Problematic Use of Internet Associates with Poor Quality of Life via Psychological Distress in Invididuals with ADHD.

Background: Problematic use of internet (PUI) may have negative impacts on psychological distress and quality of life (QoL). This situation might be more profound in people with attention-deficit/hyperactivity disorder (ADHD) due to poorer behavioral control and regulatory capacity. However, there is little evidence regarding mediated effects in the associations between PUI, psychological distress, and QoL in people with ADHD. Aims: To investigate mediating effects of psychological distress in the associations of problematic smartphone use (PSPU), problematic use of social media (PUSM), and problematic gaming (PG) with QoL in individuals with ADHD. Methods and Procedures: PUI behaviors of participants with ADHD (n = 99) were assessed using the Smartphone Application-Based Addiction Scale, Bergen Social Media Addiction Scale, and Internet Gaming Disorder-Short Form. Psychological distress was assessed using the Depression, Anxiety, Stress Scale and QoL using the Kid-KINDL. Outcomes and Results: Psychological distress mediated the associations between PUI and different domains of QoL, except for self-esteem QoL. There were also positively direct effects between PG and physical QoL, PUSM and friends' QoL, and PSPU and physical QoL. Conclusions and Implications: PUI may associate with poor QoL in people with ADHD via psychological distress. Programs on reducing PUI for people with ADHD are needed.

Family Communication as a Mediator between Family Resilience and Family Functioning under the Quarantine and COVID-19 Pandemic in Arabic Countries.

The coronavirus pandemic has become an unprecedented world crisis in which we have struggled against the most potent threat of the twenty-first century. This pandemic has had a profound impact on individuals and families. Therefore, the study aimed to examine family communication as a mediator of the relationship between family resilience and family functioning under the quarantine and coronavirus pandemic in Algeria and Iraq. This study was conducted among individuals in Iraq and Algeria (N = 361). The respondents completed the Family Communication Scale (FCS), Walsh Family Resilience Questionnaire (WFRQ), and Family Functioning Scale (FFS). Structural equation modeling (SEM) with the bootstrapping method was used to conduct the mediated effects of family communication. Using the bootstrapping method in SEM, family resilience and communication significantly affected family functioning (coefficient = 0.808). Moreover, the direct effect and indirect effect (via family functioning) of family resilience on family functioning were both significant, with coefficients of 0.682 and 0.126. In addition, numerous groups from Iraq and Algeria have been analyzed as a sample and have shown no differences in the relationships between family resilience, family communication, and family functioning. In conclusion, the results showed that family communication mediated the relationship between family resilience and family functioning. Moreover, the type of this mediation seemed to be partial because of the significant direct relationship between family resilience and family functioning. According to the findings, healthcare providers should consider improving family resilience and communication to achieve good family functioning.

Inversely engineered biomimetic flexible network scaffolds for soft tissue regeneration.

Graft-host mechanical mismatch has been a longstanding issue in clinical applications of synthetic scaffolds for soft tissue regeneration. Although numerous efforts have been devoted to resolve this grand challenge, the regenerative performance of existing synthetic scaffolds remains limited by slow tissue growth (comparing to autograft) and mechanical failures. We demonstrate a class of rationally designed flexible network scaffolds that can precisely replicate nonlinear mechanical responses of soft tissues and enhance tissue regeneration via reduced graft-host mechanical mismatch. Such flexible network scaffold includes a tubular network frame containing inversely engineered curved microstructures to produce desired mechanical properties, with an electrospun ultrathin film wrapped around the network to offer a proper microenvironment for cell growth. Using rat models with sciatic nerve defects or Achilles tendon injuries, our network scaffolds show regenerative performances evidently superior to that of clinically approved electrospun conduit scaffolds and achieve similar outcomes to autologous nerve transplantation in prevention of target organ atrophy and recovery of static sciatic index.

