Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the ...Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.
Abstract Body dysmorphic disorder (BDD) is characterized by imagined or slight defects in one's appearance. We evaluated implicit and explicit biases among individuals diagnosed with BDD ( n = 21), ...individuals with subclinical BDD symptoms ( n = 21), and healthy control participants ( n = 21). Specifically, we used the Implicit Association Test IAT; Greenwald, A. G., McGhee, D. E., & Schwartz, J. L. K. (1998). Measuring individual differences in implicit cognition: the implicit association test. Journal of Personality and Social Psychology , 74 , 1464–1480 to examine automatic associations related to self-esteem, associations between attractive and important, and a physical attractiveness stereotype (associations between attractive and competent). BDD participants had significantly lower implicit self-esteem, relative to control participants, and the subclinical BDD participants were intermediate between these groups. Although no group differences were observed on the implicit Attractive Important IAT; as predicted, BDD participants had significantly stronger implicit associations between attractive and competent than the other groups, in line with a common stereotype about physical attractiveness. Both the Attractive Competent IAT and Self-Esteem IAT were significant predictors of BDD symptom severity, and distress and avoidance during a mirror exposure task. Findings are discussed in light of cognitive-behavioral models of BDD.
Many individuals restrict their food intake to prevent weight gain. This restriction has both homeostatic and hedonic effects but their relative contribution is currently unclear. To isolate hedonic ...effects of food restriction, we exposed regular chocolate eaters to one week of chocolate deprivation but otherwise regular eating. Before and after this hedonic deprivation, participants viewed images of chocolate and images of high-calorie but non-chocolate containing foods, while experiential, behavioral and eyeblink startle responses were measured. Compared to satiety, hedonic deprivation triggered increased chocolate wanting, liking, and chocolate consumption but also feelings of frustration and startle potentiation during the intertrial intervals. Deprivation was further characterized by startle inhibition during both chocolate and food images relative to the intertrial intervals. Individuals who responded with frustration to the manipulation and those who scored high on a questionnaire of impulsivity showed more relative startle inhibition. The results reveal the profound effects of hedonic deprivation on experiential, behavioral and attentional/appetitive response systems and underscore the role of individual differences and state variables for startle modulation. Implications for dieting research and practice as well as for eating and weight disorders are discussed.
There is still a lack of reliable molecular predictors to achieve major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) in the ...therapeutic management of newly diagnosed chronic myeloid leukemia (CML). Employing a proprietary fluorogenic flow cytometry assay, we recently identified separase proteolytic activity as a potential marker of molecular response and BCR::ABL1 positivity of CD34+ cells in TKI-treated CML patients. Here, we analyzed the expression and predictive value of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein transcript levels in white blood cells of CML patients (n = 97) at the time of diagnosis by means of qRT-PCR. We establish a novel distance (cut-off) score based on ESPL1, PTTG1 and PTTG1IP gene expression levels that can serve as predictors of TKI non-response in about 10% of analyzed non-responding patients and may have potential benefit for the risk stratification of CML patients. The achievement of major molecular response (MMR, BCR::ABL1 ≤ 0.1% IS) within the first year of treatment with tyrosine kinase inhibitors (TKI) is a milestone in the therapeutic management of patients with newly diagnosed chronic myeloid leukemia (CML). We analyzed the predictive value of gene expression levels of ESPL1/Separase, PTTG1/Securin and PTTG1IP/Securin interacting protein for MMR achievement within 12 months. Relative expression levels (normalized to GUSB) of ESPL1, PTTG1 and PTTG1IP in white blood cells of patients (responders n = 46, non-responders n = 51) at the time of diagnosis were comparatively analyzed by qRT-PCR. 3D scatter plot analysis combined with a distance analysis performed with respect to a commonly calculated centroid center resulted in a trend to larger distances for non-responders compared to the responder cohort (p = 0.0187). Logistic regression and analysis of maximum likelihood estimates revealed a positive correlation of distance (cut-off) with non-achieving MMR within 12 months (p = 0.0388, odds ratio 1.479, 95%CI: 1.020 to 2.143). Thus, 10% of the tested non-responders (cut-off ≥ 5.9) could have been predicted already at the time of diagnosis. Future scoring of ESPL1, PTTG1 and PTTG1IP transcript levels may be a helpful tool in risk stratification of CML patients before initiation of TKI first = line treatment.
