The experiences of pregnancy in women with SSA/Ro52 autoantibodies

Objective: Congenital heart block may develop in the foetus during pregnancy in SSA/Ro52 autoantibody‐positive women. The aim of this study was to investigate how women with SSA/Ro52 autoantibodies experience their pregnancy in terms of the risk of developing foetal heart block, and in undergoing serial ultrasound Doppler echocardiography to detect early signs of congenital heart block. Methods: Data were collected through individual semi‐structured interviews with SSA/Ro52‐positive women post‐pregnancy (n = 14). The interviews were audio‐taped, transcribed verbatim and analysed according to qualitative content analysis. Results: Three categories emerged from the responses: information, emotional response and support. The information received prior to and during early pregnancy was focused on the need for attending a specialized antenatal clinic, and information on the risk for congenital heart block was scarce or missing. During gestational weeks 18–24, when the ultrasound/Doppler examinations were performed, all women described increased stress. However, the interaction with the caregivers made the women feel more safe and secure. Several women also said that they did not emotionally acknowledge the pregnancy until after gestational week 24. None had been offered psychological support. Conclusion: There is a need for structured information and organized programmes for the surveillance of women who are SSA/Ro52 positive during their pregnancy. Further, offering psychological support to the women and their families to manage the stress and to facilitate the early attachment to the child should be considered. Copyright © 2010 John Wiley & Sons, Ltd.     

结构化教育在1型糖尿病管理中的作用

1 型糖尿病（type 1 diabetes mellitus,T1DM）需要终身依赖外源性胰岛素治疗。从儿童青少年到成年,在不同成 长阶段中,目标血糖以及治疗需求受到多种内在和外在因素的影响。因此在T1DM的终生管理中,为了尽可能达到 血糖控制目标的同时又能避免严重低血糖的发生,是一项非常有挑战性的任务,需要具有良好的自我管理能力。结 构化教育是一种高质量、有计划、分阶段进行的糖尿病自我管理教育项目,是提高患者自我管理能力及改善患者不良 结局的重要环节,亟待实施推广。     

Extraordinary strain hardening by gradient structure

Gradient structures have evolved over millions of years through natural selection and optimization in many biological systems such as bones and plant stems, where the structures change gradually from the surface to interior. The advantage of gradient structures is their maximization of physical and mechanical performance while minimizing material cost. Here we report that the gradient structure in engineering materials such as metals renders a unique extra strain hardening, which leads to high ductility. The grain-size gradient under uniaxial tension induces a macroscopic strain gradient and converts the applied uniaxial stress to multiaxial stresses due to the evolution of incompatible deformation along the gradient depth. Thereby the accumulation and interaction of dislocations are promoted, resulting in an extra strain hardening and an obvious strain hardening rate up-turn. Such extraordinary strain hardening, which is inherent to gradient structures and does not exist in homogeneous materials, provides a hitherto unknown strategy to develop strong and ductile materials by architecting heterogeneous nanostructures.Mankind has much to learn from nature on how to make engineering materials with novel and superior physical and mechanical properties (1, 2). For examples, the clay-polymer multilayers mimicking naturally grown seashells are found to have exceptional mechanical properties (3). Another example is the gradient structure, which exists in many biological systems such as teeth and bamboos. A typical gradient structure exhibits a systematic change in microstructure along the depth on a macroscopic scale. Gradient structures have been evolved and optimized over millions of years to make the biological systems strong and tough to survive nature. They are greatly superior to manmade engineering materials with homogeneous microstructures.Here we report the discovery of a hitherto unknown, to our knowledge, strain hardening mechanism, which is intrinsic to the gradient structure in an engineering material. The gradient structure shows a surprising extra strain hardening along with an up-turn and subsequent good retention of strain hardening rate. Strain hardening is critical for increasing the material ductility (4–6). We also show a superior ductility–strength combination in the gradient structure that is not accessible to conventional homogeneous microstructures.     

99mTc-sestamibi can improve the inferior attenuation of TL-201 myocardial spect imaging

Tl-201 myocardial scintigraphy (Tl study) tends to be attenuated by soft tissues (such as the diaphragm) due to its low energy emission. 99mTc-sestamibi (2-methoxy isobutyl isonitrile) is a relatively new agent with a higher energy emission and this characteristic accounts for the higher quality of 99mTc-sestamibi images. The purpose of this study is to evaluate the ability of 99mTc-sestamibi in alleviating the inferior attenuation of Tl studies. 99mTc-sestamibi SPECT myocardial scintigraphy was performed on 13 patients with inferior wall perfusion defects as determined by Tl study (but with normal coronary artery as evidenced by cardiac catheterization). All patients underwent Tl SPECT study using a standard procedure. Same-day protocol (rest-stress sequence) was used for 99mTc-sestamibi SPECT imaging. All images were analyzed by two independent observers. The results of our study reveal that 99mTc-sestamibi produced better images. The inferior wall perfusion defects in the Tl study were noted in one case only (l/13)in the 99mTc-sestamibi study. Our study suggests that 99mTc-sestamibi can remarkably reduce the inferior attenuation of Tl study.     

