Antiphosphatidylethanolamine antibodies are associated with an increased odds ratio for thrombosis. A multicenter study with the participation of the European Forum on antiphospholipid antibodies

A multicenter study was set up to evaluate the prevalence, clinical and biological significance of antiphosphatidylethanolamine antibodies (aPE) in thrombotic patients with or without the main known clinical and biological risk factors for thrombosis. APE and antibodies, defined as the laboratory criteria of antiphospholipid syndrome (APS) -lupus anticoagulant, anticardiolipin and anti-beta(2)-GPI antibodies were measured in 270 patients with thrombosis (234 venous and 37 arterial) and 236 matched controls. APE were found in 15% of thrombotic patients compared to 3% of controls (p < 0.001) with no predominant isotype, no association with the main known clinical or biological risk factors for thrombosis neither with a type of thrombosis, arterial or venous. In a multivariate logistic regression analysis of antibodies, aPE showed the highest association with thrombosis (odds ratio [OR]: 4.2, p < 0.001). Moreover, using a multivariate analysis in a case-control subgroup study on 158 patients, IgGaPE were found to be significantly associated with venous thrombosis (OR:6;p = 0.005). Interestingly, 25 of the 40 aPE-positive patients (63%) were negative for the APS laboratory criteria. Most of them (21/25) had venous thrombosis, recurrent in ten of them. Four patients also suffered from early or late miscarriages. Our results underline the strength of the association between the presence of aPE and thrombosis and suggest their measurement in thrombotic patients, especially when lupus anticoagulant, anticardiolipin or anti-beta(2)-GPI antibodies are absent.     

PTEN Contributes to Profound PI3K/Akt Signaling Pathway Deregulation in Dystrophin-Deficient Dog Muscle

Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy, and although the genetic basis of this disease is well defined, the overall mechanisms that define its pathogenesis remain obscure. Alterations in individual signaling pathways have been described, but little information is available regarding their putative implications in Duchenne muscular dystrophy pathogenesis. Here, we studied the status of various major signaling pathways in the Golden Retriever muscular dystrophy dog that specifically reproduces the full spectrum of human pathology. Using antibody arrays, we found that Akt1, glycogen synthase kinase-3β (GSK3β), 70-kDa ribosomal protein S6 kinase (p70S6K), extracellular signal-regulated kinases 1/2, and p38δ and p38γ kinases all exhibited decreased phosphorylation in muscle from a 4-month-old animal with Golden Retriever muscular dystrophy, revealing a deep alteration of the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase pathways. Immunohistochemistry analysis revealed the presence of muscle fibers exhibiting a cytosolic accumulation of Akt1, GSK3β, and phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN), an enzyme counteracting PI3K-mediated Akt activation. Enzymatic assays established that these alterations in phosphorylation and expression levels were associated with decreased Akt and increased GSK3β and PTEN activities. PTEN/GSK3β-positive fibers were also observed in muscle sections from 3- and 36-month-old animals, indicating long-term PI3K/Akt pathway alteration. Collectively, our data suggest that increased PTEN expression and activity play a central role in PI3K/Akt/GSK3β and p70S6K pathway modulation, which could exacerbate the consequences of dystrophin deficiency.Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder that affects 1 newborn boy in 3500. This recessive disease is caused by mutations in the dystrophin gene, resulting in total lack of the protein,^1,2,3 and is characterized by severe degeneration of muscle fibers, progressive paralysis, and death. Dystrophin is located under the sarcolemma of muscle fibers, and is associated with a complex comprising several integral, peripheral membrane and cytoplasmic proteins: the dystrophin-glycoprotein complex (DGC).^4,5,6,7 By providing a strong physical link between the cytoskeleton network and the extracellular matrix, the DGC ensures the integrity of skeletal muscle fibers. In the absence of dystrophin, the complex is destabilized and this integrity is lost.^5,8 However, the impaired structural role of the DGC alone may not be sufficient to account for the massive degenerative process observed in DMD muscles. Numerous observations suggest that signaling pathway alterations may also participate in DMD pathogenesis.Dystrophin and various DGC proteins have been demonstrated to interact with a number of signaling proteins, including growth factor receptor-bound protein 2,⁹ neuronal nitric oxide synthase,¹⁰ calmodulin,¹¹ focal adhesion kinase,¹² and caveolin-3.^13,14,15 Moreover, studies of the X chromosome-linked muscular dystrophy (mdx) mouse¹⁶ revealed modulations in mitogen-activated protein kinase (MAPK) signaling cascades, as dystrophic animals exhibited increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2)^17,18 and c-jun N-terminal kinases 1 and 2 (JNK1/2),^19,20,21 and decreased phosphorylation of p38.¹⁸ Also, the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway has been shown to be affected in the mdx mouse, with increased synthesis and phosphorylation of Akt.^22,23In addition to the limited information related to the origin of signal perturbations in dystrophic muscle, almost no information is available regarding signaling pathways in clinically relevant animal models or human tissue samples.²³ It is noteworthy that the mdx mouse model of DMD is characterized by successive degeneration/regeneration processes, but does not exhibit the progressive muscle wasting and accumulation of connective tissue observed during the development of the human disease.^24,25,26 The Golden Retriever muscular dystrophy (GRMD) dog, characterized by rapidly progressive clinical dysfunction, severe muscle weakness, and abundant fiber necrosis, displays a disease progression that is far more similar to human DMD.^27,28In this study, we used antibody arrays to assess the global phosphorylation status of key proteins of the PI3K/Akt and MAPK signaling pathways in skeletal muscles of 4-month-old healthy and GRMD dogs. Our data indicated that Akt1, glycogen synthase kinase-3β (GSK3β) and p70S6K, as well as ERK1/2 and p38δ and γ kinases all displayed a decreased phosphorylation level in GRMD muscle. Western immunoblot, immunohistochemistry analysis, and enzymatic assays allowed us to confirm these results and demonstrated that they were associated with a reduction in Akt activity and with enhanced GSK3β expression and activity. Analysis of key enzymes involved in Akt regulation revealed that phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN) was present at a much higher level and was more active in GRMD muscle. Moreover, immunohistochemistry analysis showed that all of the GSK3β-positive fibers observed in GRMD muscle sections exhibited a strong cytosolic labeling of PTEN, suggesting that the accumulation of the phosphatase could play a central role in PI3K/Akt signaling pathway deregulation. The observation of PTEN/GSK3β-positive fibers in muscle sections from 3- and 36-month-old GRMD dogs further demonstrated that both the early and late stages of the disease share deregulation of the pathway. Collectively, our findings highly suggest that alterations in PTEN exist in GRMD muscle, which leads to long-term and deep modulation of the PI3K/Akt signaling pathway.     

