Association among attention-deficit hyperactivity disorder, restless legs syndrome, and peripheral iron status: a two-sample Mendelian randomization study.

Background: Epidemiological evidence indicates a high correlation and comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and Restless Legs Syndrome (RLS). Objective: We aimed to investigate the causal relationship and shared genetic architecture between ADHD and RLS, as well as explore potential causal associations between both disorders and peripheral iron status. Methods: We performed two-sample Mendelian randomization (MR) analyses using summary statistics from genome-wide meta-analyses of ADHD, RLS, and peripheral iron status (serum iron, ferritin, transferrin saturation, and total iron binding capacity). Additionally, we employed linkage disequilibrium score regression (LDSC) to assess genetic correlations between ADHD and RLS using genetic data. Results: Our MR results supports a causal effect from ADHD (as exposure) to RLS (as outcome) (inverse variance weighted OR = 1.20, 95% CI: 1.08-1.34, p = 0.001). Conversely, we found no a causal association from RLS to ADHD (inverse variance weighted OR = 1.04, 95% CI: 0.99-1.09, p = 0.11). LDSC analysis did not detect a significant genetic correlation between RLS and ADHD (Rg = 0.3, SE = 0.16, p = 0.068). Furthermore, no evidence supported a causal relationship between peripheral iron deficiency and the RLS or ADHD onset. However, RLS may have been associated with a genetic predisposition to reduced serum ferritin levels (OR = 1.20, 95% CI: 1.00-1.04, p = 0.047). Conclusion: This study suggests that ADHD is an independent risk factor for RLS, while RLS may confer a genetic predisposition to reduced serum ferritin levels. Limitations: The GWAS summary data utilized originated from populations of European ancestry, limiting the generalizability of conclusions to other populations. Clinical implications: The potential co-occurrence of RLS in individuals with ADHD should be considered during diagnosis and treatment. Moreover, iron supplementation may be beneficial for alleviating RLS symptoms.

Efficacy and Safety of Pulse Magnetic Therapy System in Insomnia Disorder: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: This study's objective is to assess the efficacy and safety of Pulsed Magnetic Therapy System (PMTS) in improving insomnia disorder. METHODS: Participants with insomnia disorder were randomly assigned to receive either PMTS or sham treatment for four weeks (n= 153; PMTS: 76, sham: 77). Primary outcomes are the Insomnia Severity Index (ISI) scores at week 0 (baseline), 1, 2, 3, 4 (treatment), and 5 (follow-up). Secondary outcomes are the Pittsburgh Sleep Quality Index at baseline and week 4, and weekly sleep diary-derived values for sleep latency, sleep efficiency, real sleep time, waking after sleep onset, and sleep duration. RESULTS: The ISI scores of the PMTS group and the sham group were 7.13±0.50, 11.07±0.51 at week 4, respectively. There was a significant group×time interaction for ISI (F3.214, 485.271=24.25, p<0.001, ηp 2=0.138). Only the PMTS group experienced continuous improvement throughout the study; in contrast, the sham group only experienced a modest improvement after the first week of therapy. At the end of the treatment and one week after it, the response of the PMTS group were 69.7% (95% confidence interval [CI]: 58.6%-79.0%), 75.0% (95% CI: 64.1%-83.4%), respectively, which were higher than the response of the sham group (p<0.001). For each of the secondary outcomes, similar group×time interactions were discovered. The effects of the treatment persisted for at least a week. CONCLUSION: PMTS is safe and effective in improving insomnia disorders.

Nomogram-Based Prediction of the Futile Recanalization Risk Among Acute Ischemic Stroke Patients Before and After Endovascular Therapy: A Retrospective Study.

