Speaking the bitter truth: The role of the creative imagination in the process of healing

This chapter is concerned with the complexity and difficulty of truth telling as it is played out in two graphic novels: Stitches: A Memoir (Small 2009) and Why We Broke Up (Handler & Kalman, 2011). These texts establish a link between creative imagination and pain as the central protagonists come to see the therapeutic value of literature and film in helping them understand the complex emotional worlds they inhabit and the bitter truths about love and relationships. The discussion examines how these texts privilege a particular kind of independent subjectivity through aesthetic creation and appropriation. It also considers how speaking and silence are co-present elements in gender relations and each has its part to play in the double process of suffering and healing.

Bees at war: Interspecific battles and nest usurpation in stingless bees

We provide the first evidence for interspecific warfare in bees, a spectacular natural phenomenon that involves a series of aerial battles and leads to thousands of fatalities from both attacking and defending colonies. Molecular analysis of fights at a hive of the Australian stingless bee Tetragonula carbonaria revealed that the attack was launched by a related species, Tetragonula hockingsi, which has only recently extended its habitat into southeastern Queensland. Following a succession of attacks by the same T. hockingsi colony over a 4-month period, the defending T. carbonaria colony was defeated and the hive usurped, with the invading colony installing a new queen. We complemented our direct observations with a 5-year study of more than 260 Tetragonula hives and found interspecific hive changes, which were likely to be usurpation events, occurring in 46 hives over this period. We discuss how fighting swarms and hive usurpation fit with theoretical predictions on the evolution of fatal fighting and highlight the many unexplained features of these battles that warrant further study.

Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition

The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is one of the most frequently activated signaling pathways in prostate cancer cells, and loss of the tumor suppressor PTEN and amplification of PIK3CA are the two most commonly detected mechanisms for the activation of these pathways. Aberrant activation of PI3K/Akt/mTOR has been implicated not only in the survival and metastasis of prostate cancer cells but also in the development of drug resistance. As such, selective inactivation of this pathway may provide opportunities to attack prostate cancer from all fronts. However, while preclinical studies examining specific inhibitors of PI3K or mTOR have yielded promising results, the evidence from clinical trials is less convincing. Emerging evidence from the analyses of some solid tumors suggests that a class of dual PI3K/mTOR inhibitors, which bind to and inactivate both PI3K and mTOR, may achieve better anti-cancer outcomes. In this review, we will summarize the mechanisms of action of these inhibitors, their effectiveness when used alone or in combination with other chemotherapeutic compounds, and their potential to serve as the next generation therapies for prostate cancer patients, particularly those who are resistant to the frontline chemotherapeutic drugs.

A strong lightweight authentication protocol for low-cost RFID systems

RFID is an important technology that can be used to create the ubiquitous society. But an RFID system uses open radio frequency signal to transfer information and this leads to pose many serious threats to its privacy and security. In general, the computing and storage resources in an RFID tag are very limited and this makes it difficult to solve its secure and private problems, especially for low-cost RFID tags. In order to ensure the security and privacy of low-cost RFID systems we propose a lightweight authentication protocol based on Hash function. This protocol can ensure forward security and prevent information leakage, location tracing, eavesdropping, replay attack and spoofing. This protocol completes the strong authentication of the reader to the tag by twice authenticating and it only transfers part information of the encrypted tag’s identifier for each session so it is difficult for an adversary to intercept the whole identifier of a tag. This protocol is simple and it takes less computing and storage resources, it is very suitable to some low-cost RFID systems.

A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis following failed epithelial repair. Mesenchymal stromal cells (MSC), a key component of the stem cell niche in bone marrow and possibly other organs including lung, have been shown to enhance epithelial repair and are effective in preclinical models of inflammation-induced pulmonary fibrosis, but may be profibrotic in some circumstances. METHODS: In this single centre, non-randomized, dose escalation phase 1b trial, patients with moderately severe IPF (diffusing capacity for carbon monoxide (DLCO ) ≥ 25% and forced vital capacity (FVC) ≥ 50%) received either 1 × 10(6) (n = 4) or 2 × 10(6) (n = 4) unrelated-donor, placenta-derived MSC/kg via a peripheral vein and were followed for 6 months with lung function (FVC and DLCO ), 6-min walk distance (6MWD) and computed tomography (CT) chest. RESULTS: Eight patients (4 female, aged 63.5 (57-75) years) with median (interquartile range) FVC 60 (52.5-74.5)% and DLCO 34.5 (29.5-40)% predicted were treated. Both dose schedules were well tolerated with only minor and transient acute adverse effects. MSC infusion was associated with a transient (1% (0-2%)) fall in SaO2 after 15 min, but no changes in haemodynamics. At 6 months FVC, DLCO , 6MWD and CT fibrosis score were unchanged compared with baseline. There was no evidence of worsening fibrosis. CONCLUSIONS: Intravenous MSC administration is feasible and has a good short-term safety profile in patients with moderately severe IPF.

