Desmethylclomipramine triggers mitochondrial damage and death in TGF-ß-induced mesenchymal type of A549 cells.

Lung cancer is the leading cause of cancer deaths, where the metastasis often causes chemodrug resistance and leads to recurrence after treatment. Desmethylclomipramine (DCMI), a bioactive metabolite of clomipramine, shows the therapeutic efficacy with antidepressive agency as well as potential cytostatic effects on lung cancer cells. Here, we demonstrated that DCMI effectively caused transforming growth factor (TGF)-ß1-mediated mesenchymal type of A549 cells to undergo mitochondrial death via myeloid cell leukemia-1 (Mcl-1) suppression and activation of truncated Bid (tBid). TGF-ß1 induced epithelial mesenchymal transition in A549 cells with the increase of fibronectin and decrease of E-cadherin, the activation of Akt/glycogen synthase kinase-3ß (GSK-ß)/Mcl-1 axis, and the hypo-responsiveness to cisplatin. DCMI initiated a dose-dependent cytotoxicity on TGF-ß1-mediated mesenchymal type of A549 cells through inactivating Akt/GSK-ß/Mcl-1 axis, in which mitochondria instability and caspase-9/3 activation also occurred concurrently. Pharmacological inhibition of caspase-8 and cathepsin B partly reversed tBid expression and mitochondrial damage to further attenuate DCMI-mediated cytotoxicity. Additionally, DCMI presented partial therapeutic effects in treating mesenchymal type of A549 tumor bearing nude mice through an acceleration of cancer cell death. Taken together, DCMI exerts antitumor effects via initiating the mechanisms of Akt/GSK-ß/Mcl-1 inactivation and cathepsin B/caspase-8-regulated mitochondrial death, which suggests its potential role in mesenchymal type of cancer cell therapy.

Determinants of Parental Intention to Vaccinate Young Adolescent Girls against the Human Papillomavirus in Taiwan: An Online Survey Study.

Since 2018, Taiwan has included the human papillomavirus (HPV) vaccination into its national immunization program for junior high school girls. However, the reports of side effects following vaccination have increased parental concerns. This study investigated parental intentions regarding the HPV vaccination for their daughters and related factors in Taiwan. A total of 213 parents of girls aged between 12 and 15 years participated in an online survey. The survey collected data on various factors, including the parental intention to vaccinate their daughters against HPV; the motivation behind the vaccinations, as measured using the Motors of Human Papillomavirus Vaccination Acceptance Scale; an understanding of the reasons behind the government's promotion of HPV vaccinations; concerns regarding the side effects of vaccinations for their daughters; an awareness of the reported side effects of HPV vaccines experienced by some individuals; the exposure to information on HPV vaccines from social media; and mental health status, measured using the Brief Symptom Rating Scale. The associations between these variables and the parental intention to vaccinate their daughters against HPV were examined using a multivariable linear regression analysis model. The findings revealed a moderate to high level of intention among participants to vaccinate their daughters against HPV. Parents who perceived a greater value in HPV vaccination for their daughters' health (B = 0.524, standard error [se] = 0.039, p < 0.001) and had greater autonomy in decision-making regarding vaccination (B = 0.086, se = 0.038, p = 0.026) exhibited a higher intention to vaccinate their daughters against HPV. Conversely, parents who expressed greater concern regarding the side effects of HPV vaccines for their daughters had a lower intention to vaccinate (B = -0.762, se = 0.203, p < 0.001). Based on these findings, this study recommends integrating these factors into the design of intervention programs aimed at enhancing parental intentions to vaccinate their daughters against HPV.

Epidemiological profiles and pathogenicity of Vancomycin-resistant Enterococcus faecium clinical isolates in Taiwan.

