis. In summary, a major causal role for apoptosis in the pathology of zinc deficiency in the skin is proposed. This role is consistent with the previously unexplained diverse range of degenerative cellular changes seen at the ultrastructural level in zinc-deficient keratinocytes.

Mobility modelling and trajectory prediction for cellular networks with mobile base stations

This paper provides mobility estimation and prediction for a variant of GSM network which resembles an adhoc wireless mobile network where base stations and users are both mobile. We propose using Robust Extended Kalman Filter (REKF)as a location heading altitude estimator of mobile user for next node (mobile-base station)in order to improve the connection reliability and bandwidth efficiency of the underlying system. Through analysis we demonstrate that our algorithm can successfully track the mobile users with less system complexity as it requires either one or two closest mobile-basestation measurements. Further, the technique is robust against system uncertainties due to inherent deterministic nature in the mobility model. Through simulation, we show the accuracy and simplicity in implementation of our prediction algorithm.

Speed control and policing in a cellular mobile network: SpeedNet

In this paper, we describe SpeedNet, a GSM network variant which resembles an ad hoc wireless mobile network where base stations (possibly other vehicles in the network) keep track of the velocities of mobile users (cars). SpeedNet is intended to track mobile users and their speed passively for both speed policing and control of traffic. The speed of the vehicle is controlled in a speed critical zone by means of an electro-mechanical control system, suitably referred to as VVLS (vehicular velocity limiting system). VVLS is mounted in the vehicle and responds to the command signals generated by the base station. It also determines the next basestation to handoff, in order to improve the connection reliability and bandwidth efficiency of the underlying network. Robust extended Kalman filter (REKF) is used as a passive velocity estimator of the mobile user with the widely used proportional and integral controller speed control. We demonstrate through simulation and analysis that our prediction algorithm can successfully estimate the mobile users velocity with low system complexity as it requires two closet mobile-base station measurement and also it is robust against system uncertainties due to the inherent deterministic nature in the mobility model.

Location based power control for mobile devices in a cellular network

This paper provides location estimation based power control strategy for cellular radio systems via a location based interference management scheme. Our approach considers the carrier-to-interference as dependent on the transmitter and receiver separation distance and therefore an accurate estimation of the precise locations can provide the power critical mobile user to control the transition power accordingly. In this fully
distributed algorithms, we propose using a Robust Extended Kalman Filter (REKF) to derive an estimate of the mobile user’s closest mobile base station from the user’s location, heading and altitude. Our analysis demonstrates that this algorithm can successfully track the mobile users with less system complexity, as it requires measurements from only one or two closest mobile base stations and hence enable the user to transmit at the rate that is sufficient for the interference management. Our power control
algorithms based on this estimation converges to the desired power trajectory. Further, the technique is robust against system uncertainties caused by the inherent deterministic nature of the mobility model. Through simulation, we show the accuracy of our prediction algorithm and the simplicity of its implementation.

Diesel exhaust particulate matter induces multinucleate cells and zinc transporter-dependent apoptosis in human airway cells

The cellular effects of biodiesel emissions particulate matter (BDEP) and petroleum diesel emissions particulate matter (PDEP) were compared using a human airway cell line, A549. At concentrations of 25 µg/ml, diesel particulate matter induced the formation of multinucleate cells. In cells treated with a mixture of 80% PDEP:20% BDEP, 52% of cells were multinucleate cells compared with only 16% of cells treated with 20% PDEP:80% BDEP with a background multinucleate rate of 7%. These results demonstrate a causal relation between the formation of multinucleate cells and exposure to exhaust particulate matter, in particular diesel exhaust. Exposure of A549 cells to PDEP induced apoptosis, seen by active caspase-3 expression and the presence of cleaved pancytokeratin. PDEP exhaust was a much stronger inducer of cellular death through apoptosis than BDEP. There was an eightfold increase in the expression of SLC30A3 (zinc transporter-3 or ZnT3) in cells exposed to 80% PDEP:20% BDEP compared to untreated cells. The increase in ZnT3 expression seen in apoptotic cells following PDEP suggests a role for this zinc transporter in the apoptotic pathway, possibly through controlling zinc fluxes. As exposure to diesel exhaust particles is associated with asthma and apoptosis in airway cells, diesel exhaust particles may directly contribute to asthma by inducing epithelial cell death through apoptotic pathway.

Simultaneous determination of irinotecan (CPT-11) and SN-38 in tissue culture media and cancer cells by high performance liquid chromatography: Application to cellular metabolism and accumulation studies

A simple and sensitive HPLC method was developed to simultaneously determine CPT-11 and its major metabolite SN-38 in culture media and cell lysates. Camptothecin (CPT) was used as internal standard (I.S.). Compounds were eluted with acetonitrile–50 mM disodium hydrogen phosphate buffer containing 10 mM sodium 1-heptane-sulfonate, with the pH adjusted to 3.0 using 85% (w/v) orthophosphoric acid (27/73, v/v) by a Hyperclon ODS (C18) column (200 mm × 4.6 mm i.d.), with detection at excitation and emission wavelengths of 380 and 540 nm, respectively. The average extraction efficiencies were 96.9–108.3% for CPT-11 in culture media and 94.3–107.2% for CPT-11 in cell lysates; and 87.7–106.8% for SN-38 in culture media and 90.1–105.6% for SN-38 in cell lysates. Within- and between-day precision and accuracy varied from 0.1 to 10.3%. The limit of quantitation (precision and accuracy <20%) was 5.0 and 2.0 ng/ml for CPT-11 and 1.0 and 0.5 ng/ml for SN-38 in culture media and cell lysates, respectively. This method was successfully applied to quantitate the cellular accumulation and metabolism of CPT-11 and SN-38 in H4-II-E, a rat hepatoma cell line.

Simulation of dynamic recrystallization using random grid cellular automata

Computer simulation is a powerful tool to predict microstructure and its evolution in dynamic and post-dynamic recrystallization. CAFE proposed as an appropriate approach by combining finite element (FE) method and cellular automata (CA) for recrystallization simulation. In the current study, a random grid cellular automaton (CA), as micro-scale model, based on finite element (FE), as macro-scale method, has been used to study initial and evolving microstructural features; including nuclei densities, dislocation densities, grain size and grain boundary movement during dynamic recrystallization in a C-Mn steel. An optimized relation has been established between mechanical variables and evolving microstructure features during recrystallization and grain growth. In this model, the microstructure is defined as cells located within grains and grain boundaries while dislocations are randomly dispersed throughout microstructure. Changes of dislocation density during deformation are described considering hardening, recovery and recrystallization. Recrystallization is assumed to initiate near grain boundaries and nucleation rate was considered constant (site-saturated condition). The model produced a mathematical formulation which captured the initial and evolving microstructural entities and linked their effects to measurable macroscopic variables (e.g. stress).