PPM1K-regulated impaired catabolism of branched-chain amino acids orchestrates polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common diseases with the coexistence of reproductive malfunction and metabolic disorders. Previous studies have found increased branched chain amino acid (BCAA) levels in women with PCOS. However, it remains unclear whether BCAA metabolism is causally associated with the risk of PCOS. METHODS: The changes of BCAA levels in the plasma and follicular fluids of PCOS women were detected. Mendelian randomization (MR) approaches were used to explore the potential causal association between BCAA levels and the risk of PCOS. The function of the gene coding the protein phosphatase Mg2+/Mn2+-dependent 1K (PPM1K) was further explored by using Ppm1k-deficient mouse model and PPM1K down-regulated human ovarian granulosa cells. FINDINGS: BCAA levels were significantly elevated in both plasma and follicular fluids of PCOS women. Based on MR, a potential direct, causal role for BCAA metabolism was revealed in the pathogenesis of PCOS, and PPM1K was detected as a vital driver. Ppm1k-deficient female mice had increased BCAA levels and exhibited PCOS-like traits, including hyperandrogenemia and abnormal follicle development. A reduction in dietary BCAA intake significantly improved the endocrine and ovarian dysfunction of Ppm1k-/- female mice. Knockdown of PPM1K promoted the conversion of glycolysis to pentose phosphate pathway and inhibited mitochondrial oxidative phosphorylation in human granulosa cells. INTERPRETATION: Ppm1k deficiency-impaired BCAA catabolism causes the occurrence and development of PCOS. PPM1K suppression disturbed energy metabolism homeostasis in the follicular microenvironment, which provided an underlying mechanism of abnormal follicle development. FUNDING: This study was supported by the National Key Research and Development Program of China (2021YFC2700402, 2019YFA0802503), the National Natural Science Foundation of China (81871139, 82001503, 92057107), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-001), Key Clinical Projects of Peking University Third Hospital (BYSY2022043), the China Postdoctoral Science Foundation (2021T140600), and the Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01).

Elevated Levels of Follicular Fatty Acids Induce Ovarian Inflammation via ERK1/2 and Inflammasome Activation in PCOS.

CONTEXT: Polycystic ovary syndrome (PCOS) is accompanied by chronic inflammation and metabolic disorders. Whether metabolic abnormalities affect inflammation in PCOS or not, the underlying mechanism remains to be clarified. OBJECTIVE: We aimed to investigate changes in fatty acids and their effects on inflammatory response in the follicular niche of PCOS patients. METHODS: This study recruited 50 PCOS patients and 50 age-matched controls for follicular fluids and ovarian mural granulosa cells collection. The human ovarian granulosa cell line KGN was used for evaluating the effect of oleic acid (OA) stimulation. The levels of follicular fatty acids were measured by liquid chromatography-tandem mass spectrometry. The concentrations of inflammatory cytokines were detected by electrochemiluminescence and enzyme-linked immunosorbent assays. The regulation of inflammation-related genes was confirmed by quantitative polymerase chain reaction and Western blotting after OA stimuli. RESULTS: Three saturated fatty acids and 8 unsaturated fatty acids were significantly elevated in follicular fluids of PCOS patients compared to those in controls. The concentrations of follicular interleukin (IL)-6, IL-8, and mature IL-18 were significantly higher in the PCOS group and were positively correlated with the levels of fatty acids. Moreover, OA stimulation upregulated the transcription levels of IL-6 and IL-8 via extracellularly regulated kinase 1/2 signaling pathways in KGN cells. Furthermore, OA treatment induced reactive oxygen species production and inflammasome activation, which is manifested by enhanced caspase-1 activity and mature IL-18 protein level. CONCLUSION: Fatty acid metabolism was significantly altered in the follicular niche of PCOS patients. Elevated levels of fatty acids could induce ovarian inflammation both at the transcriptional level and in posttranslational processing.

High power and high pulse repetition frequency transistorized pulser by time base stability improvement and power synthesis technique.

