CT of transposition of the great arteries in adults.

Transposition of the great arteries is one of the most common cyanotic congenital heart diseases. It is characterised by an abnormal connection of the ventricles and great arteries, so that the aorta arises from the morphological right ventricle and the pulmonary artery arises from the morphological left ventricle. Historically, as with many congenital heart diseases, patients with transposition of the great arteries had poor life expectancy. Advances in surgical and medical management have resulted in patients surviving into adulthood. As these patients are living longer, they will be encountered more frequently in practice. The purpose of this article is to familiarise the general radiologist with the expected postoperative anatomy, and the appearance on cross-sectional imaging as well as the long-term complications in this group of patients.

Myocardial fibrosis, inflammation, and altered cardiac gene expression profiles in rats exposed to a predator-based model of posttraumatic stress disorder.

People who are exposed to life-threatening trauma are at risk of developing posttraumatic stress disorder (PTSD). In addition to psychological manifestations, PTSD is associated with an increased risk of myocardial infarction, arrhythmias, hypertension, and other cardiovascular problems. We previously reported that rats exposed to a predator-based model of PTSD develop myocardial hypersensitivity to ischemic injury. This study characterized cardiac changes in histology and gene expression in rats exposed this model. Male rats were subjected to two cat exposures (separated by a period of 10 d) and daily cage-mate changes for 31 d. Control rats were not exposed to the cat or cage-mate changes. Ventricular tissue was analyzed by RNA sequencing, western blotting, histology, and immunohistochemistry. Multifocal lesions characterized by necrosis, mononuclear cell infiltration, and collagen deposition were observed in hearts from all stressed rats but none of the control rats. Gene expression analysis identified clusters of upregulated genes associated with endothelial to mesenchymal transition, endothelial migration, mesenchyme differentiation, and extracellular matrix remodeling in hearts from stressed rats. Consistent with endothelial to mesenchymal transition, rats from stressed hearts exhibited increased expression of α-smooth muscle actin (a myofibroblast marker) and a decrease in the number of CD31 positive endothelial cells. These data provide evidence that predator-based stress induces myocardial lesions and reprograming of cardiac gene expression. These changes may underlie the myocardial hypersensitivity to ischemia observed in these animals. This rat model may provide a useful tool for investigating the cardiac impact of PTSD and other forms of chronic psychological stress.Lay summaryChronic predator stress induces the formation of myocardial lesions characterized by necrosis, collagen deposition, and mononuclear cell infiltration. This is accompanied by changes in gene expression and histology that are indicative of cardiac remodeling. These changes may underlie the increased risk of arrhythmias, myocardial infarction, and other cardiac pathologies in people who have PTSD or other forms of chronic stress.

A predator-based psychosocial stress animal model of PTSD in females: Influence of estrous phase and ovarian hormones.

Traumatized women are more likely than traumatized men to develop post-traumatic stress disorder (PTSD). Still, the inclusion of females in animal models of PTSD has largely been avoided, likely due to the variable hormone profile of female rodents. Because a valid animal model of PTSD that incorporates females is still needed, we examined the influence of estrous stage and ovarian hormones on the female rat response to a predator-based psychosocial stress model of PTSD. Female Sprague-Dawley rats were exposed to psychosocial stress or control conditions for 31 days. Stressed rats were given two cat exposures and daily social instability; control rats were handled daily. Beginning on Day 32, rats underwent physiological or behavioral testing. In Experiment 1, vaginal smears were collected on days of the first and second cat exposures and each day of behavioral testing to determine estrous stage. In Experiments 2 and 3, ovariectomized or sham control rats were exposed to stress or control conditions. Then, they were given behavioral testing (Exp 2), or their hearts were isolated and subjected to ischemia/reperfusion on a Langendorff isolated heart system (Exp 3). Chronic stress increased anxiety-like behavior, irrespective of estrous stage or ovariectomy condition. Ovariectomized females displayed greater startle responses and anxiety-like behavior than sham rats. Stress had no impact on myocardial sensitivity to ischemic injury; however, ovariectomized females exhibited greater ischemia-induced infarction than sham rats. These findings suggest that ovarian hormones may prevent anxiety-like behavior and be cardioprotective in non-stressed controls, but they do not interact with chronic stress to influence the development of PTSD-like sequelae in female rats.