The emerging Vancomycin-resistant Enterococcus faecium (VRE-fm) is an opportunistic pathogen causing nosocomial infections. The identification of VRE-fm is important for successful prevention and control in healthcare settings. VRE-fm clinical isolates obtained from regional hospitals in northern Taiwan were characterized for antimicrobial susceptibility, virulence genes and biofilm production. Most isolates exhibited multi-drug resistance and carried the virulence genes, esp and hyl. While all isolates produce biofilms, those isolates that carried esp exhibited greater biofilm production. Isolates with different virulence gene carriages were examined for pathogenicity by using a nematode model, Caenorhabditis elegans, for determining microbial-host interactions. The survival assay showed that C. elegans was susceptible to Linezolid-resistant VRE-fm isolates with hyl. Combining the molecular epidemiological profiles regarding pathogenesis in C. elegans can serve as a guide for physicians in limiting opportunistic infections caused by VRE-fm.

Association of Affiliate Stigma with Parenting Stress and Its Moderators among Caregivers of Children with Attention-Deficit/Hyperactivity Disorder.

Caring for children with attention-deficit/hyperactivity disorder (CADHD) is stressful for caregivers. Identifying factors related to parenting stress in caregivers of CADHD can facilitate the development of intervention programs. This study aimed to examine the associations between affiliate stigma and various domains of parenting stress among caregivers of CADHD. This study also analyzed the moderating effects of demographic characteristics and the symptoms of childhood ADHD and oppositional defiant disorder (ODD) on the associations between affiliate stigma and parenting stress. In total, 213 caregivers of CADHD participated in this study. Parenting stress was assessed using the Parenting Stress Index, Fourth Edition Short Form (PSI-4-SF). Affiliate stigma was assessed using the Affiliate Stigma Scale. ADHD and ODD symptoms were assessed using the Parent Form of the Swanson, Nolan, and Pelham Scale, Version IV. The results indicated that higher affiliate stigma was significantly associated with greater parenting stress in all three domains of the PSI-4-SF. ODD symptoms increased the magnitude of parenting stress in two domains of parenting stress among caregivers with affiliate stigma. Intervention programs for relieving parenting stress among caregivers of CADHD should take affiliate stigma and child ODD symptoms into consideration.

Risks of attention-deficit/hyperactivity disorder, autism spectrum disorder, and intellectual disability in children delivered by caesarean section: A population-based cohort study.

This population-based study investigated the risks of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disabilities among children delivered by Cesarean section (CS) in comparison with those who were delivered by vaginal delivery (VD). The Taiwan Maternal and Child Health Database from 2004 to 2016 registered 675,718 and 1,208,983 children delivered by CS and by VD, respectively. The results of Cox proportional hazards regression model demonstrated that children delivered by CS had significantly higher risks of ADHD, ASD, and intellectual disability than those delivered by VD after the confounding effects of maternal and child factors were controlled for.

Redox and Metabolic Regulation of Intestinal Barrier Function and Associated Disorders.

The intestinal epithelium forms a physical barrier assembled by intercellular junctions, preventing luminal pathogens and toxins from crossing it. The integrity of tight junctions is critical for maintaining intestinal health as the breakdown of tight junction proteins leads to various disorders. Redox reactions are closely associated with energy metabolism. Understanding the regulation of tight junctions by cellular metabolism and redox status in cells may lead to the identification of potential targets for therapeutic interventions. In vitro and in vivo models have been utilized in investigating intestinal barrier dysfunction and in particular the free-living soil nematode, Caenorhabditis elegans, may be an important alternative to mammalian models because of its convenience of culture, transparent body for microscopy, short generation time, invariant cell lineage and tractable genetics.