Effects of phonological and semantic cuing on encoding and retrieval processes in adolescent psychosis

The aim of this study was to investigate the effects of cuing on encoding and retrieval processes in adolescent psychosis. Patients and controls were instructed to learn word lists under three conditions: no cue, phonological cue, and semantic cue. Memory performance was measured with free and cued recalls. In free recall, both groups showed higher performance with semantic than with phonological encoding cues, but patients had no advantage from semantic cuing relative to no cue, contrary to controls. Patients' performance improved from free to cued recall, but this was not sufficient to normalize their performance. Impaired strategic processes may lead to encoding and retrieval difficulties in patients.     

Utilisation of pharmacokinetic-pharmacodynamic modelling and simulation in regulatory decision-making.

Modelling and simulation (M&S) play an important role in regulatory decision-making that affects both the public and industry. Technological advances in various fields related to drug development call for more focus on ways to optimise current drug development practices. Recognition of the potential of M&S by regulatory agencies inevitably has a substantial impact on drug development. The objective of the current review is to present the various regulatory initiatives for application of M&S to clinical drug development. The relevant parts of the various recommendations issued by the US Food and Drug Administration (FDA), via guidance documents and advisory committee meeting proceedings, are highlighted. Application of M&S to a variety of activities, such as integrating pharmacokinetic-pharmacodynamic knowledge across a new drug application and designing efficient trials, is discussed. Some of the challenges that pharmaceutical institutions currently face when implementing M&S projects, such as team structure, communication with regulators, training and time constraints, are also presented, and solutions are proposed.     

