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Involvement of adenosinergic A1 systems in the occurrence of respiratory perturbations encountered in newborns following an in utero caffeine exposure has been investigated on pontomedullary–spinal cord, caudal pons–medullary–spinal cord and medullary–spinal cord preparations isolated from newborn rats. According to the drinking fluid of dams (tap water or 0.02% caffeine), two groups of preparations were distinguished, no-caffeine and caffeine. In the no-caffeine group, adenosine A1 receptor activation induces a decrease in respiratory frequency (Rf) in caudal pons–medullary–spinal cord and medullary–spinal cord preparations whereas, in presence of the rostral pons, an increase is observed. A parallel Fos detection indicates that this discrepancy may be due to the excitatory action of the medial parabrachial nucleus at the rostral pontine level that surpasses inhibitory influence of the adenosine A1 receptor activation at the medullary level particularly in the ventrolateral reticular nucleus of the medulla. In caffeine group, an increase in the baseline Rf in presence of the pons and no change in medullary–spinal cord preparations have been observed. Depending on Fos detection, we assume that the medial parabrachial nucleus is the main region involved in the exaggeration of Rf. Moreover, adenosine A1 receptor activation was modified by in utero caffeine exposure with an overcharge of the Rf increase in pontomedullary–spinal cord preparations and an exaggeration of the Rf decrease in medullary–spinal cord preparations. Based on Fos detection, we link the overcharge in Rf of pontomedullary spinal cord preparations to an increase in the medial parabrachial nucleus neuronal activity. Similarly, exaggeration of Rf decrease observed without the pons is linked with a decrease in activity of the ventrolateral reticular neurons.This study brings evidence for the involvement of adenosinergic A1 systems in the occurrence of respiratory perturbations in newborns following in utero caffeine exposure and the importance of rostral pons in the adenosinergic A1 modulation of the respiratory control. [Copyright &y& Elsevier]

Competing Interests: The authors report no conflicts of interest.

Total knee replacement implants consisting of a Co-29Cr-6Mo alloy femoral component and a Ti-6Al-4V tibial component are the basis for the additive manufacturing of novel solid, mesh, and foam monoliths using electron beam melting (EBM). Ti-6Al-4V solid prototype microstructures were primarily α-phase acicular platelets while the mesh and foam structures were characterized by α(')-martensite with some residual α. The Co-29Cr-6Mo containing 0.22% C formed columnar (directional) Cr(23)C(6) carbides spaced ~2 μm in the build direction, while HIP-annealed Co-Cr alloy exhibited an intrinsic stacking fault microstructure. A log-log plot of relative stiffness versus relative density for Ti-6Al-4V and Co-29Cr-6Mo open-cellular mesh and foams resulted in a fitted line with a nearly ideal slope, n = 2.1. A stress shielding design graph constructed from these data permitted mesh and foam implant prototypes to be fabricated for compatible bone stiffness., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In this paper, we examine prospects for the manufacture of patient-specific biomedical implants replacing hard tissues (bone), particularly knee and hip stems and large bone (femoral) intramedullary rods, using additive manufacturing (AM) by electron beam melting (EBM). Of particular interest is the fabrication of complex functional (biocompatible) mesh arrays. Mesh elements or unit cells can be divided into different regions in order to use different cell designs in different areas of the component to produce various or continually varying (functionally graded) mesh densities. Numerous design elements have been used to fabricate prototypes by AM using EBM of Ti-6Al-4V powders, where the densities have been compared with the elastic (Young) moduli determined by resonant frequency and damping analysis. Density optimization at the bone-implant interface can allow for bone ingrowth and cementless implant components. Computerized tomography (CT) scans of metal (aluminium alloy) foam have also allowed for the building of Ti-6Al-4V foams by embedding the digital-layered scans in computer-aided design or software models for EBM. Variations in mesh complexity and especially strut (or truss) dimensions alter the cooling and solidification rate, which alters the alpha-phase (hexagonal close-packed) microstructure by creating mixtures of alpha/alpha' (martensite) observed by optical and electron metallography. Microindentation hardness measurements are characteristic of these microstructures and microstructure mixtures (alpha/alpha') and sizes.

The microstructure and mechanical behavior of simple product geometries produced by layered manufacturing using the electron beam melting (EBM) process and the selective laser melting (SLM) process are compared with those characteristic of conventional wrought and cast products of Ti-6Al-4V. Microstructures are characterized utilizing optical metallography (OM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), and included alpha (hcp), beta (bcc) and alpha(') (hcp) martensite phase regimes which give rise to hardness variations ranging from HRC 37 to 57 and tensile strengths ranging from 0.9 to 1.45 GPa. The advantages and disadvantages of layered manufacturing utilizing initial powders in custom building of biomedical components by EBM and SLM in contrast to conventional manufacturing from Ti-6Al-4V wrought bar stock are discussed.

Caffeine, which belongs to the methylxantine family of compounds, is commonly ingested in a range of beverages such as coffee, tea, and cola drinks. It is also used therapeutically and is frequently employed in the treatment of respiratory disturbances in human neonates. The aim of the present work has been to examine the ontogeny of the adenosine A1 receptor system in the brainstem of the newborn rat following postnatal treatment with caffeine to mimic the therapeutic administration of caffeine to premature human infants. The effect of this postnatal exposure to caffeine on the gradual appearance of adenosine A1 receptors was analysed by determining immunohistochemically the distribution of the receptors. The main difference between control animals and animals exposed to caffeine was the transient increase (only at postnatal day 6) in the number of immunopositive neurons in two brainstem areas, the ventrolateral medulla and the rostral dorsolateral pons, in caffeine-treated rat pups, or more specifically, the parabrachial and Kölliker-Fuse nuclei, both of which are classically associated with respiratory control. With previous research highlighting the important role played by the rostral pons in respiratory modulation by the adenosine A1 receptor system, it is thus possible that postnatal exposure to caffeine modulates the ontogeny of the adenosine A1 receptor network. This could imply that the role of caffeine to decrease the incidence of neonatal respiratory disturbances may be due to the earlier than normal development of the adenosinergic system in the brain.

The abnormal metabolism of serotonin during the perinatal period alters respiratory network maturation at birth as revealed by comparing the monoamine oxidase A-deficient transgenic (Tg8) with the control (C3H) mice (Bou-Flores et al., 2000). To know whether these alterations occur only transiently or induce persistent respiratory dysfunction during adulthood, we studied the respiratory activity and regulations in adult C3H and Tg8 mice. First, plethysmographic and pneumotachographic analyses of breathing patterns revealed weaker tidal volumes and shorter inspiratory durations in Tg8 than in C3H mice. Second, electrophysiological studies showed that the firing activity of inspiratory medullary neurons and phrenic motoneurons is higher in Tg8 mice and that of the intercostal motoneurons in C3H mice. Third, histological studies indicated abnormally large cell bodies of Tg8 intercostal but not phrenic motoneurons. Finally, respiratory responses to hypoxia and lung inflation are weaker in Tg8 than in C3H mice. dl-p-chlorophenyl-alanine treatments applied to Tg8 mice depress the high serotonin level present during adulthood; the treated mice recover normal respiratory responses to both hypoxia and lung inflation, but their breathing parameters are not significantly affected. Therefore in Tg8 mice the high serotonin level occurring during the perinatal period alters respiratory network maturation and produces a permanent respiratory dysfunction, whereas the high serotonin level present in adults alters the respiratory regulatory processes. In conclusion, the metabolism of serotonin plays a crucial role in the maturation of the respiratory network and in both the respiratory activity and the respiratory regulations.