Output power of a transistorized pulser is usually limited by the power capacity of avalanche transistors. To improve the total output power, the power synthesis method is widely used, in which a single pulser with high output power and high time base stability is required. However, the time base stability tends to deteriorate as the output power increases. To improve the output power under the premise of high time base stability, from the perspective of carrier movement, the mechanisms of pulse jitter and pulse drift are investigated. It is found that the pulse jitter is caused by time dispersion of the ionization process in the collector depletion region, while the pulse drift is due to the decrement of the diffusion coefficient Dn and the electron mobility µn, which are both temperature-dependent. Based on the microscopic theoretical study, some macroscopic improvements on the time base stability are made. Some parameters of the trigger pulse and the circuit (e.g., charging capacitance) are optimized experimentally. Consequently, we achieved a pulser with an amplitude of 1.8 kV, pulse jitter of 25 ps, pulse drift of 100 ps/min at a pulse repetition frequency (PRF) of 100 kHz. Additionally, a new parameter k, the product of the highest PRF f and the peak power Ep, is defined to evaluate the output power. With almost the same time base stability, the proposed pulser has a k of 6.48 GHz W, which is improved significantly. Finally, a synthesized pulser with an amplitude of 2.5 kV and highest PRF of 100 kHz is achieved.

Trio-whole-exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations.

Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects. We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018. Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on disease-associated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

A portable ultrawideband electromagnetic radiator with a 1.4 MW/50 kHz solid-state subnanosecond pulser.

In this note, a portable ultrawideband (UWB) electromagnetic radiator is developed based on a transistorized pulser with the peak power of 1.4 MW, the rise time less than 150 ps, and the repetition frequency of 50 kHz. To generate high-amplitude pulses, a 100-stage Marx circuit with parallel connection of multiple transistors is proposed. To improve the pulse repetition rate, the parallel charging Marx circuit is adopted with ferrite beads connected in series between stages for high isolation of pulses. In order to radiate the UWB electromagnetic pulse directionally, a compact combined antenna array is fabricated and connected with the pulser via a coaxial feeding module. The effective potential of the UWB radiator reaches 10.5 kV with the band range (-10 dB) from 173 MHz to 2.32 GHz.

Prevalence of polycystic ovary syndrome in a metabolically healthy obese population.

OBJECTIVE: To determine whether polycystic ovary syndrome (PCOS) prevalence is increased among metabolically healthy obese (MHO) women. METHODS: A national epidemiologic survey in 10 provinces and municipalities of China between October 2007 and September 2011. Women were stratified into four groups according to metabolic health (assessment by Adult Treatment Panel III) and obesity (body mass index [BMI] ≥28): metabolically healthy nonobese (MHNO), metabolically unhealthy nonobese (MUNO), MHO, and metabolically unhealthy obese (MUO). PCOS was diagnosed via Rotterdam Criteria. Participants completed a questionnaire and underwent physical and transvaginal ultrasound examination. BMI, blood pressure, glucose, and lipid profile were measured. RESULTS: The survey included 3551 women. The MHO group had a higher prevalence of PCOS and chronic anovulation versus nonobese groups (all P<0.05). Obesity was a risk factor for PCOS (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.68-3.14, P<0.05). Being metabolically unhealthy was a risk factor for PCOS (OR, 1.32; 95% CI, 1.09-1.60; P<0.05). The MHO group had an increased risk of PCOS relative to the MHNO group (OR, 2.39; 95% CI, 1.42-4.02; P<0.05). CONCLUSION: MHO women had an increased risk of PCOS and chronic anovulation. Obesity might be an independent risk factor for these two disorders.

Metabolic characteristics of normal weight central obesity phenotype polycystic ovary syndrome women: a large-scale national epidemiological survey.

