An X-ray micro-fluorescence study to investigate the distribution of Al, Si, P and Ca ions in the surrounding soft tissue after implantation of a calcium phosphate-mullite ceramic composite in a rabbit animal model

Synthetic calcium phosphates, despite their bioactivity, are brittle. Calcium phosphate-mullite composites have been suggested as potential dental and bone replacement materials which exhibit increased toughness. Aluminium, present in mullite, has however been linked to bone demineralisation and neurotoxicity: it is therefore important to characterise the materials fully in order to understand their in vivo behaviour. The present work reports the compositional mapping of the interfacial region of a calcium phosphate-20 wt% mullite biocomposite/soft tissue interface, obtained from the samples implanted into the long bones of healthy rabbits according to standard protocols (ISO-10993) for up to 12 weeks. X-ray micro-fluorescence was used to map simultaneously the distribution of Al, P, Si and Ca across the ceramic-soft tissue interface. A well defined and sharp interface region was present between the ceramic and the surrounding soft tissue for each time period examined. The concentration of Al in the surrounding tissue was found to fall by two orders of magnitude, to the background level, within similar to 35 mu m of the implanted ceramic.

Clinical outcomes after implantation of a new hydrophobic acrylic toric IOL during routine cataract surgery

PURPOSE: To assess the clinical outcomes after implantation of a new hydrophobic acrylic toric intraocular lens (IOL) to correct preexisting corneal astigmatism in patients having routine cataract surgery. SETTING: Four hospital eye clinics throughout Europe. DESIGN: Cohort study. METHODS: This study included eyes with at least 0.75 diopter (D) of preexisting corneal astigmatism having routine cataract surgery. Phacoemulsification was performed followed by insertion and alignment of a Tecnis toric IOL. Patients were examined 4 to 8 weeks postoperatively; uncorrected distance visual acuity (UDVA), corrected distance visual acuity, manifest refraction, and keratometry were measured. Individual patient satisfaction with uncorrected vision and the surgeon’s assessment of ease of handling and performance of the IOL were also documented. The cylinder axis of the toric IOL was determined by dilated slitlamp examination. RESULTS: The study enrolled 67 eyes of 60 patients. Four to 8 weeks postoperatively, the mean UDVA was 0.15 logMAR G 0.17 (SD) and the UDVA was 20/40 or better in 88% of eyes. The mean refractive cylinder decreased significantly postoperatively, from -1.91 +/- 1.07 D to -0.67 +/- 0.54 D. No significant change in keratometric cylinder was observed. The mean absolute IOL misalignment from the intended axis was 3.4 degrees (range 0 to 12 degrees). The good UDVA resulted in high levels of patient satisfaction. CONCLUSION: Implantation of the new toric IOL was an effective, safe, and predictable method to manage corneal astigmatism in patients having routine cataract surgery.

Visual outcomes and subjective experience after bilateral implantation of a new diffractive trifocal intraocular lens

Purpose - To assess clinical outcomes and subjective experience after bilateral implantation of a diffractive trifocal intraocular lens (IOL). Setting - Midland Eye Institute, Solihull, United Kingdom. Design - Cohort study. Methods - Patients had bilateral implantation of Finevision trifocal IOLs. Uncorrected distance visual acuity, corrected distance visual acuity (CDVA), and manifest refraction were measured 2 months postoperatively. Defocus curves were assessed under photopic and mesopic conditions over a range of +1.50 to -4.00 diopters (D) in 0.50 D steps. Contrast sensitivity function was assessed under photopic conditions. Halometry was used to measure the angular size of monocular and binocular photopic scotomas arising from a glare source. Patient satisfaction with uncorrected near vision was assessed using the Near Activity Visual Questionnaire (NAVQ). Results - The mean monocular CDVA was 0.08 logMAR ± 0.08 (SD) and the mean binocular CDVA, 0.06 ± 0.08 logMAR. Defocus curve testing showed an extended range of clear vision from +1.00 to -2.50 D defocus, with a significant difference in acuity between photopic conditions and mesopic conditions at -1.50 D defocus only. Photopic contrast sensitivity was significantly better binocularly than monocularly at all spatial frequencies. Halometry showed a glare scotoma of a mean size similar to that in previous studies of multifocal and accommodating IOLs; there were no subjective complaints of dysphotopsia. The mean NAVQ Rasch score for satisfaction with near vision was 15.9 ± 10.7 logits. Conclusions - The trifocal IOL implanted binocularly produced good distance visual acuity and near and intermediate visual function. Patients were very satisfied with their uncorrected near vision.