Milestones in cardiac ultrasound: echoes from the past History of cardiac ultrasound

Although the antecedents of cardiac ultrasound can be traced back to the 1870s, it was in 1954 that Edler and Hertz published their milestone paper. M-mode echocardiography reached its peak in the early 1970s, when the fibre-optic recorder made the method clinically viable. It was not long before real-time two-dimensional imaging was developed, however, and the invention of pulsed Doppler laid the foundation of duplex scanning. In 1985, colour flow imaging gave a fresh impetus to echocardiography. In parallel with the main developments, intravascular and transoesophageal scanning have gained clinical popularity within the last decade, together with techniques for the display of three-dimensional images. Other innovations include contrast agents, pressure gradient measurement and promising methods for tissue characterisation. It seems that current techniques are safe, but this needs to be kept continuously under review.     

Site-specifically labeled CA19.9-targeted immunoconjugates for the PET,NIRF, and multimodal PET/NIRF imaging of pancreatic cancer

Molecular imaging agents for preoperative positron emission tomography (PET) and near-infrared fluorescent (NIRF)-guided delineation of surgical margins could greatly enhance the diagnosis, staging, and resection of pancreatic cancer. PET and NIRF optical imaging offer complementary clinical applications, enabling the noninvasive whole-body imaging to localize disease and identification of tumor margins during surgery, respectively. We report the development of PET, NIRF, and dual-modal (PET/NIRF) imaging agents, using 5B1, a fully human monoclonal antibody that targets CA19.9, a well-established pancreatic cancer biomarker. Desferrioxamine (DFO) and/or a NIRF dye (FL) were conjugated to the heavy-chain glycans of 5B1, using a robust and reproducible site-specific (ss) labeling methodology to generate three constructs (^ssDFO-5B1, ^ssFL-5B1, and ^ssdual-5B1) in which the immunoreactivity was not affected by the conjugation of either label. Each construct was evaluated in a s.c. xenograft model, using CA19.9-positive (BxPC3) and -negative (MIAPaCa-2) human pancreatic cancer cell lines. Each construct showed exceptional uptake and contrast in antigen-positive tumors with negligible nonspecific uptake in antigen-negative tumors. Additionally, the dual-modal construct was evaluated in an orthotopic murine pancreatic cancer model, using the human pancreatic cancer cell line, Suit-2. The ^ssdual-5B1 demonstrated a remarkable capacity to delineate metastases and to map the sentinel lymph nodes via tandem PET-computed tomography (PET/CT) and NIRF imaging. Fluorescence microscopy, histopathology, and autoradiography were performed on representative sections of excised tumors to visualize the distribution of the constructs within the tumors. These imaging tools have tremendous potential for further preclinical research and for clinical translation.Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer mortality and is expected to surpass both colorectal and breast cancer in total annual deaths by 2030 (1, 2). Surgical resection of the pancreas is the only curative treatment, but the presence of metastases precludes over 80% of patients from resection ab initio (3). The overall 5-y survival rate is ∼5%, and for those who qualify for surgical resection, the 5-y survival rate is only 25% due to the high incidence of undiscovered metastases (4, 5). Further complicating this dire situation, patients with PDAC are regularly misdiagnosed or understaged, confounding treatment strategies and preventing proper enrollment in clinical trials. Many of these problems could be avoided and outcomes improved if adequate clinical tools for diagnosing, staging, and treating PDAC were available.Positron emission tomography (PET) is a promising technological platform for detecting, staging, and monitoring the progression or regression of many solid tumors, including PDAC. Optical imaging is a complementary platform that makes possible the accurate identification of tumor tissue in an intraoperative setting, which was recently demonstrated in human patients with ovarian cancer (6). Currently, the only Food and Drug Administration approved imaging agent for PDAC is 2-deoxy-2-[¹⁸F]-fluoro-D-glucose (FDG). FDG PET imaging relies on increased tumor metabolism relative to nonmalignant cells (Warburg effect) (7). However, FDG has numerous shortcomings when it comes to PDAC, including unreliable detection of small primary lesions (<7 mm) (8) or liver metastases (<1 cm) (9), an inherent inability to discriminate between benign disease (i.e., pancreatitis) and malignancy (10), and decreased tumor avidity for FDG upon chemo- or radiation therapy (11). The development of an arsenal of imaging tools, particularly a dual-modal imaging agent that seamlessly incorporates the advantages of both PET and optical imaging, could definitively improve the outcomes in patients with PDAC.Monoclonal antibodies (mAbs) can provide the necessary specificity, sensitivity, and flexibility for the development of such tools. PET imaging with a radiolabeled mAb (immunoPET) would enhance our ability to noninvasively detect small lesions and slowly growing epithelial cancers (12–14). Near-infrared fluorescent (NIRF) dyes are particularly attractive in intraoperative applications because they show good tissue penetration (up to 1 cm) and low background from autofluorescence. Optical imaging with a NIRF-labeled mAb would allow surgeons to precisely identify tumor margins during resection, ensuring minimal healthy tissue is removed and that no residual tumor tissue is overlooked. Technological advancements in the clinic are now at a stage that allows clinical translation into humans, providing renewed impetus for the preclinical development of tools for NIRF imaging (15, 16).CA19.9 (also known as sialyl Lewis^a) is a ligand for epithelial leukocyte adhesion molecules, and its overexpression is a key event in invasion and metastasis of many cancers, including PDAC (17). CA19.9 is an attractive target for imaging of PDAC because it is the most highly expressed tumor antigen (18, 19) and is minimally expressed in healthy pancreas tissue (20). In fact, the diagnosis of PDAC is often aided by the detection of elevated levels of circulating CA19.9 (21, 22). The promise of CA19.9 as a biomarker of PDAC led to the initiation of several antibody discovery programs (14, 20, 23) and the development of the fully human mAb 5B1, which binds an extracellular epitope of CA19.9 with low nanomolar affinity (23). Recently, we demonstrated that CA19.9 could serve as a target for immunoPET imaging of PDAC, even in the context of circulating antigen (24). Based on those results, we set out to improve and expand upon the usefulness of 5B1 in the context of PDAC imaging.The canonical methodology for the development of mAbs for PET and/or optical imaging suffers from several shortcomings that are a consequence of the indiscriminate conjugation of chelators or dyes to nucleophilic amino acids. Those shortcomings include the loss of immunoreactivity due to conjugation at the antigen-binding region, random conjugation that leads to poorly defined constructs, and an intrinsic lack of reproducibility, as well as laborious, costly optimization of each novel construct. The combination of glycan engineering and bioorthogonal “click” chemistry has proved a successful strategy for conjugating molecules distal to the antigen-binding region of mAbs in a manner that is highly specific and reproducible, circumventing the aforementioned problems (25, 26). Specifically, using a site-specific conjugation strategy for affixing chelator and/or dye molecules via the heavy chain glycans leads to well-defined, robust immunoconjugates in a highly reproducible manner that requires minimal optimization and results in a minimal loss of immunoreactivity. Furthermore, conjugation via the heavy chain glycans offers an exceptional opportunity to construct site-specific, dual-modal immunoconjugates, which are otherwise challenging to develop using traditional conjugation methodology.Herein, we describe the development of three distinct immunoconjugates that were site-specifically conjugated with DFO for radiolabeling with ⁸⁹Zr and PET imaging, a NIRF dye for optical imaging, or a dual-labeled construct with both DFO and NIRF dye combining the advantages of PET and NIRF into a single construct. Using the site-specific, bioorthogonal conjugation strategy produced well-defined constructs that retained high levels of immunoreactivity compared with their nonspecifically labeled counterparts. The dual-labeled 5B1 construct, in particular, showed excellent uptake in murine models of PDAC, including delineation of small metastases and dissemination of antigen to sentinel lymph nodes in an orthotopic model.     

PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains

Spatial compartmentalization of signaling pathway components generally defines the specificity and enhances the efficiency of signal transduction. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be compartmentalized within plasma membrane microdomains; however, the underlying mechanisms and functional impact of this compartmentalization are not well understood. Here, we show that phosphoinositide-dependent kinase 1 is activated in membrane rafts in response to growth factors, whereas the negative regulator of the pathway, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is primarily localized in nonraft regions. Alteration of this compartmentalization, either by genetic targeting or ceramide-induced recruitment of PTEN to rafts, abolishes the activity of the entire pathway. These findings reveal critical steps in raft-mediated PI3K/Akt activation and demonstrate the essential role of membrane microdomain compartmentalization in enabling PI3K/Akt signaling. They further suggest that dysregulation of this compartmentalization may underlie pathological complications such as insulin resistance.