Complementary and alternative medicine (CAM) information and support needs of Chinese-speaking cancer patients.

PURPOSE: Complementary and alternative medicine (CAM) is popular among Chinese-speaking cancer patients (CSCPs), but little research examines CAM use by Canadian CSCPs. The use of CAM is controversial because of potential interactions with conventional cancer treatments. The purpose of this study was to explore CSCPs' use of CAM, sources of CAM information, and decision support needs, as well as their experience of making CAM decisions. METHODS: A sequential, multi-method research design was used: a secondary data analysis of a CAM use survey conducted in a Western Canadian regional cancer agency followed by a qualitative interpretive description approach to inquiry using semi-structured interviews with CSPCs and support persons. RESULTS: More than 65% of CSCPs reported using CAM. CSCPs favored biologically-based therapies, including traditional Chinese medicine herbs and other natural health products. Many CSCPs were using CAM without adequate culturally appropriate information and decision support. Those who made decisions spontaneously relied on peers for advice whereas deliberate decision makers sought information from multiple sources, including peers and the Internet, selecting therapies congruent with their cultural health perspectives and previous experiences with CAM. CSCPs rarely spoke with oncology healthcare providers (HCPs) about CAM use. CONCLUSIONS: CSCPs reported using CAM at rates significantly higher than for non-CSCPs. Given the predominance of biological-based therapies and the lack of consultation with oncology HCPs, it is imperative that CAM use be assessed and documented to ensure CSCPs' safety during cancer treatment. Culturally appropriate information and decision support is required to ensure that CSCPs are making safe and informed CAM decisions.

Employment characteristics of a complex adult congenital heart disease cohort.

BACKGROUND: Due to advances in surgical techniques and subsequent management, there have been remarkable improvements in the survival of patients with congenital heart disease. In particular, larger numbers of patients with complex disease are now living into adulthood and are entering the workforce. AIMS: To establish the types of employment complex adult congenital heart disease (ACHD) patients are engaged in, based on the largest cohort of patients with a single-ventricle circulation in the UK. METHODS: Records of all patients with a univentricular (Fontan) circulation at the Queen Elizabeth Hospital were reviewed. Employment status was categorized according to the Standard Occupational Classification criteria (2010). RESULTS: A total of 210 patient records were reviewed. There was the same proportion of professionals in our cohort compared to the rest of the UK (20% versus 20%). There were greater proportions working in the caring, leisure and other service occupations (15% versus 9%), the elementary occupations (17% versus 11%), sales and customer service occupations (14% versus 8%) and administrative and secretarial occupations (12% versus 11%). The reverse trend was observed for associate professions and technical occupations (7% versus 14%), skilled trades (10% versus 11%), process, plant and machine operatives (3% versus 6%) and managers, directors and senior officials (2% versus 10%). CONCLUSIONS: The data show that ACHD patients with a single ventricle are engaged in a diverse range of occupations. It is essential that early education and employment advice are given to this cohort to maximize future employment potential.

Taking culture seriously: Can we improve the developmental health and well-being of Australian Aboriginal children in out-of-home care?

BACKGROUND: Children in out-of-home care have well-documented health and developmental needs. Research suggests that Aboriginal children in care have unmet health and intervention needs. In metropolitan Sydney, Kari Aboriginal Resources Inc. (KARI), an Aboriginal organization, provides support to indigenous children in care, including clinical assessment and intervention. We wanted to determine the health and developmental needs of a subset of children in out-of-home care with KARI, who had been in stable care for at least a year. We wanted to identify child, carer, and intervention characteristics that contributed to children doing well. We also wanted to identify enablers and barriers to providing culturally competent intervention. METHODS: We used mixed methods. From the KARI clinic database over the past 3 years, we identified children who had been in stable care with KARI for >12 months. We compared clinical measures and outcomes for these children with results from previous audits. We carried out a group discussion and key informant interviews with therapists and caseworkers to identify risk and resilience factors for each child, as well as enablers and barriers to culturally competent intervention. RESULTS: The health and developmental profile of the 26 children identified as being in stable care was similar to that of previous audits. Most (88%) were getting speech pathology intervention; one third were getting occupational therapy and psychological intervention; most children and their carers attended cultural programmes. The majority of children (25/26) improved in their developmental health. Caseworkers and therapists identified risk and resilience factors related to child, carer, and home characteristics. They also identified elements of good practice; systemic issues prevented some interventions from being carried out. CONCLUSIONS: There are challenges delivering a trauma-informed, culturally respectful service to Aboriginal children in out-of-home care in an urban setting, but it can be done if attention is paid to culture and the enablers and barriers are identified.

