[Shared decision making in involuntary treatment: four case studies from court ordered psychiatric treatment]. / Gedeelde besluitvorming in het gedwongen kader: vier casestudies uit de tbs.

BACKGROUND: Shared decision making (SDM) can result in better treatment outcomes. Little is known about the practice of SDM in forensic psychiatry; a context in which not only psychiatric problems are present, but also freedom restrictions and involuntary hospitalisation. AIM: To explore the current degree of SDM in a forensic psychiatric setting and to identify factors that influence SDM. METHOD: Semi-structured interviews (n = 4 triads: treatment coordinator, sociotherapeutic mentor and patient) combined with scores on questionnaires (SDM-Q-Doc and SDM-Q-9). RESULTS: The SDM-Q showed a relatively high degree of SDM. Themes like cognitive and executive functions of the patient, subcultural differences, insight into the disease and reciprocal cooperation appeared to influence the SDM. In addition, SDM in forensic psychiatry appeared to be more of a means of improving communication about the decisions of the treatment team than truly ‘shared’ decision making. CONCLUSION: This first exploration shows that SDM is applied in forensic psychiatry, however operationalised differently than the theory behind SDM prescribes.

Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer.

BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis. CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.

Determinants of label non-adherence to non-vitamin K oral anticoagulants in patients with newly diagnosed atrial fibrillation.

Aims: To evaluate the extent and determinants of off-label non-vitamin K oral anticoagulant (NOAC) dosing in newly diagnosed Dutch AF patients. Methods and results: In the DUTCH-AF registry, patients with newly diagnosed AF (<6 months) are prospectively enrolled. Label adherence to NOAC dosing was assessed using the European Medicines Agency labelling. Factors associated with off-label dosing were explored by multivariable logistic regression analyses. From July 2018 to November 2020, 4500 patients were registered. The mean age was 69.6 ± 10.5 years, and 41.5% were female. Of the 3252 patients in which NOAC label adherence could be assessed, underdosing and overdosing were observed in 4.2% and 2.4%, respectively. In 2916 (89.7%) patients with a full-dose NOAC recommendation, 4.6% were underdosed, with a similar distribution between NOACs. Independent determinants (with 95% confidence interval) were higher age [odds ratio (OR): 1.01 per year, 1.01-1.02], lower renal function (OR: 0.96 per ml/min/1.73 m2, 0.92-0.98), lower weight (OR: 0.98 per kg, 0.97-1.00), active malignancy (OR: 2.46, 1.19-5.09), anaemia (OR: 1.73, 1.08-2.76), and concomitant use of antiplatelets (OR: 4.93, 2.57-9.46). In the 336 (10.3%) patients with a reduced dose NOAC recommendation, 22.9% were overdosed, most often with rivaroxaban. Independent determinants were lower age (OR: 0.92 per year, 0.88-0.96) and lower renal function (OR: 0.98 per ml/min/1.73 m2, 0.96-1.00). Conclusion: In newly diagnosed Dutch AF patients, off-label dosing of NOACs was seen in only 6.6% of patients, most often underdosing. In this study, determinants of off-label dosing were age, renal function, weight, anaemia, active malignancy, and concomitant use of antiplatelets.

The foundations of the working alliance in assertive community treatment teams.

BACKGROUND: In this study, we aimed to identify and define the fundamental components of the working alliance in multidisciplinary (Flexible) Assertive Community Treatment teams with shared caseloads, in order to support their daily practice and further research. METHODS: After reviewing the literature, concept mapping with professionals and clients was used to define the working alliance in (F) ACT teams. The resulting concept maps formed the basis for the working alliance assessment instrument, which was pilot tested with professionals and clients through cognitive interviews with a think-aloud procedure. RESULTS: The study led to the development of a twenty five-item assessment instrument to evaluate working alliances in multidisciplinary teams (WAM) that was comprised of three subscales: bond, task/goal and team. Two different versions were developed for clients and professionals. CONCLUSIONS: The WAM instrument was developed to determine the quality of the working alliance in (F) ACT teams. Future research will focus on testing its psychometric properties and predictive value.

Robust metabolic transcriptional components in 34,494 patient-derived cancer-related samples and cell lines.