Background and Purpose: Futile recanalization (FRC) is common among large artery occlusion (LAO) patients after endovascular therapy (EVT). We developed nomogram models to identify LAO patients at a high risk of FRC pre- and post-EVT to help neurologists select the optimal candidates for EVT. Methods: From April 2020 to July 2022, EVT and mTICI score ≥2b LAO patients were recruited. Nomogram models was developed by two-step approach for predicting the outcomes of LAO patients. First, the least absolute shrinkage and selection operator (LASSO) regression analysis was to optimize variable selection. Then, a multivariable analysis was to construct an estimation model with significant indicators from the LASSO. The accuracy of the model was verified using receiver operating characteristic (ROC), calibration curve, and decision curve analyses (DCA), along with validation cohort (VC). Results: Using LASSO, age, sex, hypertension history, baseline NIHSS, ASPECTS and baseline SBP upon admission were identified from the pre-EVT variables. Model 1 (pre-EVT) showed good predictive performance, with an area under the ROC curve (AUC) of 0.815 in the training cohort (TrC) and 0.904 in VC. Under the DCA, the generated nomogram was clinically applicable where risk cut-off was between 15%-85% in the TrC and 5%-100% in the VC. Moreover, age, ASPECTS upon admission, onset duration, puncture-to-recanalization (PTR) duration, and lymphocyte-to-monocyte ratio (LMR) were screened by LASSO. Model 2 (post-EVT) also demonstrated good predictive performance with AUCs of 0.888 and 0.814 for TrC and VC, respectively. Under the DCA, the generated nomogram was clinically applicable if the risk cut-off was between 13-100% in the TrC and 22-85% of VC. Conclusion: In this study, two nomogram models were generated that showed good discriminative performance, improved calibration, and clinical benefits. These nomograms can potentially accurately predict the risk of FRC in LAO patients pre- and post-EVT and help to select appropriate candidates for EVT.

lncRNA miR4458HG modulates hepatocellular carcinoma progression by activating m6A-dependent glycolysis and promoting the polarization of tumor-associated macrophages.

Long non-coding RNAs (lncRNAs) play significant roles in different biological functions of cancers. However, their function in the metabolism of glucose in patients with human hepatocellular carcinoma (HCC) remains largely unknown. In this study, HCC and paired intact liver tissues were utilized to examine the miR4458HG expression using qRT-PCR and human HCC cell lines to examine cell proliferation, colony formation, and glycolysis after transfection of siRNAs targeting miR4458HG or miR4458HG vectors. The molecular mechanism of miR4458HG was clarified through in situ hybridization, Western blotting, qRT-PCR, RNA pull-down, and RNA immunoprecipitation analysis. The results showed that the miR4458HG affected HCC cell proliferation, activated the glycolysis pathway, and promoted the polarization of tumor-associated macrophage in vitro and in vivo models. Mechanistically, miR4458HG bound IGF2BP2 (a key RNA m6A reader) and facilitated IGF2BP2-mediated target mRNA stability, including HK2 and SLC2A1 (GLUT1), and consequently altered HCC glycolysis and tumor cell physiology. At the same time, HCC-derived miR4458HG could be wrapped in the exosomes and promoted the polarization of tumor-associated macrophage by increasing ARG1 expression. Hence, miR4458HG is oncogenic in nature among patients with HCC. To develop an effective treatment strategy of HCC patients presenting with high glucose metabolism, physicians should focus on miR4458HG and its pathway.

Targeting UBR5 in hepatocellular carcinoma cells and precise treatment via echinacoside nanodelivery.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and malignant cancers with no effective therapeutic approaches. Echinacoside (ECH), a phenylethanoid glycoside isolated from Chinese herbal medicine, Cistanche salsa, can inhibit HCC progression; however, poor absorption and low bioavailability limit its biological applications. METHODS: To improve ECH sensitivity to HepG2 cells, we developed a mesoporous silica nanoparticle (MSN)-based drug delivery system to deliver ECH to HepG2 cells via galactose (GAL) and poly(ethylene glycol) diglycidyl ether (PEGDE) conjugation (ECH@Au@MSN-PEGDE-GAL, or ECH@AMPG). Gain- and loss-of-function assays were conducted to assess the effects of UBR5 on HCC cell apoptosis and glycolysis. Moreover, the interactions among intermediate products were also investigated to elucidate the mechanisms by which UBR5 functions. RESULTS: The present study showed that ubiquitin protein ligase E3 component N-recognin 5 (UBR5) acted as an oncogene in HCC tissues and that its expression was inhibited by ECH. AMPG showed a high drug loading property and a slow and sustained release pattern over time. Moreover, owing to the valid drug accumulation, ECH@AMPG promoted apoptosis and inhibited glycolysis of HepG2 cells in vitro. In vivo experiments demonstrated that AMPG also enhanced the antitumor effects of ECH in HepG2 cell-bearing mice. CONCLUSIONS: Our results indicated the clinical significance of UBR5 as a therapeutic target. On the basis of the nontoxic and high drug-loading capabilities of AMPG, ECH@AMPG presented better effects on HCC cells compared with free ECH, indicating its potential for the chemotherapy of HCC.