Functional impairment, insight, and comparison between criteria for gaming disorder in the International Classification of Diseases, 11 Edition and internet gaming disorder in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

Aim: This study evaluated the consistency between the International Classification of Diseases, 11th Edition (ICD-11) for gaming disorder (ICD-11-GD) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for internet gaming disorder (DSM-5-IGD). Moreover, the functional impairment of participants and their insight of their GD were evaluated. Methods: We recruited 60 participants with GD, 45 participants who engaged in hazardous gaming (HG), and 120 controls based on a diagnostic interview. Their operationalization of functional impairment and stage of change were evaluated by interviews and questionnaires, including the Brief Gaming Negative Consequence Scale (BGNCS). Results: We observed satisfactory consistency (kappa value = 0.80) with a diagnostic accuracy of 91.5% between the ICD-11-GD and DSM-5-IGD criteria. Furthermore, 16 participants with IGD in DSM-5 were determined to have HG based on the ICD-11 criteria. Participants of GD group experienced impaired functioning in their health (96.7%), career (73.3%), social life (61.6%), academic performance (36.7%), and job performance (35%). Moreover, a proportion of them were in the pre-contemplation (25.0%), contemplation (61.7%), preparation (10%), and action stages (3.3%). Conclusion: There is a good consistency between ICD-11-GD and DSM-5-IGD criteria. The ICD-11 criteria have a high threshold for diagnosing GD. HG criteria could compensate for this high threshold and identify individuals with a gaming-related functional impairment who require help. Most of the participants with GD were in the early stage of change. Interventions to promote their insight are essential. The BGNCS can be used to examine the negative consequences of gaming and aid mental health professionals in assessing functional impairment.

Cardiac Autonomic and Cardiac Vagal Control During and After Depressive and Happiness Autobiographical Memories in Patients With Major Depressive Disorder.

Background: Heart rate variability (HRV) and respiratory sinus arrhythmia (RSA) are indices of cardiac autonomic and cardiac vagal control (CVC), both of which are markers of emotional regulation and physical health. This study examined (1) the differences in cardiac autonomic regulation and CVC during baseline, depressive, and happiness autobiographical memory tasks between participants with major depressive disorder (MDD group) and healthy controls (HC group); (2) the associations between depressive symptoms and cardiac autonomic and CVC; and (3) the reactivity and recovery of cardiac autonomic and CVC between the MDD and HC groups. Methods: A total of 168 and 178 participants were included in the MDD and HC groups, respectively. Demographic data and the Beck Depression Inventory-II were collected before the experimental procedure. Lead II electrocardiograph (ECG) was measured during baseline, depressive, and happiness autobiographical memory tasks, and then interbeat intervals from ECG were converted to the time and frequency domains of HRV and RSA. Results: The participants in the MDD group showed lower HRV (including standard deviation of normal to normal intervals, low frequency, the natural logarithm of low frequency, and the natural logarithm of high frequency) and CVC (RSA and lnRSA) than those in the HC group. Depressive symptoms were positively correlated with heart rate and negatively correlated with the indices of cardiac autonomic and CVC. There was significantly increased reactivity and recovery of cardiac autonomic and CVC during and after depressive and happiness autobiographical memory tasks in the HC group, but not in the MDD group. Discussion: Participants with MDD had cardiac autonomic and CVC dysregulation, decreased reactivity, and did not recover to baseline after emotional provocations. These results can be the theoretical basis for clinical intervention by using HRV biofeedback to restore cardiac autonomic regulation and CVC during and after emotional events in the future.

The Effects of Heart Rate Variability (HRV) Biofeedback on HRV Reactivity and Recovery During and After Anger Recall Task for Patients with Coronary Artery Disease.

Patients with coronary artery disease (CAD) often experience anger events before cardiovascular events. Anger is a psychological risk factor and causes underlying psychophysiological mechanisms to lose balance of the autonomic nervous system (ANS). The heart rate variability (HRV) was the common index for ANS regulation. It has been confirmed that heart rate variability biofeedback (HRV-BF) restored ANS balance in patients with CAD during the resting state. However, the effects of HRV-BF during and after the anger event remain unknown. This study aimed to examine the effects of HRV-BF on ANS reactivity and recovery during the anger recall task in patients with CAD. This study was a randomized control trial with a wait-list control group design, with forty patients in the HRV-BF group (for six sessions) and 44 patients in the control group. All patients received five stages of an anger recall task, including baseline, neutral recall task, neutral recovery, anger recall task, and anger recovery. HRV reactivity in the HRV-BF group at the post-test was lower than that in the control group. HRV recovery at the post-test in the HRV-BF group was higher than that in the control group. The HRV-BF reduced ANS reactivity during anger events and increased ANS recovery after anger events for CAD patients. The possible mechanisms of HRV-BF may increase total HRV, ANS regulation, and baroreflex activation at anger events for patients with CAD, and may be a suitable program for cardiac rehabilitation.

