Investigation of retinoic acid function during embryonic brain development using retinaldehyde‐rescued Rdh10 knockout mice

Background: Retinoic acid (RA) signaling controls patterning and neuronal differentiation within the hindbrain, but forebrain RA function remains controversial. RA is produced from metabolism of retinol to retinaldehyde by retinol dehydrogenase (RDH), followed by metabolism of retinaldehyde to RA by retinaldehyde dehydrogenase (RALDH). Previous studies on Raldh2?/? and Raldh3?/? mice demonstrated an RA requirement for γ‐aminobutyric acid (GABA)ergic and dopaminergic differentiation in forebrain basal ganglia, but no RA requirement was observed during early forebrain patterning or subsequent forebrain cortical expansion. However, other studies suggested that RA controls forebrain patterning, and analysis of ethylnitrosourea‐induced Rdh10 mutants suggested that RA synthesized in the meninges stimulates forebrain cortical expansion. Results: We generated Rdh10?/? mouse embryos that lack RA activity early in the head and later in the meninges. We observed defects in hindbrain patterning and eye RA signaling, but early forebrain patterning was unaffected. Retinaldehyde treatment of Rdh10?/? embryos from E7–E9 rescues a cranial skeletal defect, resulting in E14.5 embryos lacking meningeal RA activity but maintaining normal forebrain shape and cortical expansion. Conclusions: Rdh10?/? embryos demonstrate that RA controls hindbrain but not early forebrain patterning, while studies on retinaldehyde‐rescued Rdh10?/? embryos show that meningeal RA synthesis is unnecessary to stimulate forebrain cortical expansion. Developmental Dynamics 242:1056–1065, 2013. © 2013 Wiley Periodicals, Inc.     

Elastic distortion determining conduction in BiFeO3 phase boundaries

It is now well-established that boundaries separating tetragonal-like (T) and rhombohedral-like (R) phases in BiFeO₃ thin films can show enhanced electrical conductivity. However, the origin of this conductivity remains elusive. Here, we study mixed-phase BiFeO₃ thin films, where local populations of T and R can be readily altered using stress and electric fields. We observe that phase boundary electrical conductivity in regions which have undergone stress-writing is significantly greater than in the virgin microstructure. We use high-end electron microscopy techniques to identify key differences between the R–T boundaries present in stress-written and as-grown microstructures, to gain a better understanding of the mechanism responsible for electrical conduction. We find that point defects (and associated mixed valence states) are present in both electrically conducting and non-conducting regions; crucially, in both cases, the spatial distribution of defects is relatively homogeneous: there is no evidence of phase boundary defect aggregation. Atomic resolution imaging reveals that the only significant difference between non-conducting and conducting boundaries is the elastic distortion evident – detailed analysis of localised crystallography shows that the strain accommodation across the R–T boundaries is much more extensive in stress-written than in as-grown microstructures; this has a substantial effect on the straightening of local bonds within regions seen to electrically conduct. This work therefore offers distinct evidence that the elastic distortion is more important than point defect accumulation in determining the phase boundary conduction properties in mixed-phase BiFeO₃.

The localized crystallography of conducting and non-conducting phase boundaries in mixed-phase BiFeO₃ is directly compared using scanning transmission electron microscopy techniques.