Improved linear cryptanalysis of reduced-round SIMON-32 and SIMON-48

In this paper we analyse two variants of SIMON family of light-weight block ciphers against variants of linear cryptanalysis and present the best linear cryptanalytic results on these variants of reduced-round SIMON to date. We propose a time-memory trade-off method that finds differential/linear trails for any permutation allowing low Hamming weight differential/linear trails. Our method combines low Hamming weight trails found by the correlation matrix representing the target permutation with heavy Hamming weight trails found using a Mixed Integer Programming model representing the target differential/linear trail. Our method enables us to find a 17-round linear approximation for SIMON-48 which is the best current linear approximation for SIMON-48. Using only the correlation matrix method, we are able to find a 14-round linear approximation for SIMON-32 which is also the current best linear approximation for SIMON-32. The presented linear approximations allow us to mount a 23-round key recovery attack on SIMON-32 and a 24-round Key recovery attack on SIMON-48/96 which are the current best results on SIMON-32 and SIMON-48. In addition we have an attack on 24 rounds of SIMON-32 with marginal complexity.

Glycodelin A, an immunomodulatory protein in the endometrium, inhibits proliferation and induces apoptosis in monocytic cells

Glycodelin A (GdA), is a lipocalin with an immunomodulatory role, secreted by the endometrium under progesterone regulation and proposed to play a role in protecting the fetus from maternal immune attack. Glycodelin A has an inhibitory effect on the proliferation of T cells and B cells and also on the activity of natural killer cells. We have earlier demonstrated that the inhibitory effect of glycodelin A on T cell proliferation is due to apoptosis induced in these cells through the caspase-dependent intrinsic mitochondrial pathway. Studies reported until now have shown that glycodelin modulates the adaptive immune responses. We, therefore, decided to look at its effect, if any, on the innate immune system. The effect of glycodelin on monocytes was studied using human monocytic cell lines, THP1 and U937, and primary human monocytes as model systems. We demonstrated that glycodelin inhibited the proliferation of THP1 and U937 and induced apoptosis in these cells as well as in primary monocytes. We found that this signaling was caspase-independent but followed the intrinsic mitochondrial pathway of apoptosis. No effect of glycodelin was seen on the phagocytic ability of monocytes post-differentiation into macrophages. These observations suggest that, at the fetomaternal interface, glycodelin plays a protective role by deleting the monocytes that could become pro-inflammatory. Importantly, leaving the macrophages untouched to carry on with efficient clearance of the apoptotic cells.

Cardiovascular diseases and vulnerable plaques: data, modeling, predictions and clinical applications PREFACE

Introduction Two symposia on “cardiovascular diseases and vulnerable plaques” Cardiovascular disease (CVD) is the leading cause of death worldwide. Huge effort has been made in many disciplines including medical imaging, computational modeling, bio- mechanics, bioengineering, medical devices, animal and clinical studies, population studies as well as genomic, molecular, cellular and organ-level studies seeking improved methods for early detection, diagnosis, prevention and treatment of these diseases [1-14]. However, the mechanisms governing the initiation, progression and the occurrence of final acute clinical CVD events are still poorly understood. A large number of victims of these dis- eases who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs [8,9]. Most cardiovascular diseases are associated with vulnerable plaques. A grand challenge here is to develop new imaging techniques, predictive methods and patient screening tools to identify vulnerable plaques and patients who are more vulnerable to plaque rupture and associated clinical events such as stroke and heart attack, and recommend proper treatment plans to prevent those clinical events from happening. Articles in this special issue came from two symposia held recently focusing on “Cardio-vascular Diseases and Vulnerable Plaques: Data, Modeling, Predictions and Clinical Applications.” One was held at Worcester Polytechnic Institute (WPI), Worcester, MA, USA, July 13-14, 2014, right after the 7th World Congress of Biomechanics. This symposium was endorsed by the World Council of Biomechanics, and partially supported by a grant from NIH-National Institute of Biomedical Image and Bioengineering. The other was held at Southeast University (SEU), Nanjing, China, April 18-20, 2014.

