New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol.

BACKGROUND: Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported. METHODS: The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet. RESULTS: We identified 2 PCSK9 mutations-E144K and C378W-in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus-mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum. CONCLUSIONS: Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well.

Clinical application of repetitive transcranial magnetic stimulation for post-traumatic stress disorder: A literature review.

The efficacy of traditional treatment for post-traumatic stress disorder (PTSD) is still unsatisfactory. Repetitive transcranial magnetic stimulation (rTMS) has been widely used in the treatment of various types of mental disorders, including PTSD. Although rTMS has been demonstrated to be effective in many cases, there are still arguments regarding its mechanism and protocol. This review aims to summarize the origin, development, principle, and future direction of rTMS and introduce this neuro-stimulation therapy to relevant clinicians.

SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1.

Inducible degrader of the low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase mediating degradation of low-density lipoprotein (LDL) receptor (LDLR). IDOL also controls its own stability through autoubiquitination, primarily at lysine 293. Whether IDOL may undergo other forms of posttranslational modification is unknown. In this study, we show that IDOL can be modified by small ubiquitin-like modifier 1 at the K293 residue at least. The SUMOylation of IDOL counteracts its ubiquitination and augments IDOL protein levels. SUMOylation and the associated increase of IDOL protein are effectively reversed by SUMO-specific peptidase 1 (SENP1) in an activity-dependent manner. We further demonstrate that SENP1 affects LDLR protein levels by modulating IDOL. Overexpression of SENP1 increases LDLR protein levels and enhances LDL uptake in cultured cells. On the contrary, loss of SENP1 lowers LDLR levels in an IDOL-dependent manner and reduces LDL endocytosis. Collectively, our results reveal SUMOylation as a new regulatory posttranslational modification of IDOL and suggest that SENP1 positively regulates the LDLR pathway via deSUMOylation of IDOL and may therefore be exploited for the treatment of cardiovascular disease.

The psychological impact of COVID-19 on the families of first-line rescuers.

Under the COVID-19 epidemic, the families of front-line rescue workers are under unusual pressure. We aim to understand the extent of their psychological distress in this epidemic and whether they have received sufficient support. Thus targeted to provide support for them and indirectly reduce the concerns of the rescue workers. From February 27 to March 1, 2020, we used the scales of Perceived Stress Scale, 10-items Connor-Davidson Resilience Scale, Generalized Anxiety Disorder-7, Patient Health Questionnaire-2, and primary care-posttraumatic stress disorder (PTSD) to evaluate the mental health level of the family members of front-line rescue workers online. Six hundred and seventy one family members voluntarily filled out the questionnaire after reading the purpose of the study. A total of 671 family members of front-line rescue workers participated in the survey, including 194 husbands/wives, 52 parents, 49 children, 76 brothers and sisters, and 300 other relationships. Among them, 55% of the family members reported sleep problems, 49.0% of the family members had mild, and above anxiety symptoms, 12.2% of the family members reported clinically significant depression symptoms, and 10.4% of the family members may have PTSD, 8.3% of family members had thoughts of self-injury or suicide. The feeling of stress was positively correlated with anxiety and depression, but there was no significant correlation between psychological elasticity and various symptoms. Family members who are more worried about the safety, physical condition and living security of front-line rescue workers are more likely to report symptoms such as sleep disorders, anxiety, and depression. Family members' first-line rescue has a significant impact on their daily life, raising children and supporting the elderly, which is also related to the occurrence of mental and psychological symptoms. During the period of front-line support, they received support from the units or organizations of the first-line workers, mainly including telephone greetings and daily necessities. The top three concerns about the information of the epidemic were the time of the end of the epidemic, the time of the return of the family and the progress of COVID-19's treatment. After the end of the epidemic, what they most want to do is to pay more attention to and accompany their families, family gatherings, and do more exercise. The psychological impact of this epidemic on the families of front-line rescue workers is mainly sleep problems and anxiety. The psychological intervention of family members should mainly start from the relief of stress and increase of material and spiritual support.

Psychometric property study of the posttraumatic stress disorder checklist for DSM-5 (PCL-5) in Chinese healthcare workers during the outbreak of corona virus disease 2019.

BACKGROUND: Previous studies about the reliability and validity of the updated PCL version for the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (PCL-5) have only been evaluated in certain samples of the population, which lacks in the sample of Healthcare Workers. Our study focused on the factor structure, reliability and validity of the PCL-5 among Chinese Healthcare Workers during the Outbreak of Corona Virus Disease 2019. METHODS: We conducted an online survey of frontline healthcare workers using the PCL-5 for PTSD. Total of 212 frontline healthcare providers were included in this study. RESULTS: The findings showed that PCL-5 is a reliable instrument in our sample. The total and subscale scores showed good internal consistency. The convergent and discriminant validity of the PCL-5 were also well demonstrated. Our result showed a better fit with the seven-factor hybrid model compared with other models and supported that the PCL-5 Chinese version can be used as a reliable screening tool to conduct psychological screening for Chinese healthcare workers. LIMITATION: We could not examine other aspects of reliability and validity like test-retest reliability or criterion validity. We didn't use the gold-standard structured interview for PTSD in our study. Besides, most of our samples were young people who had access to the internet. Not all professional levels and seniorities were presented because our sample had a lower mean income and educational level. CONCLUSION: Our study shows that the Chinese PCL-5 has good validity and reliability in frontline healthcare workers during the outbreak.