The complexity of electrical conductivity in domain walls in BiFeO₃ (and in ferroics in general) is as multifaceted as ever. Various influences such as point defect accumulation, octahedral rotations, magnetic interactions and electrostatic discontinuities are thought to be possible mechanisms at play,^1–8 either alone or in combination. The research area of domain wall conductivity is currently flourishing and the view that domain walls offer exciting prospects in terms of engineering systems in which the domain walls act as distinct identities to the domains which they separate is now widely accepted. We believe that it is pertinent timing to address a lack of experimental investigations providing meaningful direct comparison of the localised crystallography and defect structure responsible for observed enhanced electrical conductivity. This study is stimulated by the interesting discoveries of conductive phase boundaries, specifically, in mixed-phase BiFeO₃.^9,10 By tuning the local populations of the tetragonal-like (T) and rhombohedral-like (R) phases in BiFeO₃ thin films via electric and stress fields, we demonstrate that electrical conductivity along phase boundaries is significantly greater after stress-writing. We probe the key crystallographic differences between the R–T boundaries created via stress, compared to those already present in the as-grown microstructures, to disentangle the mechanism determining electrical conduction in mixed-phase BiFeO₃.The growth of BiFeO₃ on substrates enforcing a large in-plane compressive strain drives the formation of monoclinic phases that are approximately rhombohedral (R) and tetragonal (T). Similar to materials such as PbZr_0.53Ti_0.47O₃ that straddle a morphotropic phase boundary, highly strained BiFeO₃ can readily undergo phase transitions between the R and T phases (and vice versa). The high-strain T phase exhibits a tetragonal-like symmetry (almost P4mm) with a c/a ratio of ∼1.2; the Fe displacement towards one of the apical oxygens along [001]_pc results in fivefold oxygen coordinated Fe, and an enhanced polarisation roughly 1.5 times that of the bulk single crystal.^7,11 The R phase, on the other hand, resembles the rhombohedral bulk phase (almost R3c), where the Fe is octahedrally coordinated, with a ferroelectric distortion along the pseudocubic [111]_pc axis, and antiferrodistortive rotations of the FeO₆ octahedra around [111]_pc occur. The crystal structure and misfit strain associated with the native (as-grown) R and T phases is reported elsewhere, both theoretically^12–15 and experimentally,^6,7,16–21 making it well-known that the ferroelectric and the antiferrodistortive degrees of freedom in mixed-phase BiFeO₃ set it apart from other typical perovskites. Notably, despite the ample evidence provided on phase reversal and characterisation of the as-grown phases, most of the literature (especially regarding electric field cycling of the mixed-phase state) has been primarily concerned with X-ray diffraction (XRD) i.e. global measurements that will not necessarily pick up on the more subtle, atomic-scale aspects of structure local to the phase boundaries. The importance of the study described herein resides in the uniqueness of creating microstructures such that both the as-grown and stress-induced R–T phase boundaries can be included within one single cross-sectional transmission electron microscopy (TEM) lamella; this gives the best possible scenario to allow meaningful direct comparison of the localised crystallography and defect structure responsible for the observed enhanced electrical conductivity found at stress-induced phase boundaries.     

Return to sporting activity after Birmingham hip resurfacing arthroplasty: Mid term results

Background:

Hip resurfacing arthroplasty (HRA) is primarily indicated for young, active patients with disabling coxarthrosis who wish to remain active and return to sports after surgery. Relatively few prospective studies have assessed return to sporting activity and impact of gender and age on this.

Materials and Methods:

Seventy-nine consecutive patients treated with HRA were included. Patients were reviewed clinically and radiologically. Function was assessed using the modified University of California Los Angeles (UCLA) activity score. The Oxford, Harris and WOMAC hip scores were calculated.

Results:

Average age at the time of surgery was 54.9 years (range 34.5–73.6 years). Average preoperative and postoperative UCLA scores were 4 and 7.6 respectively. Patients were involved in 2 (0–4) sporting activities preoperatively and 2 (0–5) postoperatively. Preoperative and postoperative Oxford Hip Scores, Harris Hip Score and WOMAC scores were 40, 46 and 51 and 16, 94 and 3 respectively (P < 0.0001). Patients returned to sports at an average of 3 months postoperatively.

Conclusion:

Patients were able to return to sports by 3 months and perform the same number of activities at preoperative intensity. Activity levels are maintained up to the medium term with few complications.     

Systematic review of enhanced recovery after gastro-oesophageal cancer surgery

Introduction

Fast track methodology or enhanced recovery schemes have gained increasing popularity in perioperative care. While evidence is strong for colorectal surgery, its importance in gastric and oesophageal surgery has yet to be established. This article reviews the evidence of enhanced recovery schemes on outcome for this type of surgery.