The role of PYCR1 in inhibiting 5-fluorouracil-induced ferroptosis and apoptosis through SLC25A10 in colorectal cancer.

Although PYCR1 is a well-recognized oncogenic gene for malignant tumors, the causal relationship of its expression with malignant growth and cytotoxic chemotherapeutics remains unclear. Therefore, this study aimed to clarify the role of PYCR1 and its interaction with SLC25A10 in a chemotherapeutic agent 5-fluorouracil (5-FU)'s toxicity to colorectal cancer cells. PYCR1 and SLC25A10 expressions were detected in The Cancer Genome Atlas database and colon adenocarcinoma (COAD) clinical samples. PYCR1 upregulation was associated with SLC25A10 expression and poor prognosis, and its high expression indicated decreased survival rates in patients with COAD. PYCR1 overexpression inhibited lipid reactive oxygen species production and promoted SLC25A10 expression in colorectal cancer cells. PYCR1 silencing enhanced the antitumor effects of 5-FU. Ferroptosis inhibitor deferoxamine suppressed the antitumor effects of PYCR1 silencing, whereas ferroptosis inducer erastin inhibited the protumor effects of PYCR1 overexpression. SLC25A10 overexpression reversed the antitumor effects of PYCR1 silencing in vitro and inhibited the antitumor effects of erastin in vivo. Therefore, PYCR1 is an oncogenic gene that promotes colorectal tumor growth and desensitizes colorectal cancer cells to 5-FU cytotoxicity by preventing apoptosis and ferroptosis.

CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer.

OBJECTIVE: Adaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC). DESIGN: We screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line. We evaluated the ability of the cyclin-dependent kinase (CDK) inhibitor dinaciclib to block IFNG-induced IDO1 and CD274 expression in 24 human and mouse cancer cell lines as well as in primary cancer cells from patients with PDAC or ovarian carcinoma. We tested the effects of dinaciclib on IFNG-induced signal transducer and activator of transcription 1 activation and immunological cell death, and investigated the potential utility of dinaciclib in combination with IFNG for pancreatic cancer therapy in vivo, and compared gene expression levels between human cancer tissues with patient survival times using the Cancer Genome Atlas datasets. RESULTS: Pharmacological (using dinaciclib) or genetic (using shRNA or siRNA) inactivation of CDK1/2/5 not only blocks JUN-dependent immune checkpoint expression, but also triggers histone-dependent immunogenic cell death in immortalised or primary cancer cells in response to IFNG. This dual mechanism turns an immunologically 'cold' tumour microenvironment into a 'hot' one, dramatically improving overall survival rates in mouse pancreatic tumour models (subcutaneous, orthotopic and transgenic models). The abnormal expression of CDK1/2/5 and IDO1 was associated with poor patient survival in several cancer types, including PDAC. CONCLUSION: CDK1/2/5 kinase activity is essential for IFNG-mediated cancer immunoevasion. CDK1/2/5 inhibition by dinaciclib provides a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumour immunity.

Extracellular SQSTM1 mediates bacterial septic death in mice through insulin receptor signalling.

Sepsis is the most common cause of death for patients in intensive care worldwide due to a dysregulated host response to infection. Here, we investigate the role of sequestosome-1 (SQSTM1/p62), an autophagy receptor that functions as a regulator of innate immunity, in sepsis. We find that lipopolysaccharide elicits gasdermin D-dependent pyroptosis to enable passive SQSTM1 release from macrophages and monocytes, whereas transmembrane protein 173-dependent TANK-binding kinase 1 activation results in the phosphorylation of SQSTM1 at Ser403 and subsequent SQSTM1 secretion from macrophages and monocytes. Moreover, extracellular SQSTM1 binds to insulin receptor, which in turn activates a nuclear factor kappa B-dependent metabolic pathway, leading to aerobic glycolysis and polarization of macrophages. Intraperitoneal injection of anti-SQSTM1-neutralizing monoclonal antibodies or conditional depletion of Insr in myeloid cells using the Cre-loxP system protects mice from lethal sepsis (caecal ligation and puncture or infection by Escherichia coli or Streptococcus pneumoniae) and endotoxaemia. We also report that circulating SQSTM1 and the messenger RNA expression levels of SQSTM1 and INSR in peripheral blood mononuclear cells are related to the severity of sepsis in 40 patients. Thus, extracellular SQSTM1 has a pathological role in sepsis and could be targeted to develop therapies for sepsis.