Fatigue crack propagation analysis of plaque rupture

Rupture of atheromatous plaque is the major cause of stroke or heart attack. Considering that the cardiovascular system is a classic fatigue environment, plaque rupture was treated as a chronic fatigue crack growth process in this study. Fracture mechanics theory was introduced to describe the stress status at the crack tip and Paris' law was used to calculate the crack growth rate. The effect of anatomical variation of an idealized plaque cross-section model was investigated. The crack initiation was considered to be either at the maximum circumferential stress location or at any other possible locations around the lumen. Although the crack automatically initialized at the maximum circumferential stress location usually propagated faster than others, it was not necessarily the most critical location where the fatigue life reached its minimum. We found that the fatigue life was minimum for cracks initialized in the following three regions: the midcap zone, the shoulder zone, and the backside zone. The anatomical variation has a significant influence on the fatigue life. Either a decrease in cap thickness or an increase in lipid pool size resulted in a significant decrease in fatigue life. Comparing to the previously used stress analysis, this fatigue model provides some possible explanations of plaque rupture at a low stress level in a pulsatile cardiovascular environment, and the method proposed here may be useful for further investigation of the mechanism of plaque rupture based on in vivo patient data.

The impact of wall shear stress and pressure drop on the stability of the atherosclerotic plaque

Rupture of vulnerable atheromatous plaque in the carotid and coronary arteries often leads to stroke and heart attack respectively. The mechanism of blood flow and plaque rupture in stenotic arteries is still not fully understood. A three dimensional rigid wall model was solved under steady state conditions and unsteady conditions by assuming a time-varying inlet velocity profile to investigate the relative importance of axial forces and pressure drops in arteries with asymmetric stenosis. Flow-structure interactions were investigated for the same geometry and the results were compared with those retrieved with the corresponding 2D cross-section structural models. The Navier-Stokes equations were used as the governing equations for the fluid. The tube wall was assumed hyperelastic, homogeneous, isotropic and incompressible. The analysis showed that the three dimensional behavior of velocity, pressure and wall shear stress is in general very different from that predicted by cross-section models. Pressure drop across the stenosis was found to be much higher than shear stress. Therefore, pressure may be the more important mechanical trigger for plaque rupture other than shear stress, although shear stress is closely related to plaque formation and progression.

Does calcium deposition play a role in the stability of atheroma? Location may be the key

Background: Rupture of vulnerable atheromatous plaque in the carotid and coronary arteries often leads to stroke and heart attack respectively. The role of calcium deposition and its contribution to plaque stability is controversial. This study uses both an idealized and a patient-specific model to evaluate the effect of a calcium deposit on the stress distribution within an atheromatous plaque. Methods: Using a finite-element method, structural analysis was performed on an idealized plaque model and the location of a calcium deposit within it was varied. In addition to the idealized model, in vivo high-resolution MR imaging was performed on 3 patients with carotid atheroma and stress distributions were generated. The individual plaques were chosen as they had calcium at varying locations with respect to the lumen and the fibrous cap. Results: The predicted maximum stress was increased by 47.5% when the calcium deposit was located in the thin fibrous cap in the model when compared with that in a model without a deposit. The result of adding a calcium deposit either to the lipid core or remote from the lumen resulted in almost no increase in maximal stress. Conclusion: Calcification at the thin fibrous cap may result in high stress concentrations, ultimately increasing the risk of plaque rupture. Assessing the location of calcification may, in the future, aid in the risk stratification of patients with carotid stenosis.

An extension of the continual reassessment method using decision theory

The primary goal of a phase I trial is to find the maximally tolerated dose (MTD) of a treatment. The MTD is usually defined in terms of a tolerable probability, q*, of toxicity. Our objective is to find the highest dose with toxicity risk that does not exceed q*, a criterion that is often desired in designing phase I trials. This criterion differs from that of finding the dose with toxicity risk closest to q*, that is used in methods such as the continual reassessment method. We use the theory of decision processes to find optimal sequential designs that maximize the expected number of patients within the trial allocated to the highest dose with toxicity not exceeding q*, among the doses under consideration. The proposed method is very general in the sense that criteria other than the one considered here can be optimized and that optimal dose assignment can be defined in terms of patients within or outside the trial. It includes as an important special case the continual reassessment method. Numerical study indicates the strategy compares favourably with other phase I designs.