In 2000, the European Union (EU) introduced orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products ...(COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as PA and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.
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Palomo, Mariz and colleagues describe the particularities of viral vector-based gene therapy products seeking for the OD in rare non-oncological conditions. Moreover, the authors dig into the usage of regulatory incentives and how the sponsors can benefit from these schemes.
•We tested emotion regulation (ER) and food processing in restrained eaters (RE).•ER significantly reduced P300 and LPP compared to a food control condition.•P300 and subjective craving were ...significantly correlated.
This study tested the effects of cognitive regulation (CR) on the attentional processing of food cues in restrained eaters (RE) by means of event-related potentials (ERPs). In a within-subject-design, RE (n = 23) were presented pictures of highly palatable food and office items while ERPs were recorded. Prior to the presentation of the food stimuli, participants were either instructed to engage in reappraisal or to attempt to suppress cravings – both cognitive regulation (CR) strategies – or to simply watch the pictures. Prior to the presentation of the neutral stimuli, participants were instructed to simply watch them. Following each picture presentation, momentary craving was assessed. Main results showed that engaging in CR significantly reduced ERP amplitudes compared to the food watch condition. Passively attending to food pictures yielded significantly higher craving scores compared to engaging in CR. In addition, craving was significantly lower in the reappraisal than in the suppression condition. Therefore, reappraisal could potentially increase the ability to inhibit the appetitive motivation to eat.
Figure Legend – Patients presenting at the emergency department in whom acute myocardial infarction is not the issue undergoing coronary angiography for suspected obstructive coronary artery disease ...with presenting symptoms, presence of intermediate risk criteria* (diabetes mellitus, renal insufficiency (eGFR <60 ml/min/1.73m2), early post-infarction angina (defined as <3 months after AMI), prior coronary revascularization, or a GRACE Score between 110 and 139) or prior non-invasive, image-guided testing** (with either stress-echocardiography, coronary CT-angiography, myocardial perfusion scintigraphy or stress cardiac magnetic resonance imaging). Evaluation of the guideline adherence in the use of a coronary angiography according to the 2015 and 2020 European Society of Cardiology guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation*** (ESC ACS GL), respectively.
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•Guideline-adherent use of coronary angiography in 64% with the 2015 but only 20% with the 2020 ESC-ACS guideline recommendations.•Fundamental shift in recommendations from invasive to non-invasive testing between the 2015 and 2020 ESC-ACS guidelines.•Efforts to overcome structural barriers to expand the use of non-invasive image guided testing are crucial.
For patients with acute myocardial infarction (AMI), direct coronary angiography (CA) is recommended, while for non-AMI patients, the diagnostic work-up depends on clinical criteria. This analysis provides initial prospective German data for the degree of guideline-adherence (GL) in the use of CA on non-AMI patients presenting at the emergency department (ED) with suspected acute coronary syndrome (ACS) according to the 2015 ESC-ACS-GL. Furthermore the implications of the application of the 2020 ESC-ACS-GL recommendations were evaluated.
Patient symptoms were identified using a standardized questionnaire; medical history and diagnostic work-up were acquired from health records. In accordance with the 2015 ESC-ACS-GL, CA was considered GL-adherent if intermediate risk criteria (IRC) were present or non-invasive, image-guided testing (NIGT) was pathological.
Between January 2019 and August 2021, 229 patients were recruited across seven centers. Patients presented with chest pain, dyspnea, and other symptoms in 66.7%, 16.2% and 17.1%, respectively, were in mean 66.3 ± 10.5 years old, and 36.3% were female. In accordance with the 2015 ESC-ACS-GL, the use of CA was GL-adherent for 64.0% of the patients. GL-adherent compared to non-adherent use of CA resulted in revascularization more often (44.5% vs. 17.1%, p < 0.001). Applying the 2020 ESC-ACS-GL, 20.4% of CA would remain GL-adherent.