Hypoxia induces dilated cardiomyopathy in the chick embryo:mechanism, intervention, and long-term consequences

Background - Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods - Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings - Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance - Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

The value of magnetoencephalography to guide electrode implantation in epilepsy

To investigate if Magnetoencephalography (MEG) can add non-redundant information to guide implantation sites for intracranial recordings (IR). The contribution of MEG to intracranial recording planning was evaluated in 12 consecutive patients assessed pre-surgically with MEG followed by IR. Primary outcome measures were the identification of focal seizure onset in IR and favorable surgical outcome. Outcome measures were compared to those of 12 patients matched for implantation type in whom non-invasive pre-surgical assessment suggested clear hypotheses for implantation (non-MEG group). In the MEG group, non-invasive assessment without MEG was inconclusive, and MEG was then used to further help identify implantation sites. In all MEG patients, at least one virtual MEG electrode generated suitable hypotheses for the location of implantations. No differences in outcome measures were found between non-MEG and MEG groups. Although the MEG group included more complex patients, it showed similar percentage of successful implantations as the non-MEG group. This suggests that MEG can contribute to identify implantation sites where standard methods failed. © 2013 Springer Science+Business Media New York.

Parental diet, pregnancy outcomes and offspring health:metabolic determinants in developing oocytes and embryos

The periconceptional period, embracing the terminal stages of oocyte growth and post-fertilisation development up to implantation, is sensitive to parental nutrition. Deficiencies or excesses in a range of macro- and micronutrients during this period can lead to impairments in fertility, fetal development and long-term offspring health. Obesity and genotype-related differences in regional adiposity are associated with impaired liver function and insulin resistance, and contribute to fatty acid-mediated impairments in sperm viability and oocyte and embryo quality, all of which are associated with endoplasmic reticulum stress and compromised fertility. Disturbances to maternal protein metabolism can elevate ammonium concentrations in reproductive tissues and disturb embryo and fetal development. Associated with this are disturbances to one-carbon metabolism, which can lead to epigenetic modifications to DNA and associated proteins in offspring that are both insulin resistant and hypertensive. Many enzymes involved in epigenetic gene regulation use metabolic cosubstrates (e.g. acetyl CoA and S-adenosyl methionine) to modify DNA and associated proteins, and so act as 'metabolic sensors' providing a link between parental nutritional status and gene regulation. Separate to their genomic contribution, spermatozoa can also influence embryo development via direct interactions with the egg and by seminal plasma components that act on oviductal and uterine tissues. © IETS 2014.

Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring

Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18% casein) or an isocaloric low-protein diet throughout gestation (LPD; 9% casein), or fed the LPD exclusively during the pre-implantation period (3.5d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P=0.04 and P=0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na /K ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P=0.044), whilst Emb-LPD males had elevated lung ACE activity (P=0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected. © 2010 The Authors.

The preimplantation embryo:handle with care

The past decade has seen considerable advances in our understanding of intrinsic developmental mechanisms associated with gametogenesis and embryogenesis and accompanying applications in the fields of reproductive medicine, embryonic stem cell biology, and nuclear reprogramming. However, a new focus has recently emerged concerning the homeostatic regulation of embryonic cells, how this is set, and how it may influence the longitudinal progression and optimization of the developmental program and indeed the phenotype of the offspring. Attention has been drawn to the preimplantation stage of development as a sensitive "window" when in vitro and in vivo manipulations, such as culture conditions or maternal diet, may have critical consequences. In this article, we review how changes in environmental conditions, mediated via a range of epigenetic, cellular, and metabolic mechanisms in the preimplantation embryo, may alter the pattern of cell division, gene expression, morphology, and potential. We consider how fetal and postnatal phenotype may become susceptible to the plasticity of the preimplantation embryo and the risks for adult health and physiology. Copyright © 2008 by Thieme Medical Publishers, Inc.