Isotonic designs for phase I trials

The purpose of a phase I trial in cancer is to determine the level (dose) of the treatment under study that has an acceptable level of adverse effects. Although substantial progress has recently been made in this area using parametric approaches, the method that is widely used is based on treating small cohorts of patients at escalating doses until the frequency of toxicities seen at a dose exceeds a predefined tolerable toxicity rate. This method is popular because of its simplicity and freedom from parametric assumptions. In this payer, we consider cases in which it is undesirable to assume a parametric dose-toxicity relationship. We propose a simple model-free approach by modifying the method that is in common use. The approach assumes toxicity is nondecreasing with dose and fits an isotonic regression to accumulated data. At any point in a trial, the dose given is that with estimated toxicity deemed closest to the maximum tolerable toxicity. Simulations indicate that this approach performs substantially better than the commonly used method and it compares favorably with other phase I designs.

Toxoplasmosis in Indo-Pacific humpbacked dolphins (Sousa chinensis) from Queensland

Objective: To describe the clinical signs, gross pathology, serology, bacteriology, histopathology, electron microscopy and immunohistochemistry findings associated with toxoplasmosis in four Indo-Pacific humpbacked dolphins (Sousa chinensis) that stranded in Queensland in 2000 and 2001. Design: Clinical assessment, gross necropsy, and laboratory examinations. Procedure: Necropsies were performed on four S chinensis to determine cause of death. Laboratory tests including serology, bacteriology, histopathology and transmission electron microscopy were done on the four dolphins. lmmunohistochemistry was done on the brain, heart, liver, lung, spleen and adrenal gland from various dolphins to detect Toxoplasma gondii antigens. Results: Necropsies showed all of four S chinensis that stranded in Queensland in 2000 and 2001 had evidence of predatory shark attack and three were extremely emaciated. Histopathological examinations showed all four dolphins had toxoplasmosis with tissue cysts resembling T gondii in the brain. Tachyzoite stages of T gondii were detected in the lungs, heart, liver, spleen and adrenal gland, variously of all four dolphins. Electron microscopy studies and immunohistochemistry confirmed the tissues cysts were those of Tgondii. All four dolphins also had intercurrent disease including pneumonia, three had peritonitis and one had pancreatitis. Conclusion: Four S chinensis necropsied in Queensland in 2000 and 2001 were found to be infected with toxoplasmosis. It is uncertain how these dolphins became infected and further studies are needed to determine how S chinensis acquire toxoplasmosis. All four dolphins stranded after periods of heavy rainfall, and coastal freshwater runoff may be a risk factor for T gondii infection in S chinensis. This disease should be of concern to wildlife managers since S chinensis is a rare species and its numbers appear to be declining.

Activating Mango Fruit Defence to Anthracnose Disease

The fungus causing anthracnose disease in mango, Colletotrichum gloeosporioides, (C g.), infects immature fruit early in the season, then enters a long latent phase. After harvest, when fruit start to ripen, the latency breaks and the fungus ramifies through the peel and pulp tissues causing black disease lesions. The breaking of pathogen latency in ripening mango fruit has been correlated with decreasing concentrations of the endogenous antifungal resorcinol compounds (Droby et al., 1986). The level of these antifungal resorcinols vary among mango cultivars (Droby et a1 , 1986). Controlling diseases by managing natural resistance of fruit to fungal attack could minimize the use of pesticides, which have become of major public concern on health and environmental grounds. The plant resistance activator benzo(l,2,3)thiadiazole-7-carbothioic acid S-methyl ester (trade name Bion®) has been widely reported as an effective inducer of systemic resistance. For example, Bion® was reported to induce pathogenesis-related proteins (PR proteins) and stimulate plant defence in peas (Dann and Deverall, 2000) and roses (Suo and Leung, 2001). However, until now, there is no information about the role of Bion® in activation of mango (cv. Kensington Pride) fruit resistance to anthracnose disease. The aim of this research is to determine the effect of resistance activators on defence responses of mango fruit to anthracnose disease.