BACKGROUND: Patient-derived bulk expression profiles of cancers can provide insight into the transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus independent component analyses (c-ICA) can capture statistically independent transcriptional footprints of both subtle and more pronounced metabolic processes. METHODS: We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify the transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs was determined in all samples to create a metabolic transcriptional landscape. RESULTS: A set of 555 mTCs was identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore the associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. CONCLUSIONS: To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal ( www.themetaboliclandscapeofcancer.com ). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment.

How memory effects, check dams, and channel geometry control erosion and deposition by debris flows.

Debris flows can grow greatly in size and hazardous potential by eroding bed and bank material, but effective hazard assessment and mitigation is currently hampered by limited understanding of erosion and deposition dynamics. We have collected high-resolution pre- and post-flow topography for 6 debris flows over a 3 km long unconsolidated reach of the Illgraben channel in the Swiss Alps with drone-based photogrammetry. We show that the spatio-temporal patterns of erosion and deposition in debris-flow torrents are highly variable and dynamic. Check dams strongly control the spatial patterns of erosion and deposition. We identify a memory effect where erosion is strong at locations of strong deposition during previous flows and vice versa. Large sediment inputs from subcatchments initially result in new channel erosion through the subcatchment deposits and simultaneous upstream deposition, likely as a result of backwater effects. It is generally believed that erosion increases with debris-flow magnitude, but we show that there is a limit to debris-flow bulking set by channel geometry. These findings provide key guidelines for flow volume forecasting, emphasizing the importance of memory effects and the need to resolve both erosion and deposition in predictive models.

Ranking Self-reported Gastrointestinal Side Effects of Pharmacotherapy in Sarcoidosis.

BACKGROUND: Clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. So far, no curative treatment exists; the disease can only be suppressed. All treatment options cause side effects affecting quality of life. The aim of this study was to establish and rank the prevalence of self-reported gastrointestinal side effects of drugs used in the treatment of sarcoidosis. METHODS: A cross-sectional web-based anonymous survey about complaints and side effects was conducted among sarcoidosis patients in the Netherlands, United Kingdom, and United States of America. RESULTS: Of the participants, 70% were being treated with one or more drugs. The most important reported side effect was weight gain, associated with increased appetite among prednisone users (as monotherapy as well as in combination with other drugs). Methotrexate (MTX) users especially experienced nausea, with monotherapy as well as combination therapy. Vomiting and weight loss were most prominent among azathioprine and mycophenolate mofetil (MMF) users, whereas diarrhoea was frequently mentioned by MMF and MTX users. The reported side effects of hydroxychloroquine were generally rather mild. CONCLUSION: The current study ranked the gastrointestinal side effects associated with pharmacotherapy in sarcoidosis patients. Pharmacotherapy does have multiple gastrointestinal side effects. The strongest association between a reported side effect and drug use was that of weight gain associated with increased appetite among prednisone users. It would therefore be useful for future research to look further into dietary interventions to counter these side effects and reduce their burden.

Evaluation of p16/Ki-67 dual-stain cytology performed on self-collected vaginal and clinician-collected cervical specimens for the detection of cervical pre-cancer.

OBJECTIVES: To compare the performance of dual immunostaining of p16INK4a and Ki-67 proteins performed on self-collected vaginal specimens and clinician-collected cervical specimens, and to evaluate the performance of this technique in predicting high-grade disease. METHODS: Women aged 30-59 years (n = 1005) were recruited at two well-women clinics in Papua New Guinea. Each woman provided both cervical and vaginal specimens that were tested for high-risk human papillomavirus (hrHPV) DNA using the Xpert HPV Test (Cepheid) at point of care. A subset of paired cervical and vaginal specimens (n = 243) were selected to undergo CINTec® PLUS (Roche) p16/Ki-67 dual-stain cytology and liquid-based cytology (LBC). RESULTS: Fifty-five pairs (22%) were excluded from further analysis because the smears were not assessable. Of the 189 remaining paired specimens, 74 pairs (39.1%) were positive for one or more hrHPV genotypes. When comparing results of the dual stain, the overall percent agreement, positive and negative percent agreements and κ value between the cervical and vaginal specimens were 87.8% (CI 82.3-92.1%), 64.6% (CI 49.5-77.8%), 95.7% (CI 91.0-98.0%) and 0.65 (CI 0.51-0.79%) respectively. The sensitivity of the dual stain performed on the cervical specimen to predict high-grade disease, determined by LBC, was superior to that of the dual stain performed on the vaginal specimen: 100% (CI 84.6-100%) versus 68.2% (CI 45.1-86.1%). CONCLUSION: Although further evaluation may be warranted, these findings indicate that dual-stain testing of vaginal specimens cannot be advocated as part of cervical screening programmes in low- and middle-income countries. However, dual-stain cytology performed on cervical specimens may have a role in quality assurance in such settings.