Mouse embryo culture induces changes in postnatal phenotype including raised systolic blood pressure

A key factor in the use of assisted reproductive technologies (ART) for diverse species is the safety of procedures for long-term health. By using a mouse model, we have investigated the effect of in vitro culture and embryo transfer (ET) of superovulated embryos on postnatal growth and physiological activity compared with that of embryos developing in vivo. Embryo culture from two-cell to blastocyst stages in T6 medium either with or without a protein source reduced blastocyst trophectoderm and inner cell mass cell number compared with that of embryos developing in vivo. Embryo culture and ET had minimal effects on postnatal growth when compared with in vivo development with an equivalent litter size. However, embryo culture, and to a lesser extent ET, led to an enhanced systolic blood pressure at 21 weeks compared with in vivo development independent of litter size, maternal origin, or body weight. Moreover, activity of enzymatic regulators of cardiovascular and metabolic physiology, namely, serum angiotensin-converting enzyme and the gluconeogenesis controller, hepatic phosphoeno/pyruvate carboxykinase, were significantly elevated in response to embryo culture and/or ET in female offspring at 27 weeks, independent of maternal factors and postnatal growth. These animal data indicate that postnatal physiological criteria important in cardiovascular and metabolic health may be more sensitive to routine ART procedures than growth. © 2007 by The National Academy of Sciences of the USA.

The embryo and its future

The preimplantation mammalian embryo from different species appears sensitive to the environment in which it develops, either in vitro or in vivo, for example, in response to culture conditions or maternal diet. This sensitivity may lead to long-term alterations in the characteristics of fetal and/or postnatal growth and phenotype, which have implications for clinical health and biotechnological applications. We review the breadth of environmental influences that may affect early embryos and their responses to such conditions along epigenetic, metabolic, cellular, and physiological directions. In addition, we evaluate how embryo environmental responses may influence developmental potential and phenotype during later gestation. We conclude that a complex of different mechanisms may operate to associate early embryo environment with future health.

Flt1 acts as a negative regulator of tip cell formation and branching morphogenesis in the zebrafish embryo

Endothelial tip cells guide angiogenic sprouts by exploring the local environment for guidance cues such as vascular endothelial growth factor (VegfA). Here we present Flt1 (Vegf receptor 1) loss- and gain-of-function data in zebrafish showing that Flt1 regulates tip cell formation and arterial branching morphogenesis. Zebrafish embryos expressed soluble Flt1 (sFlt1) and membrane-bound Flt1 (mFlt1). In Tg(flt1(BAC):yfp) × Tg(kdrl:ras-cherry)(s916) embryos, flt1:yfp was expressed in tip, stalk and base cells of segmental artery sprouts and overlapped with kdrl:cherry expression in these domains. flt1 morphants showed increased tip cell numbers, enhanced angiogenic behavior and hyperbranching of segmental artery sprouts. The additional arterial branches developed into functional vessels carrying blood flow. In support of a functional role for the extracellular VEGF-binding domain of Flt1, overexpression of sflt1 or mflt1 rescued aberrant branching in flt1 morphants, and overexpression of sflt1 or mflt1 in controls resulted in short arterial sprouts with reduced numbers of filopodia. flt1 morphants showed reduced expression of Notch receptors and of the Notch downstream target efnb2a, and ectopic expression of flt4 in arteries, consistent with loss of Notch signaling. Conditional overexpression of the notch1a intracellular cleaved domain in flt1 morphants restored segmental artery patterning. The developing nervous system of the trunk contributed to the distribution of Flt1, and the loss of flt1 affected neurons. Thus, Flt1 acts in a Notch-dependent manner as a negative regulator of tip cell differentiation and branching. Flt1 distribution may be fine-tuned, involving interactions with the developing nervous system.

Increasing the fracture toughness of silicon by ion implantation

Previous studies have shown that moderate doses of radiation can lead to increased fracture toughness in ceramics. An experimental investigation was conducted to determine the effects of ion implantation on fracture toughness in silicon. Specimens implanted with Ne showed increased fracture toughness, over the entire range of implantations tested. Using ions of various energies to better distribute implantation damage further increased the fracture toughness even though the region of amorphous damage was slightly decreased. The implantation damage accumulated in a predictable manner so that fracture toughness could be optimized.