In the majority of cases, the use of CA was adherent to the 2015 ESC-ACS-GL. With regard to the 2020 and 2023 ESC-ACS-GL, efforts to expand the utilization of NIGT are crucial, especially as GL-adherent use of CA is more likely to result in revascularization.
(German Clinical Trials Register DRKS00015638; https://drks.de/search/de/trial/DRKS00015638; (registration date: 19 February 2019))
Purpose
Numerous studies highlight the relevance of body image in the development and maintenance of overweight and obesity mostly using self-reported data. Given the importance of physiological ...assessment methods, the present study aimed at investigating vocally encoded emotional arousal as a correlate of body distress in women with overweight and obesity.
Methods
Cognitions of women with overweight and obesity (OW;
n
= 22) as well as normal weight controls (NW;
n
= 22) were assessed by means of a thought-sampling procedure during a mirror exposure and a control condition. Fundamental frequency (
f
0) as a marker of vocally encoded emotional arousal as well as verbalized body-related cognitions were analyzed during this experimental task.
Results
A stronger increase in
f
0 between the control and the mirror exposure condition was found in OW compared to NW. Furthermore, there were significant positive correlations between vocally encoded emotional arousal and various measures of body image.
Conclusion
The findings support the utility of vocally encoded emotional arousal as an objective physiological correlate of the evaluative dimension of body image in women with overweight and obesity.
Level of evidence
Level I, experimental study.
Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Dysregulation of protein synthesis plays a major role in carcinogenesis, a process regulated at multiple ...levels, including translation of mRNA into proteins. Ribosome assembly requires correct association of ribosome subunits, which is ensured by eukaryotic translation initiation factors (eIFs). eIFs have become targets in cancer therapy studies, and promising data on eIF6 in various cancer entities have been reported. Therefore, we hypothesised that eIF6 represents a crossroad for pulmonary carcinogenesis. High levels of eIF6 are associated with shorter patient overall survival in adenocarcinoma (ADC), but not in squamous cell carcinoma (SQC) of the lung. We demonstrate significantly higher protein expression of eIF6 in ADC and SQC than in healthy lung tissue based on immunohistochemical data from tissue microarrays (TMAs) and on fresh frozen lung tissue. Depletion of eIF6 in ADC and SQC lung cancer cell lines inhibited cell proliferation and induced apoptosis. Knockdown of eIF6 led to pre-rRNA processing and ribosomal 60S maturation defects. Our data indicate that eIF6 is upregulated in NSCLC, suggesting an important contribution of eIF6 to the development and progression of NSCLC and a potential for new treatment strategies against NSCLC.
•eIF6 is overexpressed in non–small cell lung cancer and is associated with worse overall survival in adenocarcinoma.•Knockdown of eIF6 in lung cancer cells reduces proliferation and induces apoptosis.•Depletion of eIF6 leads to pre-rRNA processing and ribosomal 60S maturation defects.
Abstract Recent models on the development and maintenance of eating disorders propose negative emotions to be important precursors for the occurrence of eating disorder symptomatology. In fact, ...previous research on bulimia nervosa (BN) and binge eating disorder provides evidence that negative emotions are an antecedent condition for binge eating. However, there is a lack of research examining the influence of negative emotions on restrictive eating and exercising in individuals with anorexia nervosa (AN). In an experimental study, women with AN ( n =39) and BN ( n =34) as well as a non-eating disordered control group (CG; n =34) watched a sadness-inducing film clip. Before and after the film clip participants rated their current desire to engage in dietary restriction (DTR) and desire to exercise (DTE). Main results reveal that DTR significantly increased after the film clip in women with AN only, while DTE decreased over time in all groups. Results are in line with the notion that negative emotions have a prominent influence on the core eating pathology in AN.
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