Measuring empathy in schizophrenia: The Empathic Accuracy Task and its correlation with other empathy measures.

INTRODUCTION: Empathy is an interpersonal process impaired in schizophrenia. Past studies have mainly used questionnaires or performance-based tasks with static cues to measure cognitive and affective empathy. We used the Empathic Accuracy Task (EAT) designed to capture dynamic aspects of empathy by using videoclips in which perceivers continuously judge emotionally charged stories. We compared individuals with schizophrenia with a healthy comparison group and assessed correlations among EAT and three other commonly used empathy measures. METHOD: Patients (n = 92) and a healthy comparison group (n = 42) matched for age, gender and education completed the EAT, the Interpersonal Reactivity Index, Questionnaire of Cognitive and Affective Empathy and Faux Pas. Differences between groups were analyzed and correlations were calculated between empathy measurement instruments. RESULTS: The groups differed in EAT performance, with the comparison group outperforming patients. A moderating effect was found for emotional expressivity of the target: while both patients and the comparison group scored low when judging targets with low expressivity, the comparison group performed better than patients with more expressive targets. Though there were also group differences on the empathy questionnaires, EAT performance did not correlate with questionnaire scores. CONCLUSIONS: Individuals with schizophrenia benefit less from the emotional expressivity of other people than the comparison group, which contributes to their impaired empathic accuracy. The lack of correlation between the EAT and the questionnaires suggests a distinction between self-report empathy and actual empathy performance. To explore empathic difficulties in real life, it is important to use instruments that take the interpersonal perspective into account.

Metacognitive reflection and insight therapy (MERIT) for patients with schizophrenia.

BACKGROUND: Impaired metacognition is associated with difficulties in the daily functioning of people with psychosis. Metacognition can be divided into four domains: Self-Reflection, Understanding the Other's Mind, Decentration, and Mastery. This study investigated whether Metacognitive Reflection and Insight Therapy (MERIT) can be used to improve metacognition. METHODS: This study is a randomized controlled trial. Patients in the active condition (n = 35) received forty MERIT sessions, the control group (n = 35) received treatment as usual. Multilevel intention-to-treat and completers analyses were performed for metacognition and secondary outcomes (psychotic symptomatology, cognitive insight, Theory of Mind, empathy, depression, self-stigma, quality of life, social functioning, and work readiness). RESULTS: Eighteen out of 35 participants finished treatment, half the drop-out stemmed from therapist attrition (N = 5) or before the first session (N = 4). Intention-to-treat analysis demonstrated that in both groups metacognition improved between pre- and post-measurements, with no significant differences between the groups. Patients who received MERIT continued to improve, while the control group returned to baseline, leading to significant differences at follow-up. Completers analysis (18/35) showed improvements on the Metacognition Assessment Scale (MAS-A) scales Self Reflectivity and metacognitive Mastery at follow-up. No effects were found on secondary outcomes. CONCLUSIONS: On average, participants in the MERIT group were, based on MAS-A scores, at follow-up more likely to recognize their thoughts as changeable rather than as facts. MERIT might be useful for patients whose self-reflection is too limited to benefit from other therapies. Given how no changes were found in secondary measures, further research is needed. Limitations and suggestions for future research are discussed.

Inducing intravesical hyperthermia of the ex-vivo porcine bladder wall: radiofrequency-induction versus recirculation using a custom-made device.

