Association between frailty index based on routine laboratory tests and risk of cerebral small vessel disease in elderly patients: a hospital-based observational study.

BACKGROUND: The association between frailty and cerebral small vessel disease (CSVD) remains controversial due to the use of different methods to assess frailty, including physical frailty phenotype and frailty scores containing measures of cognition. A frailty index based on laboratory tests (FI-Lab), which assesses frailty by the combination of routine laboratory measures and several vital signs, is independent of cognition and function status. We aimed to evaluate the association of FI-Lab with CSVD. METHODS: An observational study was carried out in a hospitalized cohort of older patients with minor ischemic stroke or TIA. The FI-Lab was constructed by 20 routine laboratory tests, plus systolic blood pressure, diastolic blood pressure, and pulse pressure. Manifestations of CSVD including white matter hyperintensity (WMH), silent lacunar infarcts, microbleed, enlarged perivascular spaces (EPVS), as well as deep brain atrophy, were measured on magnetic resonance imaging (MRI). An ordinal score system constructed by WMH, EPVS, silent lacunar infarcts, and microbleed was used to reflect the total burden of CSVD. The associations between FI-lab and CSVD were examined by logistic regression analysis and ordinal regression. RESULTS: A total of 398 patients were recruited from January 2016 to December 2018. The mean FI-Lab value was 0.26 ± 0.11. The prevalence of extensive periventricular WMH, extensive deep WMH, extensive basal ganglia EPVS, extensive centrum semiovale EPVS, silent lacunar infarcts, and deep microbleed was 26.1, 66.6, 68.6, 80.7, 32.9, and 6.5%, respectively. A higher FI-Lab value was associated with increased risks of extensive deep WMH (OR = 1.622; 95% CI, 1.253 ~ 2.100), extensive basal ganglia EPVS (OR = 1.535; 95% CI, 1.187 ~ 1.985), extensive centrum semiovale EPVS (OR = 1.584; 95% CI, 1.167 ~ 2.151), silent lacunar infarcts (OR = 1.273; 95% CI, 1.007 ~ 1.608), and higher total burden of CSVD. These associations remained after the adjustment of potential confounding factors. CONCLUSION: This study demonstrated that a higher FI-Lab score might be associated with the presence of WMH, EPVS, silent lacunar infarcts, as well as severe total CSVD burden in older patients with minor stroke or TIA. The FI-Lab provides a basis for the prediction of CSVD.

Dopaminergic afferents from midbrain to dorsolateral bed nucleus of stria terminalis inhibit release and expression of corticotropin-releasing hormone in paraventricular nucleus.

Dopaminergic (DAergic) neurons of the midbrain ventral tegmental area (VTA) are known to regulate the hypothalamic-pituitary-adrenal (HPA) axis but have no direct projections to the paraventricular nucleus (PVN) of the hypothalamus. This study investigated whether VTA DAergic afferents modulate glutamatergic transmission-dependent GABAergic neurons in dorsolateral bed nucleus of stria terminalis (dlBNST) to affect the activity of the HPA-axis. Herein, we demonstrate that systemic administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or the VTA-injection of 1-methyl-4-phenylpyridinium ion (MPP+) in male mice (MPTP-mice and MPP+mice) caused a decline of tyrosine hydroxylase positive (TH+) cells in VTA with a reduction in TH+fibers in the dlBNST. MPTP-mice and MPP+mice displayed a clear increase in serum levels of corticosterone (CORT) and adrenocorticotropic hormone, corticotropin-releasing hormone (CRH) expression, and CRH neuron activity in PVN. The presynaptic glutamate release, glutamatergic synaptic transmission and induction of long-term potentiation in dlBNST of MPTP-mice were suppressed, and these effects were rescued by a D1-like DAergic receptor (D1R) agonist and mimicked in control dlBNST by blockade of D1R. MPTP-mice exhibited low expression of glutamic acid decarboxylase and dysfunction of the excitatory-dependent GABAergic circuit in dlBNST, and these effects were recovered by the administration of D1R agonist. Furthermore, either dlBNST-injection of D1R agonist or PVN-injection of GABAA receptor (GABAA R) agonist could correct the increased secretion and expression of CRH in MPTP-mice. The results indicate that the DAergic afferents from VTA enhance excitatory-dependent activation of GABAergic neurons in dlBNST, which suppress the activity of the HPA-axis.