Mediating role of social support between sleep quality, anxiety and depressive symptoms in Chinese women undergoing in vitro fertilization treatment.

INTRODUCTION: Infertility is a significant health problem, and the prevalence of infertility among women is increasing in developing countries. This study aims to explore whether social support plays a mediating role in the links between exogenous variables, sleep quality, anxiety, and depressive symptoms in Chinese women undergoing in vitro fertilization. METHODS: This is a cross-sectional study comprising a sample of Chinese women undergoing in vitro fertilization treatment at a tertiary reproductive medicine center located in South China. RESULTS: The final testing model showed good fit, with normed χ2 = 39.317, p = 0.055, comparative fit index = 0.948, Tucker-Lewis index = 0.902, incremental fit index = 0.951, normed fit index = 0.906, root mean square error of approximation = 0.046). The final path model supported the proposed model: partner relationship, a woman's age, financial strain, duration of infertility, and cycles of in vitro fertilization were exogenous variables for depressive symptoms, while social support was a significant mediator between sleep quality, anxiety, and depressive symptoms. CONCLUSION: The empirical support from this study could facilitate the development of appropriate interventions to reduce depressive symptoms, and to promote the mental health of Chinese women undergoing in vitro fertilization treatment.

Duloxetine-Induced Neural Cell Death and Promoted Neurite Outgrowth in N2a Cells.

Duloxetine is a clinical drug that is primarily used for treatment of depression and pain, but it has side effects of addiction and tolerance. Cytochrome P450 (CYP) is its metabolic enzyme, and the drug's biofunction results from its neuro-protective effect in animal and cell models. We aimed to investigate the duloxetine-induced neural cytotoxicity effect and its performance in an N2a cell neurite outgrowth model. Cell death was assessed as cell viability using a Cell Count Kit-8 and further evaluated using bright-field images, propidium iodide (PI) and annexin V staining, colony-formation analysis, TUNEL staining of the cells, and biochemical testing. N2a cells were committed to differentiation by serum withdrawal and RA induction, and the neurite outgrowth was evaluated as the number of differentiated cells, longest neurite length, and average neurite length. Cell cycle analysis, PI and annexin V staining, mRNA expression, and biochemical testing were used to evaluate the drug effects on differentiation. The induction of neural cell death by duloxetine was not affected by classic cell death inhibitors but was promoted by the CYP inducer rifampicin. N2a cell neurite outgrowth was promoted by duloxetine via reduction of the CYP2D6 and MDA levels and induction of Bdnf protein levels. Duloxetine induces neural cell death through effects on CYP and promotes N2a cell neurite outgrowth by regulating CYP, Bdnf protein, and the intracellular lipid peroxidation level.

TMEM173 Drives Lethal Coagulation in Sepsis.

The discovery of TMEM173/STING-dependent innate immunity has recently provided guidance for the prevention and management of inflammatory disorders. Here, we show that myeloid TMEM173 occupies an essential role in regulating coagulation in bacterial infections through a mechanism independent of type I interferon response. Mechanistically, TMEM173 binding to ITPR1 controls calcium release from the endoplasmic reticulum in macrophages and monocytes. The TMEM173-dependent increase in cytosolic calcium drives Gasdermin D (GSDMD) cleavage and activation, which triggers the release of F3, the key initiator of blood coagulation. Genetic or pharmacological inhibition of the TMEM173-GSDMD-F3 pathway blocks systemic coagulation and improves animal survival in three models of sepsis (cecal ligation and puncture or bacteremia with Escherichia coli or Streptococcus pneumoniae infection). The upregulation of the TMEM173 pathway correlates with the severity of disseminated intravascular coagulation and mortality in patients with sepsis. Thus, TMEM173 is a key regulator of blood clotting during lethal bacterial infections.