RESEARCH QUESTION: The aim was to investigate the metabolic profiles of women with normal weight but central obesity in polycystic ovary syndrome (PCOS). DESIGN: In total, 727 women with PCOS from a large-scale epidemiological survey were included. Diagnosis of PCOS was based on Rotterdam criteria. Subjects were categorized into four subgroups: (i) normal weight non-central obesity (NWNCO): body mass index (BMI) ≤18.5 kg/m2 to <25 kg/m2 and waist-to-hip ratio (WHR) <0.85; (ii) normal weight central obesity (NWCO): BMI ≤18.5 kg/m2 to <25 kg/m2 and WHR ≥0.85; (iii) obese non-central obesity (ONCO): BMI ≥25 kg/m2 and WHR <0.85; and (iv) obese central obesity (OCO): BMI ≥25 kg/m2 and WHR ≥0.85. BMI, WHR, blood pressure, glucose and lipid profiles were measured. RESULTS: NWCO subjects had significantly higher percentages of insulin resistance, high triglycerides and low high-density lipoprotein cholesterol (HDL-C) than NWNCO subjects (all P < 0.05), and similar percentages compared with ONCO subjects. Compared with the NWNCO group, the NWCO group had higher age-adjusted risks of insulin resistance, high triglycerides and low HDL-C (odds ratio [OR] = 3.83, 95% confidence interval [CI] = 2.23-6.58; OR = 1.66, 95% CI = 1.00-2.77, OR = 1.60, 95% CI = 1.11-2.30, respectively). CONCLUSIONS: PCOS women with normal weight but central obesity had increased risks of insulin resistance and dyslipidaemia compared with normal weight PCOS women without central obesity, suggesting that combining BMI with measurement of central obesity may provide better adiposity-related metabolic risk factor stratification in clinical practice than either method alone.

Insulin resistance and ß-cell dysfunction and the relationship with cardio-metabolic disorders among women with polycystic ovary syndrome.

OBJECTIVE: To investigate both independent and combined effects of insulin resistance and ß-cell dysfunction on cardio-metabolic abnormalities in polycystic ovary syndrome (PCOS). DESIGN: A national epidemiologic survey was performed in reproductive aged females in China from October 2007 to September 2011. METHODS: A total of 824 PCOS and 2715 non-PCOS were included. The Rotterdam Criteria were applied for PCOS diagnosis. We used the homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA of ß-cell function (HOMA-ß) to evaluate insulin resistance and ß-cell dysfunction, respectively. RESULTS: Compared with non-PCOS, PCOS showed a higher index of HOMA-IR and HOMA-ß, and a higher prevalence of obesity, central obesity, and dyslipidaemia. High HOMA-IR was independently related to a high prevalence of obesity, central obesity, dyslipidaemia, and high blood glucose in PCOS. In contrast, a low index of HOMA-ß index was independently correlated with a low prevalence of obesity, and central obesity, but negatively correlated with an elevated prevalence of high blood glucose in PCOS. In addition, proportion of insulin resistance was higher than that of ß-cell dysfunction in PCOS with cardio-metabolic disorders. ß-cell dysfunction was negatively correlated with the prevalence of central obesity and obesity. CONCLUSIONS: Insulin resistance and ß-cell dysfunction independently affected cardio-metabolic abnormalities in PCOS, while insulin resistance was correlated with a higher prevalence of cardio-metabolic abnormalities than that of ß-cell dysfunction. Moreover, ß-cell dysfunction and insulin resistance showed divergent correlations with obesity in PCOS.

[Improving the Storage Integrity of Electroencephalography (EEG) Recordings in the Pediatric Ward].