INTRODUCTION: Several techniques can be used to treat intravesical chemohyperthermia (ChHT). We compared radiofrequency-induced hyperthermia (RF-HT) with conductive hyperthermia (C-HT) for their ability to induce bladder wall temperatures of >40.5 °C, the target temperature for ChHT. MATERIALS AND METHODS: Fresh porcine bladders (n = 12) were placed in a temperature-controlled saline bath to simulate body temperature and circulation. HT was induced with RF-HT (43 °C) or C-HT (inflow temperature 44 and 46 °C) using a custom-made device. In two additional bladders, we varied intravesical solution and volume. Temperatures were recorded with a three-way catheter containing three mucosal and two urethral thermocouples (TCs) and a 915 MHz RF antenna, and with external TCs in the bladder wall at three different levels and three different locations. RESULTS: Target temperature (40.5 °C) was reached in the submucosa at all locations by both techniques. In the detrusor, target temperature was reached by RF-HT at the bladder neck and side wall. C-HT46 reached significantly higher submucosal temperatures at the side wall. The bladder dome seemed best heated by C-HT, although a high inflow temperature (46 vs. 44 °C) was required (ns). Intravesical saline resulted in higher temperatures than sterile water for RF-HT. A volume of 100 mL resulted in higher bladder dome temperatures for RF-HT, and higher bladder neck with lower dome temperatures for C-HT. CONCLUSION: Our results indicate a slightly superior heating capacity for RF-HT compared to C-HT, whereas for the bladder dome, the reverse seems true. Comparative studies are warranted to evaluate whether HT efficacy differs between both techniques, with emphasis on tumor location.

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential.

Genome-wide expression and response to exposure-based psychological therapy for anxiety disorders.

Exposure-based psychological treatments for anxiety have high efficacy. However, a substantial proportion of patients do not respond to therapy. Research examining the potential biological underpinnings of therapy response is still in its infancy, and most studies have focussed on candidate genes. To our knowledge, this study represents the first investigation of genome-wide expression profiles with respect to treatment outcome. Participants (n=102) with panic disorder or specific phobia received exposure-based cognitive behavioural therapy. Treatment outcome was defined as percentage reduction from baseline in clinician-rated severity of their primary anxiety diagnosis at post treatment and 6 month follow-up. Gene expression was determined from whole blood samples at three time points using the Illumina HT-12v4 BeadChip microarray. Linear regression models tested the association between treatment outcome and changes in gene expression from pre-treatment to post treatment, and pre-treatment to follow-up. Network analysis was conducted using weighted gene co-expression network analysis, and change in the detected modules from pre-treatment to post treatment and follow-up was tested for association with treatment outcome. No changes in gene expression were significantly associated with treatment outcomes when correcting for multiple testing (q<0.05), although a small number of genes showed a suggestive association with treatment outcome (q<0.5, n=20). Network analysis showed no association between treatment outcome and change in gene expression for any module. We report suggestive evidence for the role of a small number of genes in treatment outcome. Although preliminary, these findings contribute to a growing body of research suggesting that response to psychological therapies may be associated with changes at a biological level.

Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid.

The blood-brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10-8, ß=0.08) and DDX6 (P=2.9 × 10-7, ß=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10-52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.

Metacognitive Reflection and Insight Therapy (MERIT) with a Patient with Persistent Negative Symptoms.

Metacognition comprises a spectrum of mental activities involving thinking about thinking. Metacognitive impairments may sustain and trigger negative symptoms in people with schizophrenia. Without complex ideas of the self and others, there may be less reason to pursue goal-directed activities and less ability to construct meaning in daily activities, leading to the experience of negative symptoms. As these symptoms tend to be nonresponsive to pharmacotherapy and other kinds of treatment metacognition might be a novel treatment target; improvement of metacognition might lead to improvements in negative symptoms. One therapy that seeks to promote metacognition is the Metacognitive Reflection and Insight Therapy (MERIT). In this study, a case is presented in which a first episode patient with severe negative symptoms is treated with MERIT. A case illustration and the eight core principles of MERIT are presented. Independent assessments of metacognition and negative symptoms before and after therapy show a significant increase of metacognition and decrease of negative symptoms over the course of 40 weeks.