The correlation between adiponectin and FGF9 in depression disorder.

Adiponectin (ADPN) and fibroblast growth factor 9 (FGF9) has been reported as anti-depressive and pro-depressive factor, respectively. However, it is unknown whether there is directly interaction between ADPN and FGF9 in depression. The present study aims to investigate the correlation between ADPN and FGF9 in depression disorder. Firstly, the decreased level of ADPN and the increased level of FGF9 in plasma of depressive patients compared with non-depressive subjects were observed. Furthermore, these is a significant negative correlation between the ratio of ADPN to FGF9 and the total score of Hamilton Depression Scale in total investigated subjects. The similar changes of ADPN and FGF9 were also observed in elder adiponectin gene knockout (Adipo-/-) mice with an increasing trend to depressive-like behaviors. Secondly, the decreasing level of ADPN and increasing level of FGF9 in plasma and hippocampus tissues were observed in chronic unpredictable mild stress (CUMS)-induced depression in ICR mice with significant depressive-like behaviors and hippocampus damage, which attenuated by injection of recombinant ADPN or FGF9 antibody into lateral ventricle. In Adipo-/- mice, injection of FGF9 antibody into lateral ventricle also attenuated CUMS-induced depressivelike behaviors. The protein expression of FGF receptor 3 (FGFR3), the main receptor of FGF9, was significantly down-regulated in hippocampus tissues of CUMS-treated mice, which could be attenuated by treatment with either recombinant ADPN or anti-FGF9. In summary, the present results suggest that ADPN maybe a key negative regulator of FGF9/FGFR3 in depressive disorder and the dysfunction of ADPN-FGF9 pathway plays a key role in stress-induced depression.

A shared effect of paroxetine treatment on gray matter volume in depressive patients with and without childhood maltreatment: A voxel-based morphometry study.

AIMS: This study assessed whether antidepressant drug treatment has a common effect on gray matter (GM) volume in MDD patients with and without childhood maltreatment (CM). METHODS: T1-weighted structural magnetic resonance imaging data were collected from 168 participants, including 51 MDD patients with CM, 31 MDD patients without CM, 48 normal controls with CM, and 38 normal controls without CM. MDD patients received 6 months of treatment with paroxetine, and 24 patients with CM, and 16 patients without CM received a second MRI scan. A whole-brain voxel-based morphometry approach was used to estimate GM volume in each participant at two time points. Two-way analysis of variance (ANOVA) was used to determine the effects of MDD and CM on GM volume at baseline. Repeated measures two-way ANOVA was used to determine the treatment-by-CM interactive effect and main effect of treatment during paroxetine treatment. We further investigated the relationship between GM volume and clinical variables. RESULTS: At baseline, significant MDD-by-CM interactive effects on GM volume were mainly observed in the left parahippocampal gyrus, left entorhinal cortex, and left cuneus. GM volume was significantly lower mainly in the right middle temporal gyrus in patients with MDD than in normal controls. We did not find any significant treatment-by-CM interactive effects. However, a treatment-related increase in GM was found in the right middle temporal gyrus in both MDD groups. CONCLUSIONS: These results suggest that paroxetine treatment operates via a shared neurobiological mechanism in MDD patients with and without CM.

Clinical evaluation of the efficacy and safety of tandospirone versus sertraline monotherapy for social anxiety disorder: a randomized open-label trial.

OBJECTIVE: Although selective serotonin reuptake inhibitors are now established as first-line pharmacotherapy for social anxiety disorder (SAD), other agents with different mechanisms have shown promise in treating SAD. The aim of this study was to examine the efficacy and safety of tandospirone in treating adolescents with SAD. METHODS: Adolescent patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for SAD were randomly assigned (1:1) to open-label treatment with either tandospirone or sertraline for 8 weeks. The primary outcome measures were changes from baseline in the Hamilton Anxiety (HAM-A) scale and response using the Clinical Global Impression of Improvement (CGI-I) scale. RESULTS: The adjusted mean change in HAM-A scores from baseline was indicating a significant improvement over baseline in both treatment arms (p < 0.0001). The mean CGI-I scale score at week was with no significant difference between the two arms (p = 0.42). Rates of response were 48.6% for tandospirone and 55.6% for sertraline using the CGI-I. Response rates were 37.1% for tandospirone and 41.7% for sertraline using a HAM-A response criterion (≥50% reduction). The adjusted mean change in Social Phobia Inventory scores from baseline was indicating a significant improvement over baseline in both treatment arms (p < 0.0001). CONCLUSIONS: Tandospirone is safe and effective and appears non-inferior to sertraline for SAD in youths.

Quality of life in major depressive disorder: the role of pain and pain catastrophizing cognition.