BACKGROUND & PROBLEMS: A total of 20 cases of children with epilepsy implemented electroencephalography (EEG) recording examinations in our ward between January 1st and March 10th, 2016. Fifteen (75%) of the recordings were incompletely stored, indicating that the EEG recordings storage integrity in our unit was 25%. Incomplete storage of these recordings results in prolonged hospital stays and negatively affects the ability of doctors to provide accurate diagnoses. PURPOSE: This project was developed to increase the EEG recording storage integrity for epileptic children to 100%. RESOLUTIONS: Improvement plans included reinforcing related promotions, formulating a standard flowchart for EEG recording education, making "warm bear signs", designing simple cartoon health-education flashcards, and providing in-service education. RESULTS: The EEG recording storage integrity for epileptic children in our ward rose to 100% after implementation of the resolution measures, which achieved our purpose. CONCLUSIONS: We want to share this experience to improve the storage integrity of EEG recordings at other hospitals and clinics. The greatest benefit of this project was that the family members of children with epilepsy perceived more strongly the effort and care of the nursing staffs during examinations, which reduces the costs of healthcare.

Production of 1-Dodecanol, 1-Tetradecanol, and 1,12-Dodecanediol through Whole-Cell Biotransformation in Escherichia coli.

Medium- and long-chain 1-alkanol and α,ω-alkanediols are used in personal care products, in industrial lubricants, and as precursors for polymers synthesized for medical applications. The industrial production of α,ω-alkanediols by alkane hydroxylation primarily occurs at high temperature and pressure using heavy metal catalysts. However, bioproduction has recently emerged as a more economical and environmentally friendly alternative. Among alkane monooxygenases, CYP153A from Marinobacter aquaeolei VT8 (CYP153A M.aq ; the strain is also known as Marinobacter hydrocarbonoclasticus VT8) possesses low overoxidation activity and high regioselectivity and thus has great potential for use in terminal hydroxylation. However, the application of CYP153A M.aq is limited because it is encoded by a dysfunctional operon. In this study, we demonstrated that the operon regulator AlkR M.aq is functional, can be induced by alkanes of various lengths, and does not suffer from product inhibition. Additionally, we identified a transposon insertion in the CYP153A M.aq operon. When the transposon was removed, the expression of the operon genes could be induced by alkanes, and the alkanes could then be oxyfunctionalized by the resulting proteins. To increase the accessibility of medium- and long-chain alkanes, we coexpressed a tunable alkane facilitator (AlkL) from Pseudomonas putida GPo1. Using a recombinant Escherichia coli strain, we produced 1.5 g/liter 1-dodecanol in 20 h and 2 g/liter 1-tetradecanol in 50 h by adding dodecane and tetradecane, respectively. Furthermore, in 68 h, we generated 3.76 g/liter of 1,12-dodecanediol by adding a dodecane-1-dodecanol substrate mixture. This study reports a very efficient method of producing C12/C14 alkanols and C12 1,12-alkanediol by whole-cell biotransformation.IMPORTANCE To produce terminally hydroxylated medium- to long-chain alkane compounds by whole-cell biotransformation, substrate permeability, enzymatic activity, and the control of overoxidability should be considered. Due to difficulties in production, small amounts of 1-dodecanol, 1-tetradecanol, and 1,12-dodecanediol are typically produced. In this study, we identified an alkane-inducible monooxygenase operon that can efficiently catalyze the conversion of alkane to 1-alkanol with no detection of the overoxidation product. By coexpressing an alkane membrane facilitator, high levels of 1-dodecanol, 1-tetradecanol, and 1,12-dodecanediol could be generated. This study is significant for the bioproduction of medium- and long-chain 1-alkanol and α,ω-alkanediols.

Vitamin D Signaling through Induction of Paneth Cell Defensins Maintains Gut Microbiota and Improves Metabolic Disorders and Hepatic Steatosis in Animal Models.