SHP2: The protein tyrosine phosphatase involved in chronic pulmonary inflammation and fibrosis.

Chronic respiratory diseases (CRDs), including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), lung cancer, and asthma, are significant global health problems due to their prevalence and rising incidence. The roles of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) in controlling tyrosine phosphorylation of targeting proteins modulate multiple physiological cellular responses and contribute to the pathogenesis of CRDs. Src homology-2 domain-containing PTP2 (SHP2) plays a pivotal role in modulating downstream growth factor receptor signaling and cytoplasmic PTKs, including MAPK/ERK, PI3K/AKT, and JAK/STAT pathways, to regulate cell survival and proliferation. In addition, SHP2 mutation and activation are commonly implicated in tumorigenesis. However, little is known about SHP2 in chronic pulmonary inflammation and fibrosis. This review discusses the potential involvement of SHP2 deregulation in chronic pulmonary inflammation and fibrosis, as well as the therapeutic effects of targeting SHP2 in CRDs.

Association of Internet gaming disorder with catechol-O-methyltransferase: Role of impulsivity and fun-seeking.

Dopamine functioning is an essential mechanism underlying addictive behaviors. This paper evaluates the association of Internet gaming disorder (IGD) with the catechol-O-methyltransferase (COMT) val158met polymorphism and examines the roles of impulsivity and reinforcement sensitivity in this association. Using diagnostic interviews, this study recruited 69 participants with IGD and 138 participants without. All participants underwent diagnostic interviews for IGD and an evaluation for the COMT val158met polymorphism, impulsivity, and reinforcement sensitivity. Among participants with the Val/Val genotype, the odds ratio (95% confidence interval) for IGD was 2.09 (1.15-3.80). The IGD-Val/Val genotype association was mediated by impulsivity and fun-seeking. The Val/Val genotype is indicative of low frontal functioning and is a predictive factor of IGD, with this effect being confounded by impulsivity and fun-seeking. Interventions targeting impulsivity and fun-seeking might attenuate the risk of IGD, particularly among individuals with the Val/Val genotype. Additional studies are necessary to elucidate the possible role of dopamine functioning.

Prefrontal Lobe and Posterior Cingulate Cortex Activations in Patients with Major Depressive Disorder by Using Standardized Weighted Low-Resolution Electromagnetic Tomography.

BACKGROUND: The differences in brain activity between patients with major depressive disorder (MDD) and healthy adults have been confirmed by functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and electroencephalography (EEG). The prefrontal lobe and posterior cingulate cortex (PCC) are related to emotional regulation in patients with MDD. However, the high cost and poor time resolution of fMRI and PET limit their clinical application. Recently, researchers have used high time resolution of standardized weighted low-resolution electromagnetic tomography (swLORETA) to investigate deep brain activity. This study aimed to convert raw EEG signals into swLORETA images and explore deep brain activity in patients with MDD and healthy adults. METHODS: BrainMaster EEG equipment with a 19-channel EEG cap was used to collect resting EEG data with eyes closed for 5 min. NeuroGuide software was used to remove the EEG artifacts, and the swLORETA software was used to analyze 12,700 voxels of current source density (CSD) for 139 patients with MDD and co-morbid anxiety symptoms (mean age = 43.08, SD = 13.76; 28.78% were male) and 134 healthy adults (mean age = 40.60, SD = 13.52; 34.33% were male). Deep brain activity in the frontal lobe and PCC at different frequency bands was analyzed, including delta (1-4 Hz), theta (5-7 Hz), alpha (8-11 Hz), beta (12-24 Hz), beta1 (12-14 Hz), beta2 (15-17 Hz), beta3 (18-24 Hz), and high beta (25-29 Hz). RESULTS: There was lower delta and theta and higher beta, beta1, beta2, beta3, and high-beta activity at the prefrontal lobe (dorsal medial prefrontal cortex [dmPFC], ventral medial prefrontal cortex [vmPFC], and dorsal lateral prefrontal cortex [dlPFC], ventral lateral prefrontal cortex [vlPFC], orbital frontal cortex [OFC]) and PCC in MDD patients compared with healthy adults. There was no significant difference in alpha activity between the two groups. CONCLUSION: This study indicates brain hyperactivity in the right prefrontal lobe (dlPFC and vmPFC) and PCC in patients with MDD with co-morbid anxiety symptoms, and the dlPFC and PCC were also related to emotion regulation in MDD. Inhibiting high-beta activity or restoring delta and theta activity to the normal range in the right frontal lobe and PCC may be possible in z-score neurofeedback protocols for patients with MDD in future studies.