Plasminogen activator inhibitor-1 4G/5G polymorphism and ischemic stroke risk: a meta-analysis in Chinese population.

BACKGROUND: The guanosine insertion/deletion polymorphism (4G/5G) of plasminogen activator inhibitor-1 (PAI-1) gene has been suggested as a risk factor for ischemic stroke (IS), but direct evidence from genetic association studies remains inconclusive even in Chinese population. Therefore, we performed a meta-analysis to evaluate this association. METHODS: All of the relevant studies were identified from PubMed, Embase, Chinese National Knowledge Infrastructure database and Chinese Wanfang database up to September 2013. Statistical analyses were conducted with Revman 5.2 and STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. Heterogeneity was evaluated by Q-test and the I² statistic. The Begg's test and Egger's test were used to assess the publication bias. RESULTS: A significant association and a borderline association between the PAI-1 4G/5G polymorphism and IS were found under the recessive model (OR = 1.639, 95% CI = 1.136-2.364) and allelic model (OR = 1.256, 95% CI = 1.000-1.578), respectively. However, no significant association was observed under homogeneous comparison model (OR = 1.428, 95% CI = 0.914-2.233), heterogeneous comparison model (OR = 0.856, 95% CI = 0.689-1.063) and dominant model (OR = 1.036, 95% CI = 0.846-1.270). CONCLUSION: This meta-analysis suggested that 4G4G genotype of PAI-1 4G/5G polymorphism might be a risk factor for IS in the Chinese population.

Predictive value of ultrasonic artificial intelligence in placental characteristics of early pregnancy for gestational diabetes mellitus.

Background: To explore the predictive value of placental features in early pregnancy for gestational diabetes mellitus (GDM) using deep and radiomics-based machine learning (ML) applied to ultrasound imaging (USI), and to develop a nomogram in conjunction with clinical features. Methods: This retrospective multicenter study included 415 pregnant women at 11-13 weeks of gestation from two institutions: the discovery group from center 1 (n=305, control group n=166, GDM group n=139), and the independent validation cohort (n=110, control group n=57, GDM group n=53) from center 2. The 2D USI underwent pre-processed involving normalization and resampling. Subsequently, the study performed screening of radiomics features with Person correlation and mutual information methods. An RBF-SVM model based on radiomics features was constructed using the five-fold cross-validation method. Resnet-50 as the backbone network was employed to learn the region of interest and constructed a deep convolutional neural network (DLCNN) from scratch learning. Clinical variables were screened using one-way logistic regression, with P<0.05 being the threshold for statistical significance, and included in the construction of the clinical model. Nomogram was built based on ML model, DLCNN and clinical models. The performance of nomogram was assessed by calibration curves, area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA). Results: The AUCs for the ML model in the discovery cohort and independent validation cohort were 0.91 (0.88-0.94) and 0.86 (0.79-0.93), respectively. And 0.65 (0.59-0.71), 0.69 (0.59-0.79) for the DLCNN, 0.66 (0.59-0.72), 0.66 (0.55-0.76) for the clinical model, respectively. The nomogram exhibited the highest performance with AUCs of 0.93 (0.90-0.95) and 0.88 (0.81-0.94) The receiver operating characteristic curve (ROC) proved the superiority of the nomogram of clinical utility, and calibration curve showed the goodness of fit of the model. The DCA curve indicated that the nomogram outperformed other models in terms of net patient benefit. Conclusions: The study emphasized the intrinsic relationship between early pregnancy placental USI and the development of GDM. The use of nomogram holds potential for clinical applications in predicting the development of GDM.