OBJECTIVE: Pain symptoms are frequent complaints in patients with major depressive disorder (MDD). Although it is known that pain intensity and pain-related cognition predict quality of life (QOL) in patients with chronic pain, limited studies have examined their roles in MDD. The study aimed to determine whether pain and pain catastrophizing were independent predictors of QOL in MDD after accounting for the impact of anxiety and depression. METHODS: This is a prospective, naturalistic follow-up study. Ninety-one Chinese patients were enrolled during an acute episode of MDD, 82 of them were reassessed 3 months later using the same assessment on pain, anxiety, depression, and QOL. Pain intensity was evaluated using a verbal rating scale and a visual analog scale. Quality of life was assessed using the 36-item Short Form Health Survey. Pain-related cognition was assessed at baseline with the Pain Catastrophizing Scale. RESULTS: There was significant improvement in pain, anxiety, depression, and QOL from baseline to 3-month follow-up. Hierarchical regression analyses showed that pain intensity was significantly associated with QOL at baseline and 3 months. Pain complaint was more important than anxiety and depressive symptoms in predicting changes in both physical and psychosocial domains of QOL. After controlling for the severity of pain, anxiety, and depression, Pain Catastrophizing Scale score was independently associated with QOL in MDD. CONCLUSION: The study supports the specific role of pain and pain-related cognition in predicting QOL in depressed patients. Further studies targeting pain-related cognition for improving the outcome of MDD are necessary.

[Prevalence and risk factors for posttraumatic stress disorder among survivors from a coal mining accident after 2 and 10 months].

OBJECTIVE: To investigate the prevalence of posttraumatic stress disorder (PTSD) among survivors from a coal mining accident after 2 and 10 months and factors related to PTSD. METHODS: To estimate the prevalence of PTSD, 104 miners were surveyed through the PTSD Checklist-Civilian Version (PCL-C). Forty survivors including 24 severe PTSD patients and 24 non-PTSD subjects were evaluated thoroughly. RESULTS: The current prevalence rate among survivors from the coal mining accident at 2 months was 50%. There were significant differences in PTSD symptoms, anxiety and depression, personality, and memory performance between the PTSD patients and non-PTSD controls. State anxiety, time to renew the work, depression, neuroticism, and the place they were staying, and length of service were predictors of PTSD. After 10 months of the accident, 30.6% survivors still met the criterion of PTSD. Compared with 2 months after the accident, PTSD symptoms, anxiety, and memory performance improved clearly, while the depressive symptoms had no significant difference. The state anxiety, time to renew the work, positive coping, emotional balance, and length of service were the factors of PTSD symptom healing. CONCLUSION: The current prevalence of PTSD among survivors from coal mining accident is high. The mining accident has great influence on victims, and psychological or medication interventions are necessary. There are lots of risk factors for the prevalence of PTSD, such as state anxiety, depression, neuroticism, and shorter duration of service. Positive coping may be a beneficial factor for PTSD recovery.

[Effect of 5-HT and postsynaptic 5-HT1 A on the mood and recogniztion of the repeated restraint stress in rats].

OBJECTIVE: To explore the role of 5-HT and postsynaptic 5-HT1A receptors in the stress adaptation. METHODS: p-PCA was used to deplete the 5-HT in rats. The 5-HT1A agonist 8-OH-DPAT and antagonist WAY100635 were used to determine the effect of postsynaptic 5-HT1A receptors on the ratso behaviors in the Elevated Plus-Maze test, the Forced Swimming test, and the Morris Water Maze test. RESULTS: Compared with the intact rats, the 5-HT depleted rats showed more seriously anxious behaviors in the Elevated Plus-Maze test and more obvious learned helplessness in the Forced Swimming test. After having been stressed the 5-HT depleted rats showed significantly impaired learning and memory compared with the intact rats according to Morris Water Maze test. Activation of postsynaptic 5-HT1A receptors by 8-OH-DPAT in the 5-HT depleted rats or the 5-HT depleted stress rats significantly decreased the symptoms of anxiety and learned helplessness behaviors which were prevented by the treatment of WAY100635. The 8-OH-DPAT and WAY100635 had no obvious effect on the 5-HT depletion or 5-HT depleted stress rats in the Morris Water Maze test. CONCLUSION: Deficiency of 5-HT in rats may suppress its ability to stress adaptation. Activation of post-synaptic 5-HT1A receptors can attenuate the anxiety and depressive behavior symptoms, and facilitate rats to adapt stress.

Subsequently enhanced CPP to morphine following chronic but not acute footshock stress associated with corticosterone mechanism in rats.

The purpose of this study was to determine the morphine-induced place preference in rats pre-exposed to footshock stress and corticosterone (CORT). The authors also studied the involvement of dopamine mechanisms in the CORT-induced place preference. The results showed that chronic footshock or CORT exposure but not acute footshock or CORT exposure similarly potentiated the conditioned place preference to morphine. The CORT-induced conditioned place preference were established only with high and middle dose (5, 3 mg/kg) CORT. The dopamine levels in NAc of rats injected with CORT (5, 3, 1 mg/kg, i.p.) increased significantly. The findings suggest that the increase of dopamine levels in NAc induced by CORT might be the medium between stress and morphine.