CTL- vs Treg lymphocyte-attracting chemokines, CCL4 and CCL20, are strong reciprocal predictive markers for survival of patients with oesophageal squamous cell carcinoma.

BACKGROUND: Tumoural infiltration of T lymphocytes is determined by local patterns of specific chemokine expression. In this report, we examined the roles of CCL4 and CCL20 in the accumulation of CD8(+) cytotoxic T lymphocytes (CTLs) and regulatory T (Treg) lymphocytes in oesophageal squamous cell carcinoma (ESCC), and determined the correlations between chemokine expressions and ESCC patients' survival. METHODS: Reverse transcriptase-PCR and immunohistochemistry (IHC) staining were performed to examine the expressions of interested genes. Flow cytometry was adopted to check the expressions of CCL4- and CCL6-specific receptors, CCR5 and CCR6, on CTLs and Treg cells. In addition, transwell assay was carried on. RESULTS: The CCL4 expression was significantly correlated with the expression of CTL markers (CD8 and Granzyme B), whereas CCL20 was positively correlated with Treg markers (FoxP3 and IL-10). Consistently, CCR5 was found to be mainly expressed on CD8(+) T lymphocytes, while CCR6 showed prevalence on Treg lymphocytes and the frequencies of CCR5(+)CD8(+) CTLs and CCR6(+) Treg cells were higher in TIL compared with PBMC. Respectively, CCL4 and CCL20 recruited CD8(+) and regulatory T cells in vitro. Importantly, high levels of CCL4 in the lesions of ESCC patients predicted prolonged survival. Furthermore, CCL4(high)/CCL20(low) group demonstrated better overall survival, whereas CCL4(low)/CCL20(low) and CCL4(low)/CCL20(high) groups showed the worst overall survival. CONCLUSIONS: Our data showed that CCL4 and CCL20 recruit functionally different T lymphocyte subsets into oesophageal carcinoma, indicating CCL4 and CCL20 are potential predictors of ESCC patients' survival.

Cross-sectional imaging of the Fontan circuit in adult congenital heart disease.

The Fontan circuit is the result of a palliative surgical procedure that is performed in patients with a functionally single ventricle cardiac anomaly. The success of this operation has resulted in an increasing population of adults with this anatomy and physiology. The purpose of this article is to familiarize the general radiologist with the expected anatomy and cross-sectional imaging findings, highlight special imaging considerations, and examine the common complications that are encountered in this group of patients.

Manipulating the expression of chemokine receptors enhances delivery and activity of cytokine-induced killer cells.

BACKGROUND: Cytokine-induced killer (CIK) cells are ex vivo-expanded immune cells that express NK-cell and T-cell markers and that are routinely used in the treatment of many cancers. One key advantage of CIK cells is their ability to efficiently traffic to many solid tumours. Although likely to be mediated by chemokine receptor (CKR) expression, a thorough examination of the mechanism of tumour targeting has not been previously explored. METHODS: Here, human CIK cell expansions were examined for the level, profile and kinetics of CKR expression. RESULTS: It was found that CIK cells express a panel of CKRs, with considerable variation between donors. Importantly, CKR levels dropped considerably beyond 14 days in culture, being significantly reduced by day 28 (the time at which cytolytic activity peaked). As such, CIK preparations that are used clinically may not have optimal CKR expression. Several approaches were found to re-stimulate CKR cell-surface levels at these later time points. These approaches also enhanced cytolytic activity in vitro and were demonstrated to increase both in vivo tumour trafficking and anti-tumour activity in mouse models. CONCLUSIONS: Simple modifications of the CIK expansion protocol could therefore be used to significantly enhance the anti-tumour effects of this therapy.

Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination.