Methods

A systematic literature search was conducted up to March 2014. Studies were retrieved and analysed using predetermined criteria.

Results

From 34 articles reviewed, 18 eligible studies were identified: 7 on gastric and 11 on oesophageal resection. Three randomised controlled trials, five case-controlled studies and ten case series were identified. The reported protocols included changes to each stage of the patient journey from pre to postoperative care. The specific focus following oesophageal resections was on early mobilisation, a reduction in intensive care unit stay, early drain removal and early (or no) contrast swallow studies. Following gastric resections, the emphasis was on reducing epidural anaesthesia along with re-establishing oral intake in the first three postoperative days and early removal of nasogastric tubes.In the papers reviewed, mortality rates following fast track surgery were 0.8% (9/1,075) for oesophageal resection and 0% (0/329) for gastric resection. The reported morbidity rate was 16.5% (54/329) following gastric resection and 38.6% (396/1,075) following oesophageal resection. Length of stay was reduced in both groups compared with conventional recovery groups in comparative studies.

Conclusions

The evidence for enhanced recovery schemes following gastric and oesophageal resection is weak, with only three (low volume) published randomised controlled trials. However, the enhanced recovery approach appears safe and may be associated with a reduction in length of stay.     

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design

Heart failure (HF) affects >5 million patients in the United States, and its prevalence is increasing every year. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors and β-blockers reduce hospitalizations and mortality rates in patients with HF, these lifesaving therapies continue to be underused. Several studies in a variety of clinical settings have documented that a significant proportion of eligible patients with HF are not receiving treatment with these guideline-recommended, evidence-based therapies. In patients hospitalized with HF, who are at particularly high risk for re-hospitalization and death, the initiation of β-blockers is often delayed because of concern that early initiation of these agents may exacerbate HF. Recent studies suggest that β-blockers can be safely and effectively initiated in patients with HF before hospital discharge and that clinical outcomes are improved. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial demonstrated that pre-discharge initiation of carvedilol was associated with a higher rate of β-blocker use after hospital discharge, with no increase in hospital length of stay. In addition, there was no increase in the risk of worsening of HF. Studies of hospital-based management systems that rely on early (pre-discharge) initiation of evidence-based therapies for patients with cardiovascular disease have also found increases in post-discharge use of therapy and a reduction in the rates of mortality and hospitalization. On the basis of these pivotal studies, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) program is designed to improve medical care and education of hospitalized patients with HF and accelerate the initiation of evidence-based HF guideline recommended therapies by administering them before hospital discharge. A registry component, planned as the most comprehensive database of the hospitalized HF population focusing on admission to discharge and 60- to 90-day follow-up, is designed to evaluate the demographic, pathophysiologic, clinical, treatment, and outcome characteristics of patients hospitalized with HF. The ultimate aim of this program is to improve the standard of HF care in the hospital and outpatient settings and increase the use of evidence-based therapeutic strategies to save lives.     

Cardiac risk underestimation in urban,black women

BACKGROUND: Black women have a disproportionately higher incidence of cardiovascular disease mortality than other groups and the reason for this health disparity is incompletely understood. Underestimation of personal cardiac risk may play a role. OBJECTIVE: We investigated the personal characteristics associated with underestimating cardiovascular disease in black women. DESIGN, SETTING, PARTICIPANTS: Trained surveyors interviewed 128 black women during the baseline evaluation for a randomized controlled trial in an urban, academic continuity clinic affiliated with a public hospital system. They provided information on the presence of cardiac risk factors and demographic and psychosocial characteristics. These self-report data were supplemented with medical record abstraction for weight. MEASUREMENTS AND MAIN RESULTS: The main outcome measure was the accurate perception of cardiac risk. Objective risk was determined by a simple count of major cardiac risk factors and perceived risk by respondent's answer to a survey question about personal cardiac risk. The burden of cardiac risk factors was high in this population: 77% were obese; 72% had hypertension; 48% had high cholesterol; 49% had a family history of heart disease; 31% had diabetes, and 22% currently used tobacco. Seventy-nine percent had 3 or more cardiac risk factors. Among those with 3 or more risk factors ("high risk"), 63% did not perceive themselves to be at risk for heart disease. Among all patients, objective and perceived cardiac risk was poorly correlated (kappa=0.026). In a multivariable model, increased perceived personal stress and lower income were significant correlates of underestimating cardiac risk. CONCLUSIONS: Urban, disadvantaged black women in this study had many cardiac risk factors, yet routinely underestimated their risk of heart disease. We found that the strongest correlates of underestimation were perceived stress and lower personal income.     