[Metacognition in psychotic disorders: from concepts to intervention]. / Metacognitie bij psychotische stoornissen: van concept naar interventie.

BACKGROUND: Persons with a psychotic disorder commonly experience difficulties with what is considered to be metacognitive capacity. In this article we discuss several definitions of this concept, the measurement instruments involved and the clinical interventions that target this concept. AIM: To present a review of various frequently used definitions of metacognition and related concepts and to describe the measurement instruments involved and the treatment options available for improving the metacognitive capacity of persons with a psychotic disorder. METHOD: We present an overview of several definitions of metacognition in psychotic disorders and we discuss frequently used measurement instruments and treatment options. The article focuses on recent developments in a model devised by Semerari et al. The measurement instrument involved (Metacognition Assessment Scale - A) is discussed in terms of it being an addition to existing methods. RESULTS: On the basis of the literature it appears that metacognition and related concepts are measurable constructs, although definitions and instruments vary considerably. The new conceptualisation of social information processing also leads to the development of a new form of psychotherapy that aims to help patients suffering from psychotic disorders to improve metacognitive capacity. CONCLUSION: There seems to be evidence that metacognitive abilities are a possible target for treatment, but further research is needed.

Serum levels of renin, angiotensin-converting enzyme and angiotensin II in patients treated by surgical excision, propranolol and captopril for problematic proliferating infantile haemangioma.

The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by ß-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH.

Elevated mean neutrophil volume represents altered neutrophil composition and reflects damage after myocardial infarction.

Myocardial infarction (MI) induces an inflammatory response in which neutrophils fulfill a prominent role. Mean neutrophil volume (MNV) represents the average size of the circulating neutrophil population. Our goal was to determine the effect of MI on MNV and investigate the mechanisms behind MNV elevation. MNV of 84 MI patients was compared with the MNV of 209 stable angina patients and correlated to simultaneously measured CK levels. Fourteen pigs were subjected to temporary coronary balloon occlusion and blood was sampled at multiple time points to measure MNV. Echocardiography was performed followed by ex vivo infarct size assessment after 72 h. MNV was higher in MI patients compared to stable angina patients (602 SD26 AU vs. 580 SD20 AU, p < 0.0001) and correlated with simultaneously measured CK levels (R = 0.357, p < 0.0001). In pigs, MNV was elevated post-MI (451 SD11 AU vs. 469 SD12 AU), p < 0.0001). MNV correlated with infarct size (R = 0.705, p = 0.007) and inversely correlated with left ventricular ejection fraction (R = -0.718, p = 0.009). Cell sorting revealed an increased presence of banded neutrophils after MI, which have a higher MNV compared to mature neutrophils post-MI (495 SD14 AU vs. 478 SD11 AU, p = 0.012). MNV from coronary sinus blood was higher than MNV of neutrophils from simultaneously sampled arterial blood (463 SD7.6 AU vs. 461 SD8.6 AU, p = 0.013) post-MI. The current study shows MNV is elevated and reflects cardiac damage post-MI. MNV increases due to altered neutrophil composition and systemic neutrophil activation. MNV may be an interesting parameter for prognostic assessment in MI and provide new insights into pathological innate immune responses evoked by ischemia-reperfusion.

Cancer-drug induced insulin resistance: innocent bystander or unusual suspect.

Epidemiological and experimental evidence strongly suggests an association between type 2 diabetes mellitus and cancer. Insulin resistance, causing hyperinsulinaemia and eventually hyperglycaemia, appears to increase cancer incidence and disease progression. In addition, insulin resistance seems to reduce the efficacy of cancer therapy. Treatment with cancer therapeutics such as glucocorticoids, chemotherapy, hormonal therapies and targeted drugs can actually induce insulin resistance. The question arises whether cancer-therapy induced insulin resistance impairs anticancer treatment efficacy and disease outcome. Here, we review current literature regarding the incidence of cancer-therapy induced insulin resistance and describe the systemic and extra- and intracellular changes that occur in insulin signalling pathways and glucose metabolism. Subsequently, clinical and preclinical evidence for consequences of insulin resistance in terms of cancer progression and survival is presented. Finally, potential interventions including diabetes medication and limiting energy availability through diets and exercise are discussed.