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.

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.

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.

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.

Regulators of G-protein signaling 2 and 4 differentially regulate cocaine-induced rewarding effects.

There is a need to identify new therapeutic targets for the treatment of cocaine addiction due to the rise in cocaine abuse and deaths due to cocaine overdose. Regulator of G protein signaling (RGS) proteins such as RGS2 and RGS4 are widely distributed in brain regions that play a role in drug reward. Importantly, RGS2 and RGS4 negatively regulate G-protein coupled receptor signaling pathways of monoaminergic neurotransmitters that play a role in the rewarding effects of cocaine by enhancing the rate of hydrolysis of Gα-bound guanine nucleotide triphosphate. Thus, the objective of this study was to investigate the effects of cocaine on conditioned place preference (CPP) and locomotor activity in mice that lacked either RGS2 or RGS4 (i.e. knockout (KO) mice) and their wildtype (WT) littermates. Moreover recent studies have reported influence of sex on RGS functioning and hence studies were conducted in both male and female mice. Cocaine-induced CPP was attenuated in male, but not female RGS4 KO mice compared to respective RGS4 WT mice. Cocaine-induced CPP was not influenced by deletion of RGS2 in either male or female mice. Similarly, cocaine-induced locomotor activity was not influenced by deletion of either RGS2 or RGS4 irrespective of sex. Together, the data indicate that the rewarding effects of cocaine were attenuated in the absence of RGS4 expression, but not in the absence of RGS2 expression in a sex-dependent manner. Importantly, these data suggest that RGS4 can serve as a potential target for medications that can be used to treat cocaine addiction.

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.

Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart.

BACKGROUND: We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. METHODS: Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. RESULTS: Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. CONCLUSIONS: Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

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.

Heart disease in pregnancy.

Cardiac disease is the leading cause of maternal mortality in the developed world. The majority of women with heart disease are able to successfully undergo pregnancy. However, in women with severely impaired ventricular function, severe left heart obstruction, pulmonary hypertension and aortopathy, such as Marfan syndrome, with significant aortic dilatation, pregnancy is associated with a significant risk, and these women should be counselled against pregnancy if there is no option for treatment that reduces risk. Although there are increasing numbers of women with congenital heart disease who are considering pregnancy, as a result of joint expert specialist cardiac and obstetric care, maternal mortality is low. Most of the observed mortality occurs in women with structurally normal hearts who were not known to have heart disease before their pregnancy. It is therefore important that those caring for pregnant women are aware of the risk factors for and presentation of cardiac conditions in pregnancy. We review the presentation and management of both congenital and acquired heart diseases in pregnancy.

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.

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.

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.

A novel method of teaching adenoidectomy using suction diathermy.

Methods which aid and enhance the teaching of surgical procedures to trainees are beneficial to both trainer and trainee. In this article, we suggest a simple way of performing suction diathermy which allows the trainer to provide a template for the trainee to reproduce. Related articles have suggested the use of additional equipment, such as an endoscope; however, the method we describe requires no additional technical elements. Thus, it represents a sound and efficient teaching tool.