Despite significant strides made in the clinical translation of adoptive immune cell therapies, it is apparent that many tumors incorporate strategies to avoid recognition by receptors expressed on the immune cells, such as NKG2D. Strategies that stabilize the expression of ligands for these receptors may enhance the therapeutic potential of these and related therapies. Doxycycline inhibits matrix metalloproteinases (MMPs) that act to cleave the extracellular domain of MICA/B, ligands for the NKG2D receptor. Doxycycline treatment blocked shedding of MICA/B from a panel of human tumor cells, but also acted to increase their expression and cell surface translocation, possibly through its action on ATM. This meant that many tumor cells displayed increased MICA/B expression and enhanced susceptibility to CIK cells. Interestingly, doxycycline also selectively enhanced the replication of oncolytic vaccinia in many tumor cell lines, leading to increased sensitivity to these therapies. Combination (CIK-oncolytic vaccinia) therapies used in conjunction with doxycycline led to increased anti-tumor effects. The unexpected and pleiotropic beneficial anti-tumor effects of doxycycline on both immune cell and oncolytic viral therapies make it an excellent candidate for rapid clinical testing.

Of Guinea pigs and gratitude: the difficult discourse of clinical trials from the cancer patient perspective.

In an ongoing longitudinal qualitative cohort study of cancer patients' needs and preferences across the cancer journey, we harvested a subset of accounts pertaining to conversations between patients and their clinicians around clinical trials. Recognising these conversations as a departure from the more routine discourses of clinical care, in that they enter into new dimensions of investment and motivation on the part of clinicians, we engaged in both secondary analysis of banked data and focussed interviewing of cancer patients to better understand how cancer patients describe communications in relation to decisions pertaining to clinical trials participation. Using constant comparative techniques informed by the interpretive description approach to applied qualitative methodology to guide a systematic analysis of this set of data, we documented patterns and themes across patient accounts. The resulting thematic depiction of clinical trials discourses from a patient perspective contrasts with assumptions apparent in the professional literature relating to the clinical advantage of trials participation, and illuminates aspects of patient-clinician interaction that are particularly amenable to disruption within this delicate and nuanced discourse. Findings from this study have implications for our understanding of the complexities of cancer communication at the delicate intersection of patient care and knowledge generation.

Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1.

Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.

Helpful communications during the diagnostic period: an interpretive description of patient preferences.

With a diagnosis of cancer, life changes for patients in a profound manner. The window of time known as cancer diagnosis is one of considerable turbulence and distress for patients. Therefore, diagnosis constitutes a time during which communication with healthcare professionals is of particular importance in setting the stage for the way cancer illness will be experienced. Our research explores communications throughout the cancer trajectory from the perspective of patients themselves. We are following a sample of 60 cancer patients, representing a range of tumour sites, from the early diagnostic period through to recovery, chronic, or advanced disease. Using interpretive description analysis techniques, we document patterns and themes related to various components of the cancer journey. In this paper, we focus on themes related to perceived helpful communication during the diagnosis experience as reported by our study participants both at the time of being newly diagnosed patients, and as they reflect on that period 12 months later. These findings illuminate experiential issues of importance to patients in relation to cancer care communication and the manner in which helpful communications during this sensitive time may facilitate the subsequent experience living with and obtaining care for cancer.

Management of pregnancy in women with acquired and congenital heart disease.

Heart disease is the leading cause of maternal mortality in the UK. Deaths from acquired conditions such as ischaemic heart disease are increasing and often occur in patients with no history of heart disease, thus emphasising the need for vigilance for risk factors in women of childbearing age. All women with known heart disease should have pre-pregnancy counselling to assess for maternal and fetal risk. Women deemed to be at moderate or high risk should be under the care of a specialist antenatal team with experience of managing women with heart disease in pregnancy. Conditions that are considered particularly high risk (mortality >10%) include Marfan syndrome with dilated aortic root, severe left heart obstructive lesions, pulmonary hypertension, and severe left ventricular dysfunction. This article reviews the management of women with heart disease during pregnancy, labour and in the puerperium.

Transcriptomic profiling of feline teeth highlights the role of matrix metalloproteinase 9 (MMP9) in tooth resorption.