Metabolic syndrome (MetS), characterized as obesity, insulin resistance, and non-alcoholic fatty liver diseases (NAFLD), is associated with vitamin D insufficiency/deficiency in epidemiological studies, while the underlying mechanism is poorly addressed. On the other hand, disorder of gut microbiota, namely dysbiosis, is known to cause MetS and NAFLD. It is also known that systemic inflammation blocks insulin signaling pathways, leading to insulin resistance and glucose intolerance, which are the driving force for hepatic steatosis. Vitamin D receptor (VDR) is highly expressed in the ileum of the small intestine, which prompted us to test a hypothesis that vitamin D signaling may determine the enterotype of gut microbiota through regulating the intestinal interface. Here, we demonstrate that high-fat-diet feeding (HFD) is necessary but not sufficient, while additional vitamin D deficiency (VDD) as a second hit is needed, to induce robust insulin resistance and fatty liver. Under the two hits (HFD+VDD), the Paneth cell-specific alpha-defensins including α-defensin 5 (DEFA5), MMP7 which activates the pro-defensins, as well as tight junction genes, and MUC2 are all suppressed in the ileum, resulting in mucosal collapse, increased gut permeability, dysbiosis, endotoxemia, systemic inflammation which underlie insulin resistance and hepatic steatosis. Moreover, under the vitamin D deficient high fat feeding (HFD+VDD), Helicobacter hepaticus, a known murine hepatic-pathogen, is substantially amplified in the ileum, while Akkermansia muciniphila, a beneficial symbiotic, is diminished. Likewise, the VD receptor (VDR) knockout mice exhibit similar phenotypes, showing down regulation of alpha-defensins and MMP7 in the ileum, increased Helicobacter hepaticus and suppressed Akkermansia muciniphila. Remarkably, oral administration of DEFA5 restored eubiosys, showing suppression of Helicobacter hepaticus and increase of Akkermansia muciniphila in association with resolving metabolic disorders and fatty liver in the HFD+VDD mice. An in vitro analysis showed that DEFA5 peptide could directly suppress Helicobacter hepaticus. Thus, the results of this study reveal critical roles of a vitamin D/VDR axis in optimal expression of defensins and tight junction genes in support of intestinal integrity and eubiosis to suppress NAFLD and metabolic disorders.

Poly(vinyl alcohol) and alginate cross-linked matrix with immobilized Prussian blue and ion exchange resin for cesium removal from waters.

Cesium (Cs) removal from contaminated water bodies is an emerging issue after the disaster at the Fukushima Daiichi Nuclear Power Plant. The Prussian blue (PB) is an effective Cs adsorbent but will release hexacyanoferrate fragments from the adsorbent matrix during adsorption. Alginate is an affordable biopolymer for PB particles immobilization. This study synthesized poly(vinyl alcohol) (PVA) and alginate cross-linked matrix for immobilization of PB nano-sized particles and a surface-modified styrene-ethyl styrene divinyl benzene resin and tested their swelling stability and Cs adsorption performance in fresh water and in seawater. The PVA-alginate granules have high structural stability in both fresh water and seawater, with the Cs adsorption capability higher for the former than the latter. The adopted resin effectively remove released PB fragments from the tested granules. The transport and reaction parameters for the granules and for the sand filter bed were estimated.

The designs and applications of a scanning interface with electrical signal detection on the scalp for the severely disabled.

This study discussed a computer-aided program development that meets the requirements of people with physical disabilities. A number of control modes, such as electrode signal recorded on the scalp and blink control, were combined with the scanning human-machine interface to improve the external input/output device. Moreover, a novel and precise algorithm, which filters noise and reduces misrecognition of the system, was proposed. A convenient assistive device can assist people with physical disabilities to meet their requirements for independent living and communication with the outside. The traditional scanning keyboard is changed, and only the phonetic notations are typed instead of characters, thus the time of tone and function selection could be saved, and the typing time could be also reduced. Barrier-free computer assistive devices and interface for people with physical disabilities in typing or speech could allow them to use a scanning keyboard to select phonetic symbols instead of Chinese characters to express their thoughts. The human-machine interface controls can obtain more reliable results as 99.8% connection success rate and 95% typing success rate.

A novel method for concentration evaluation of reading behaviors with electrical activity recorded on the scalp.