The association between Emotional Regulation and Internet Gaming Disorder.

PURPOSE: Lack of control over Internet gaming habits may result in negative consequences. This study aimed to evaluate the emotional regulation of adults with Internet gaming disorder (IGD) and the association of emotion regulation, depression, and hostility. METHODS: Advertisements were used to recruit 69 young adults with IGD, 69 sex- and age-matched controls, and 69 sex- and age-matched regular gamers. The diagnosis of IGD was according to diagnostic interviews based on DSM-5 IGD research criteria. Participants completed the Affective Style Questionnaire, the center of epidemiological studies depression scale and the short-form Chinese version of Buss-Durkee Hostility Inventory. RESULTS: In the IGD group, the emotion adjustment score was significantly lower, whereas the scores for depression, and hostility were significantly higher than in the other two groups. In addition, emotion adjustment is the most associated emotion regulation behavior of IGD, followed by emotion concealment. In IGD group, emotion adjustment had a negative correlation with depression and hostility. CONCLUSIONS: Our study demonstrate that emotion adjustment is significantly associated with IGD. The depression and hostility mediated the association. Knowing that emotion adjustment plays a critical role in IGD, future interventions should focus on this subscale of emotion regulation.

Neurocognitive function in clinically stable individuals with long-term bipolar I disorder: Comparisons with schizophrenia patients and controls.

This study compared the levels of the five domains of neurocognitive function-executive function, attention, memory, verbal comprehension, and perceptual organization-among clinically stable individuals with long-term bipolar I disorder, individuals with long-term schizophrenia, and a group of controls. We recruited a total of 93 clinically stable individuals with bipolar I disorder, 94 individuals with schizophrenia, and 106 controls in this study. Their neurocognitive function was measured using a series of neurocognitive function tests: the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), Line Cancellation Test, Visual Form Discrimination, Controlled Oral Word Association Test, Wisconsin Card Sorting Test, Continuous Performance Task, and Wechsler Memory Scale-Third Edition. Neurocognitive function was compared among the three groups through a multivariate analysis of variance. The results indicated that when the effect of age was controlled, clinically stable individuals with bipolar I disorder and those with schizophrenia demonstrated poor neurocognitive function on all tests except for the WAIS-III Similarity and Information and the Line Cancellation Test. The individuals with bipolar I disorder had similar levels of neurocognitive function compared with the schizophrenia group, but higher levels of neurocognitive function on the WAIS-III Comprehension, Controlled Oral Word Association Test, and Wechsler Memory Scale-Third Edition Auditory Immediate and Delayed Index and Visual Immediate and Delayed Index. The conclusions of this study suggest that compared with controls, individuals with long-term bipolar I disorder and those with long-term schizophrenia have poorer neurocognitive function, even when clinically stable. Individuals with long-term bipolar I disorder and those with long-term schizophrenia have similar levels of deficits in several domains of neurocognitive function.