Ferroptosis is a type of autophagy-dependent cell death.

Macroautophagy (hereafter referred to as autophagy) involves an intracellular degradation and recycling system that, in a context-dependent manner, can either promote cell survival or accelerate cellular demise. Ferroptosis was originally defined in 2012 as an iron-dependent form of cancer cell death different from apoptosis, necrosis, and autophagy. However, this latter assumption came into question because, in response to ferroptosis activators (e.g., erastin and RSL3), autophagosomes accumulate, and because components of the autophagy machinery (e.g., ATG3, ATG5, ATG4B, ATG7, ATG13, and BECN1) contribute to ferroptotic cell death. In particular, NCOA4-facilitated ferritinophagy, RAB7A-dependent lipophagy, BECN1-mediated system xc- inhibition, STAT3-induced lysosomal membrane permeabilization, and HSP90-associated chaperone-mediated autophagy can promote ferroptosis. In this review, we summarize current knowledge on the signaling pathways involved in ferroptosis, while focusing on the regulation of autophagy-dependent ferroptotic cell death. The molecular comprehension of these phenomena may lead to the development of novel anticancer therapies.

AGER-Mediated Lipid Peroxidation Drives Caspase-11 Inflammasome Activation in Sepsis.

Inflammasome activation can trigger an inflammatory and innate immune response through the release of cytokines and induction of pyroptosis. A dysfunctional inflammasome has been implicated in the development of human pathologies, including sepsis and septic shock. Here, we show that advanced glycosylation end-product specific receptor (AGER/RAGE) is required for caspase-11 inflammasome activation in macrophages. A nuclear damage-associated molecular pattern (nDAMP) complex, including high-mobility group box 1, histone, and DNA, can promote caspase-11-mediated gasdermin D cleavage, interleukin 1ß proteolytic maturation, and lactate dehydrogenase release. The inhibition of AGER-mediated lipid peroxidation via arachidonate 5-lipoxygenase (ALOX5) limits caspase-11 inflammasome activation and pyroptosis in macrophages in response to nDAMPs or cytosolic lipopolysaccharide. Importantly, the pharmacologic inhibition of the AGER-ALOX5 pathway or global depletion (Ager-/-) or conditional depletion of AGER in myeloid cells (AgerMye-/-) protects against lipopolysaccharide-induced septic death in poly(I:C)-primed mice. These data identify a molecular basis for caspase-11 inflammasome activation and provide a potential strategy to treat sepsis.

The interaction between estradiol change and the serotonin transporter gene (5-HTTLPR) polymorphism is associated with postpartum depressive symptoms.

Although estrogenic fluctuation is considered a major risk factor for postpartum depression (PPD), the effects of the interactions between the genetic background and estradiol (E2) change on PPD are not well understood. Here, a cohort study with 437 postpartum women was carried out to evaluate the role of a serotonin transporter gene polymorphism (5-HTTLPR) and E2 change on the risk of PPD symptoms. The participants were assessed using the Edinburgh Postnatal Depression Scale and the Self-Rating Depression Scale at 1 and 6 weeks after delivery. The PCR-based restriction fragment length polymorphism method was utilized to examine the genotype distribution of the 5-HTTLPR polymorphism, and the serum levels of E2 were determined in individuals in the third trimester of pregnancy and at 1 week postpartum. A significant association was observed between E2 change and PPD susceptibility in the late postpartum period (6 weeks) [P = 0.002, odds ratio (OR) = 2.341, 95% confidence interval (CI) = 1.361-4.027], but it was not observed in the early postpartum period (1 week). There was no significant association between the 5-HTTLPR genotype and PPD risk at both the early and late postpartum periods (P > 0.05). However, the interaction between E2 change and the 5-HTTLPR polymorphism could reasonably influence PPD risk. The women who carried the SS genotype with large decreases in E2 showed a significantly higher risk for PPD at both the early (P = 0.002, OR = 2.525, 95% CI = 1.384-4.059) and late postpartum periods (P < 0.001, OR = 3.108, 95% CI = 1.562-4.436) compared with those who carried the SL/LL genotype. This study suggests that there is an association between E2 change in the perinatal period with the 5-HTTLPR genotype and the occurrence of PPD.

The release and activity of HMGB1 in ferroptosis.