Nd-YAG laser photocoagulation of canine myocardium with the transparent contact probe

Laser photocoagulation of myocardium is an alternative to surgical resection in the treatment of drug resistant ventricular tachycardia. In certain areas, of the heart, however, bare fibre delivery of laser energy involves a risk of unintentional damage to nearby structures. The purpose of the study was to determine whether Nd-YAG laser irradiation, delivered with the transparent contact probe, would produce adequate laser photocoagulation of the canine myocardium in comparison to bare fibre delivery of the laser energy. In nine mongrel dogs, continuous wave Nd-YAG laser irradiation with and without a transparent contact probe was directed at the epicardium. Pulse power was 10, 15 and 20 W, pulse duration 5, 7 and 10 s, and spot size was 1 mm. A total of 178 lesions were analyzed microscopically. After a 200 J pulse energy delivered by the contact probe, the lesion depth was 4.9±0.5 mm (mean±s.d.), which is usually adequate to ablate arrhythmia sites. Bare fibre delivery of laser energy did not produce deeper lesions. There was no difference between the bare fibre and the transparent probe in the occurrence of major arrhythmias (4/86 bare fibre, 3/92 transparent probe). We conclude that the transparent contact probe allows safe and effective laser irradiation of sites of origin of ventricular arrhythmias.     

A conceptual framework contributing to nursing administration and research

The health care system has undergone major changes in the last decade. With greater acuity and complexity of illness, the adoption of innovative technologies and the shortage of health care personnel, the coordination and integration of health care services has become increasingly demanding for administrators. Growing dissatisfaction and concerns about safety issues are being expressed by the users of care who need to navigate through an increasingly complex system and by health care personnel who feel less efficient within the organization. Nursing administrators have a responsibility to address these issues but there is little scientific evidence to guide their actions. There are also few comprehensive models highlighting the main components of nursing administration - models that could guide nursing administration research. This paper presents a conceptual framework for nursing administration and research that links patient health care needs, nursing resources and the nursing care processes to the context of the health care system, and the social, political and cultural environments of care. A selected review of the oncology and cancer care literature is presented to demonstrate how this framework can organize existing knowledge about these concepts in the context of cancer care.     

Using Appreciative Inquiry to promote evidence-based practice in nursing: the glass is more than half full

It is now understood that successful implementation of evidence-based practice (EBP) requires a focus on the context of the care setting. While the focal point of many reports is the limitations and barriers, this paper proposes a new approach to "making EBP happen." Appreciative Inquiry (AI), both a method of social research and an organizational development or change intervention, is a novel means to elicit enthusiasm and support for EBP in nursing. Readers will be introduced to the theoretical foundations and assumptions as well as the "4-D Model" of AI. It is proposed that the advanced practice nurse (APN) is in a key position to introduce and support this intervention in healthcare organizations to promote the successful implementation of EBP.     

A Single Intravenous sTNFR-Fc Administration at the Time of Reperfusion Limits Infarct Size—Implications in Reperfusion Strategies in Man

Background  Reperfusion of the ischemic myocardium is associated with increased inflammatory processes that can exert deleterious effects and therefore contribute to cardiac dysfunction. The aim of the present study was to verify whether the administration of sTNFR-Fc, a scavenger of the pro-inflammatory cytokine TNF-α, at the time of reperfusion would protect against myocardial infarction and reduce the severity of early mechanical dysfunction. Methods  Male Wistar rats were subjected to 60 min coronary occlusion followed by reperfusion. A bolus of sTNFR-Fc (10 μg/kg, i.v.) (MI + sTNFR-Fc group) or a placebo (MI group) was injected prior to reperfusion. Cardiac geometry was assessed by echocardiography 1, 3 and 7 days after reperfusion. Eight days after reperfusion, left ventricular (LV) function was evaluated under basal conditions and during an experimental challenge of volume overload. Finally, infarct size was measured after euthanasia. Results  sTNFR-Fc administration markedly reduced infarct size (P < 0.01) and decreased LV dilation as assessed by the echocardiographic measurement of the LV end diastolic area, 7 days post-MI (P < 0.01). Moreover, LV end-diastolic pressure was significantly preserved by sTNFR-Fc 1 week after myocardial infarction, under basal conditions (P < 0.05) as well as during cardiac overload (P < 0.05). Conclusion  A single administration of sTNFR-Fc at the time of reperfusion after myocardial infarction is able to limit infarct size and to reduce early LV diastolic dysfunction in rats. These findings suggest that intravenous neutralization of TNF-α during surgical cardiac reperfusion might improve the outcome of myocardial infarction in humans.