In this paper, a concentration evaluation of reading behaviors with electrical signal detection on the head is presented. The electrode signal is extracted by brain-computer-interface (BCI) to monitor the user's degree of concentration, where the user is reminded by sound to concentrate, or teaching staffs are reminded to help users improve reading habits, in order to facilitate the user's ability to concentrate. The digital signal processing methods, such as the Kalman Filter, Fast Fourier Transform, the Hamming window, the average value of the total energy of a frame, correlation coefficient, and novel judgment algorithm are used to obtain the corresponding parameters of concentration evaluation. Users can correct their manner of reading with reminders. The repeated test results may be expected to lie with a probability of 95%. Such model training results in better learning effect.

Selective serotonin reuptake inhibitors reduce P2Y12 receptor-mediated amplification of platelet aggregation.

Selective serotonin reuptake inhibitors (SSRIs) have been reported to reduce platelet aggregation induced by ADP. ADP induces platelet aggregation through two purinergic receptors P2Y1 and P2Y12. We characterized the inhibitory properties of SSRIs on ADP-induced platelet aggregation and investigated the effects of SSRIs on the signaling pathways downstream of P2Y1 and P2Y12 receptors. Specific antagonists were used to evaluate which purinergic receptor-mediated aggregation was influenced by SSRIs. The primary phase of ADP-induced aggregation was not inhibited by citalopram. Citalopram failed to influence ADP-induced platelet shape change, intracellular calcium mobilization and the early phosphorylation of PKCα. Differently, citalopram inhibited the secondary phase of ADP-induced platelet aggregation in a concentration-dependent manner. Other SSRIs, including fluoxetine and sertraline, exhibited the same anti-platelet effects. Under P2Y1 blockade, citalopram inhibited platelet aggregation and integrin αIIbß3 activation in response to ADP, indicating that citalopram inhibited P2Y12-mediated aggregation. Citalopram concentration-dependently inhibited the phosphorylation of Akt, GSK3ß, p38 MAPK and Syk induced by ADP, but showed no effect on the decrease of cAMP and VASP phosphorylation. With integrin αIIbß3 blockade, however, the phosphorylation of Akt triggered by ADP was unaltered by the addition of citalopram. Taken together, under the stimulation of ADP, SSRIs inhibit the amplification of platelet aggregation secondary to the activation of P2Y12 receptor, and subsequently reduce the activation of the downstream molecules of the outside-in signaling pathways.

A selective serotonin reuptake inhibitor, citalopram, inhibits collagen-induced platelet aggregation and activation.

Clinical depression is a significant risk factor for cardiovascular diseases and confers an increased risk of mortality. Increased platelet reactivity may predispose depressed patients to cardiovascular diseases. The antidepressants selective serotonin reuptake inhibitors (SSRIs) have been found to have cardioprotective effects probably via the attenuation of platelet activation independently in addition to treatment of depression itself. However, the characters of the inhibitory effect of SSRIs on platelets remain largely unknown. Here we show that an SSRI, citalopram, specifically inhibited collagen-induced platelet aggregation. Citalopram, however, revealed only little inhibitory effect on platelet aggregation induced by thrombin, U46619, and ionomycin, and failed to inhibit reversible platelet aggregation induced by adenosine diphosphate with fibrinogen. Collagen-induced of αIIbß3 integrin activation in platelets under a static condition was not influenced by citalopram. Citalopram inhibited convulxin-induced platelet aggregation and αIIbß3 integrin activation. In the experiments with fibrinogen-induced aggregation in elastase-treated platelets, citalopram inhibited only collagen-induced αIIbß3 activation but not the binding activities between activated αIIbß3 integrin and fibrinogen. Moreover, citalopram inhibited α-granule and dense granule secretion from platelets in response to collagen, as determined by a reduced expression of P-selectin and adenosine triphosphate release, respectively. In addition, collagen-induced thromboxane A2 release in platelets was attenuated by citalopram pretreatment. These findings might specify the mechanisms of inhibitory effects of citalopram on collagen mediated platelet activation and aggregation, and further support the cardioprotective effect of SSRIs.