Damage-associated molecular pattern molecules (DAMPs) are endogenous danger signals that alert the innate immune system and shape the inflammation response to cell death. However, the release and activity of DAMPs in ferroptosis, a recently identified form of regulated necrosis characterized by iron overload and lipid peroxidation, still remain poorly understood. Here, we demonstrate that HMGB1 is a DAMP released by ferroptotic cells in an autophagy-dependent manner. Both type I and II ferroptosis activators, including erastin, sorafenib, RSL3, and FIN56, induce HMGB1 release in cancer and noncancer cells. In contrast, genetic ablation (using ATG5-/- or ATG7-/- cells) or pharmacologic inhibition (the administration of bafilomycin A1 or chloroquine) of autophagy was found to block ferroptosis activator-induced HMGB1 release. Mechanically, autophagy-mediated HDAC inhibition promotes HMGB1 acetylation, resulting in HMGB1 release in ferroptosis. Moreover, AGER, but not TLR4, is required for HMGB1-mediated inflammation in macrophages in response to ferroptotic cells. These studies suggest that HMGB1 inhibition might have some potential therapeutic effects in ferroptosis-associated human disease.

A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis.

Although the PINK1-PARK2 pathway contributes to the pathogenesis of Parkinson disease, its roles in sepsis (a major challenge for critical care) were previously unknown. Here, we show that pink1-/- and park2-/- mice are more sensitive to polymicrobial sepsis-induced multiple organ failure and death. The decrease in the circulating level of the neurotransmitter dopamine in pink1-/- and park2-/- mice accelerates the release of a late sepsis mediator, HMGB1, via HIF1A-dependent anaerobic glycolysis and subsequent NLRP3-dependent inflammasome activation. Genetic depletion of Nlrp3 or Hif1a in pink1-/- and park2-/- mice confers protection against lethal polymicrobial sepsis. Moreover, pharmacological administration of dopamine agonist (e.g., pramipexole), HMGB1-inhibitor (e.g., neutralizing antibody or glycyrrhizin), or NLRP3-inhibitor (e.g., MCC950) reduces septic death in pink1-/- and park2-/- mice. The mRNA expression of HIF1A and NLRP3 is upregulated, whereas the mRNA expression of PINK1 and PARK2 is downregulated in peripheral blood mononuclear cells of patients with sepsis. Thus, an impaired PINK1-PARK2-mediated neuroimmunology pathway contributes to septic death and may represent a novel therapeutic target in critical care medicine.

Antiferroptotic activity of non-oxidative dopamine.

Dopamine is a neurotransmitter that has many functions in the nervous and immune systems. Ferroptosis is a non-apoptotic form of regulated cell death that is involved in cancer and neurodegenerative diseases. However, the role of dopamine in ferroptosis remains unidentified. Here, we show that the non-oxidative form of dopamine is a strong inhibitor of ferroptotic cell death. Dopamine dose-dependently blocked ferroptosis in cancer (PANC1 and HEY) and non-cancer (MEF and HEK293) cells following treatment with erastin, a small molecule ferroptosis inducer. Notably, dopamine reduced erastin-induced ferrous iron accumulation, glutathione depletion, and malondialdehyde production. Mechanically, dopamine increased the protein stability of glutathione peroxidase 4, a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. Moreover, dopamine suppressed dopamine receptor D4 protein degradation and promoted dopamine receptor D5 gene expression. Thus, our findings uncover a novel function of dopamine in cell death and provide new insight into the regulation of iron metabolism and lipid peroxidation by neurotransmitters.

Generation of induced pluripotent stem cells from skin fibroblasts of a patient with olivopontocerebellar atrophy.

Generation of induced pluripotent stem (iPS) cells from somatic cells of patients represents a powerful tool for disease modeling, and they may have a wide range of applications in cell therapies. Olivopontocerebellar atrophy (OPCA) is a rare and debilitating neurologic disease of insidious onset, characterized by atrophy of the cerebellum pons and inferior olivary nuclei with concomitant ambulation deficits and dyscoordination. Here, we report the generation of iPS cells from skin fibroblasts of a 56-year-old female patient with familial OPCA. OPCA is classified in the autosomal dominant ataxia that is also named spinocerebellar ataxia (SCA) 7. The disease allele of SCA7 gene of the patient contains 45 CAG trinucleotide repeats, the number of which is larger than the normal repeat number (4 to 36 CAG repeats). The OPCA-iPS cells were generated via ectopic expression of four transcription factors: OCT4, SOX2, KLF4 and c-MYC. The OPCA-iPS cells expressed the pluripotency markers, and they can be differentiated into various somatic cell types in vitro and in vivo. Furthermore, the iPS cells also can be committed to differentiate into neural cells. Therefore, the OPCA-iPS cells offer an unprecedented cell model to investigate disease mechanisms, discover novel drugs, and develop new therapies for OPCA.