Do little embryos make big decisions? How maternal dietary protein restriction can permanently change an embryo's potential, affecting adult health

Periconceptional environment may influence embryo development, ultimately affecting adult health. Here, we review the rodent model of maternal low-protein diet specifically during the preimplantation period (Emb-LPD) with normal nutrition during subsequent gestation and postnatally. This model, studied mainly in the mouse, leads to cardiovascular, metabolic and behavioural disease in adult offspring, with females more susceptible. We evaluate the sequence of events from diet administration that may lead to adult disease. Emb-LPD changes maternal serum and/or uterine fluid metabolite composition, notably with reduced insulin and branched-chain amino acids. This is sensed by blastocysts through reduced mammalian target of rapamycin complex 1 signalling. Embryos respond by permanently changing the pattern of development of their extra-embryonic lineages, trophectoderm and primitive endoderm, to enhance maternal nutrient retrieval during subsequent gestation. These compensatory changes include stimulation in proliferation, endocytosis and cellular motility, and epigenetic mechanisms underlying them are being identified. Collectively, these responses act to protect fetal growth and likely contribute to offspring competitive fitness. However, the resulting growth adversely affects long-term health because perinatal weight positively correlates with adult disease risk. We argue that periconception environmental responses reflect developmental plasticity and 'decisions' made by embryos to optimise their own development, but with lasting consequences.

The value of magnetoencephalography to guide electrode implantation in epilepsy

Purpose: To investigate if magnetoencephalography (MEG) can identify implantation sites for intracranial recordings (IR). Method: Two groups of 12 patients assessed for surgery with IR with and without MEG were compared (MEG and control groups). In the control group, non-invasive presurgical assessment without MEG suggested clear hypotheses for implantation. In the MEG group, non-invasive assessment was inconclusive, and MEG was used to identify implantation sites. Both groups were matched for implantation type. The success of implantation was defined by findings in IR: a) Focal seizure onset; b)Unilateral focal abnormal responses to single pulse electrical stimulation(SPES); and c) Concordance between a) and b). Results: In all MEG patients, at least one virtual MEG electrode generated suitable hypotheses for the location of implantations. The proportion of patients showing focal seizure onset restricted to one hemisphere was similar in control and MEG groups (6/12 vs. 11/12, Fisher’s exact test,p = 0.0686). The proportion of patients showing unilateral responses to SPES was lower in the control than in the MEG group (7/12 vs. 12/12,p = 0.0373). Conclusion: The MEG group showed similar or higher incidence of successful implantations than controls.

Visual and quality outcomes following bilateral implantation of a trifocal intraocular lens

Purpose: To examine visual outcomes following bilateral implantation of the FineVision trifocal intraocular lens (IOL; PhysIOL, Liège, Belgium). Methods: 26 patients undergoing routine cataract surgery were implanted bilaterally with the FineVision Trifocal IOL and followed up post-operatively for 3 months. The FineVision optic features a combination of 2 diffractive structures, resulting in distance, intermediate (+1.75 D add) and near vision (+3.50 D add) zones. Apodization of the optic surface increases far vision dominance with pupil aperture. Data collected at the 3 month visit included uncorrected and corrected distance (CDVA) and near vision; subjective refraction; defocus curve testing (photopic and mesopic); contrast sensitivity (CSV-1000); halometry glare testing and a questionnaire (NAVQ) to gauge near vision function and patient satisfaction. Results: The cohort comprised 15 males and 11 females, aged 52.5–82.4 years (mean 70.6 ± 8.2 years). Mean post-operative UDVA was 0.22 ± 0.14 logMAR, with a mean spherical equivalent refraction of +0.02 ± 0.35 D. Mean CDVA was 0.13 ± 0.10 logMAR monocularly, and 0.09 ± 0.07 logMAR binocularly. Defocus curve testing showed an extensive range of clear vision in both photopic and mesopic conditions. Patients showed high levels of satisfaction with their near vision (mean ± 0.9 ± 0.6, where 0 = completely satisfied, and 4 = completely unsatisfied) and demonstrated good spectacle independence. Conclusion: The FineVision IOL can be considered in patients seeking spectacle dependence following cataract surgery, and provide good patient satisfaction with uncorrected vision.