Defining the domains of type I collagen involved in heparin- binding and endothelial tube formation

Cell surface heparan sulfate proteoglycan (HSPG) interactions with type I collagen may be a ubiquitous cell adhesion mechanism. However, the HSPG binding sites on type I collagen are unknown. Previously we mapped heparin binding to the vicinity of the type I collagen N terminus by electron microscopy. The present study has identified type I collagen sequences used for heparin binding and endothelial cell–collagen interactions. Using affinity coelectrophoresis, we found heparin to bind as follows: to type I collagen with high affinity (K_d ≈ 150 nM); triple-helical peptides (THPs) including the basic N-terminal sequence α1(I)87–92, KGHRGF, with intermediate affinities (K_d ≈ 2 μM); and THPs including other collagenous sequences, or single-stranded sequences, negligibly (K_d 10 μM). Thus, heparin–type I collagen binding likely relies on an N-terminal basic triple-helical domain represented once within each monomer, and at multiple sites within fibrils. We next defined the features of type I collagen necessary for angiogenesis in a system in which type I collagen and heparin rapidly induce endothelial tube formation in vitro. When peptides, denatured or monomeric type I collagen, or type V collagen was substituted for type I collagen, no tubes formed. However, when peptides and type I collagen were tested together, only the most heparin-avid THPs inhibited tube formation, likely by influencing cell interactions with collagen–heparin complexes. Thus, induction of endothelial tube morphogenesis by type I collagen may depend upon its triple-helical and fibrillar conformations and on the N-terminal heparin-binding site identified here.     

Autoantibodies to phosphatidylethanolamine (PE) recognize a kininogen- PE complex

Demonstration of autoimmune antiphospholipid antibodies (aPA) to negatively charged phospholipids (PL) in an enzyme-linked immunosorbent assay (ELISA) requires the presence of certain phospholipid-binding plasma proteins, eg, beta 2-glycoprotein I. We found a requirement for plasma against the electrically neutral or zwitterionic phospholipid, phosphatidylethanolamine (PE). Two of these PE-binding plasma proteins were identified as high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). We studied anti-PE antibody (aPE) seropositive plasma from 13 patients with SLE and/or recurrent spontaneous abortions by using partially purified kininogens and kininogen binding proteins from adult bovine serum isolated by carboxymethyl (CM)-papain affinity chromatography. Eleven of 13 sera recognized a kininogen-PE complex and/or a kininogen-binding protein- kininogen-PE complex. Some aPE-positive patient sera were shown to recognize highly purified HMWK and LMWK by ELISA only when the kininogens were presented on a PE substrate. These aPE sera did not recognize PE, HMWK, or LMWK when they were presented independently as the sole antigens on the ELISA plates. Other aPE-positive sera that did not react with PE-bound HMWK or LMWK reacted with the CM-papain column eluate when it was bound to PE, which suggests that these aPE recognize factor XI or prekallikrein, which normally bind to HMWK. The aPE ELISA reactivity of two patient sera were inhibited by preincubation of the CM-papain column eluate in the ELISA plate. These data show that most aPE are not specific for PE but require the presence of certain PL- binding plasma proteins that are kininogens or proteins in complex with kininogens. Our studies indicate that aPE bind to different plasma proteins than those implicated in anionic PL, aPA ELISA reactivity.