The symptomatology of climacteric syndrome: whether associated with the physical factors or psychological disorder in perimenopausal/postmenopausal patients with anxiety-depression disorder.

PURPOSE: To explore whether the symptoms of climacteric syndrome associated with its physical factors or psychological disorder in perimenopausal/postmenopausal patients with anxiety-depression disorder. METHODS: We recruited 78 climacteric patients with anxiety-depression disorder and 72 control participants in perimenopausal/postmenopausal without anxiety-depression disorder for this study. We measured symptoms using the Greene Climacteric Symptom Scale in all cases. We also collected demographic data and tested sexual hormone, blood pressure, bone density, cognitive, estrogen receptor-alpha (ERα) gene polymorphism as physiological factors, using HARS-14 and CHDS assessed psychological disorder degree. RESULTS: C-MMSE scores as well as Estradiol and progesterone levels in the anxiety-depression disorder group were significantly lower compared to the control group (P < 0.01). In addition, the anxiety-depression disorder group had significantly higher Greene Climacteric Scale scores, as well as somatic symptoms compared to controls (P < 0.01). Moreover, the anxiety, depression and somatic symptoms of the Greene Climacteric Scale were positively correlated with HARS-14 and CHDS scores (P < 0.001) and negatively with estrogen level and C-MMSE scores (P < 0.05) in the anxiety-depression disorder group. Greene Climacteric Scale Symptoms were not significantly correlated with blood pressure, bone density or other factors (P > 0.05). There was no significant change in the allele frequency or the estrogen receptor-alpha gene polymorphisms, between the two groups (P > 0.05); however, the Pp genotype was negatively associated with C-MMSE scores (r = appraises, P = 0.033). LIMITATIONS: The sample size was relatively small. CONCLUSIONS: The symptoms of somatic symptoms in patients with climacteric syndrome and anxiety-depression disorder are associated with the emotional disorder but not with a physical disease. The Pp ERα polymorphism Pvu II is associated with a cognitive decrease.

[Clinical value of protoparaxotril saporlirs combined with aspirin in the secondary prevention of cerebral infarction].

OBJECTIVE: To observe the clinical value of protoparaxotril saporlirs (PTS) combined with aspirin in the secondary prevention of cerebral infarction. METHODS: The 140 patients with cerebral infarction were collected, among them the 120 patients during recovery stage were equally assigned to three groups by randomized, single blinded and open controlled principle, and they were treated respectively by PTS (A), aspirin (B), and PTS plus aspirin (C) for 6 months. The other 20, who couldn't or were unwilling to use aspirin, were arranged in group D for control. The platelet aggregation rate, incidence of stroke recurrence, gastrointestinal adverse reaction and the NIHSS scores of patients were observed during the six-month period of treatment. RESULTS: As compared with group D, the lowering amplitude of platelet aggregation rate after treatment in the three treatment groups were significantly higher (P < 0.01). Comparison of platelet aggregation rate between group A and B showed significant difference after 3-month treatment (P < 0.05), but the difference became insignificant after 6-month treatment (P > 0.05). The incidence of stroke recurrence in the group A, B and C was 18.9%, 13.2% and 10.8% respectively, which showed no significant difference among them, but all were significantly lower than that in the group D (44.4%, P < 0.05). NIHSS scores in group A and C were significantly lower than in group B (P < 0.01); and the occurrence of gastrointestinal reaction was significantly lower in group A (P < 0.01). CONCLUSION: Long-term application of PTS has the effects for preventing stroke recurrence, lowering gastrointestinal adverse reaction and improving patients' neural function in patients with stroke. As used in combination with aspirin, it shows potential practical importance in the clinical secondary prevention of stroke.