Tooth resorption (TR) in domestic cats is a common and painful disease characterised by the loss of mineralised tissues from the tooth. Due to its progressive nature and unclear aetiology the only treatment currently available is to extract affected teeth. To gain insight into TR pathogenesis, we characterised the transcriptomic changes involved in feline TR by sequencing RNA extracted from 14 teeth (7 with and 7 without signs of resorption) collected from 11 cats. A paired comparison of teeth from the same cat with and without signs of resorption identified 1,732 differentially expressed genes, many of which were characteristic of osteoclast activity and differentiation, in particular matrix metalloproteinase 9 (MMP9). MMP9 expression was confirmed by qPCR and immunocytochemistry of odontoclasts located in TR lesions. A hydroxamate-based MMP9 inhibitor reduced both osteoclast formation and resorption activity while siRNA targeting MMP9 also inhibited osteoclast differentiation although had little effect on resorption activity. Overall, these results suggest that increased MMP9 expression is involved in the progress of TR pathogenesis and that MMP9 may be a potential therapeutic target in feline TR.

Neural Activation During Visual Attention Differs in Individuals with High versus Low Macular Pigment Density.

SCOPE: The neural efficiency hypothesis for lutein (L) and zeaxanthin (Z) suggests that higher levels of L+Z in the central nervous system (CNS) are predictive of stronger stimulus-specific brain responses. Past research suggests that supplementing L+Z can improve neural processing speed and cognitive function across multiple domains, which supports this hypothesis. The purpose of this study is to determine the extent to which CNS L+Z levels predict brain responses using an attentionally taxing task. METHODS AND RESULTS: Macular pigment optical density (MPOD) is measured at baseline in 85 participants ranging in age from 18-92 years. Brain activation is measured using dense array electroencephalography. Stimuli evoking the signal include a grating array of vertical bars, oscillating at four driving frequencies. Significant stimulus-specific interactions are detected between attend condition, location, and age (p < .002) for unattended image locations, and between age and location (p < .008) for attended locations. Although no differences are found across age by MPOD, this measure is found to be predictive of neural power at parafoveal bar locations (R2 .080). CONCLUSION: CNS L+Z status is related to differences in brain activation in conditions designed to stress visual attention. These differences are strongest for older subjects.

Integrating the biological characteristics of oncolytic viruses and immune cells can optimize therapeutic benefits of cell-based delivery.

Despite significant advances in the development of tumor-selective agents, strategies for effective delivery of these agents across biological barriers to cells within the tumor microenvironment has been limiting. One tactical approach to overcoming biological barriers is to use cells as delivery vehicles, and a variety of different cell types have been investigated with a range of agents. In addition to transporting agents with targeted delivery, cells can also produce their own tumoricidal effect, conceal a payload from an immune response, amplify a selective agent at the target site and facilitate an antitumor immune response. We have reported a therapeutic combination consisting of cytokine induced killer cells and an oncolytic vaccinia virus with many of these features that led to therapeutic synergy in animal models of human cancer. The synergy was due to the interaction of the two agents to enhance the antitumor benefits of each individual component. As both of these agents display broad tumor-targeting potential and possess unique tumor killing mechanisms, together they were able to recognize and destroy a far greater number of malignant cells within the heterogeneous tumor than either agent alone. Effective cancer therapy will require recognition and elimination of the root of the disease, the cancer stem cell, and the combination of CIK cells and oncolytic vaccinia viruses has this potential. To create effective tumor-selective agents the viruses are modified to take advantage of the unique biology of the cancer cell. Similarly, if we are to develop targeted therapies that are sufficiently multifaceted to eliminate cancer cells at all stages of disease, we should integrate the virus into the unique biology of the cell delivery vehicle.

An unusual case of misdiagnosed ventricular tachycardia.

We present the case of a 71-year-old man, with known Parkinson's disease and previous coronary artery bypass surgery, who presented with acute chest pain. His initial 12 lead electrocardiogram (ECG) was unremarkable; however, a repeat 12 lead ECG during further chest pain suggested a ventricular tachycardia (VT) for which he was commenced on an intravenous amiodarone infusion. However, later analysis of his ECGs revealed that the apparent VT was, in fact, an artefact related to his parkinsonian tremor.