Synergistic delivery of resveratrol and ultrasmall copper-based nanoparticles by aptamer-functionalized ultrasound nanobubbles for the treatment of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is related to the production of reactive oxygen species (ROS) and oxidative stress, so antioxidant treatment can prevent its further development. Ultrasmall copper-based nanoparticles (CuNPs) have shown multiple enzyme-like activities for scavenging oxygen species, providing a new strategy for the treatment of inflammatory diseases. Resveratrol (Res), a natural polyphenol compound, has attracted much attention due to its ability to inhibit oxidative stress. We therefore aimed to first combine these two agents for the treatment of NAFLD. However, due to the poor water solubility and stability of Res, which is easily metabolized in the intestine, the development of a stable and effective carrier became the key to achieving a synergistic effect. Liver-targeted nanocarriers loaded with bioactive compounds may provide a more effective approach for the treatment of NAFLD. Therefore, we developed a novel ultrasonic nanobubble carrying nucleic acid aptamers with liver targeting properties, which has the advantages of a small molecular weight, no immunogenicity, a low cost of synthesis, and high stability through chemical modification. Res and the ultrasmall CuNPs were specifically delivered to liver tissue to maximize therapeutic efficiency. This study found that the combination of these two components can effectively treat inflammation in NAFLD and suggested that liver-targeted NAFLD-specific aptamer-mediated targeted ultrasound nanobubbles that can simultaneously deliver Res and CuNPs may be a safe and effective new platform for NAFLD and other liver diseases.

Pharmacokinetics of Panax notoginseng Saponins in Adhesive and Normal Preparation of Fufang Danshen.

BACKGROUND AND OBJECTIVE: Fufang Danshen formula, a famous Chinese patent medicine containing Salvia miltiorrhiza, Panax notoginseng and borneol, has been widely used in the treatment of coronary heart disease. The application is restricted by low bioavailability partly due to Panax notoginseng saponins (PNS) instability and low in vivo absorption. Thus, adhesive pellets were developed to improve bioavailability. The objectives of the present study were to evaluate the adhesive preparation by describing PNS's plasma pharmacokinetics in vivo and compare adhesive micro pills with normal preparation. METHOD: LC-MS/MS method was established to analyze five ingredients, notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), ginsenoside Rb1 (Rb1), ginsenoside Re (Re), and ginsenoside Rd (Rd), in rats' plasma to describe the pharmacokinetic parameters of PNS. RESULTS: The pharmacokinetic parameters were significantly different after oral administration three formulations. The results show adhesive formulations are superior to Fufang Danshen tablet (FDT); there are differences between the two adhesive, but not obvious. CONCLUSIONS: It was found that the modification with adhesive materials improved PNS bioavailability in Fufang Danshen formula. These findings provide a way for further in vivo evaluation of different formulations.

A novel P755L mutation in LRRK2 gene associated with Parkinson's disease.

Parkinson's disease is a common neurodegenerative disorder. The identification of leucine-rich repeat kinase 2 (LRRK2) gene mutations as a cause of Parkinson's disease has greatly expanded our knowledge of the genetic and molecular pathogenesis of this disorder. By denaturing high-performance liquid chromatography and gene sequencing in patients and controls, we identified a novel frequent heterozygous 2264C-->T substitution, which causes a proline-to-leucine mutation (P755L) in LRRK2 gene. In our sample of 598 patients of Chinese Han ancestry, 12 cases carried the same LRRK2 mutation. Our results indicated that this single mutation was implicated in 2% of sporadic patients. We suggest that testing for this mutation will be important in the management and genetic counseling of patients with Parkinson's disease.

TGF-ß1 prevents blood-brain barrier damage and hemorrhagic transformation after thrombolysis in rats.

Transforming growth factor-beta1 (TGF-ß1) is well known to promote extracellular matrix accumulation. Recent studies demonstrated that TGF-ß1 protects against blood-brain barrier (BBB) disruption in the condition of inflammatory pain and stroke. In the present study, we investigated whether TGF-ß1 can maintain BBB integrity and prevent hemorrhagic transformation (HT) after recombinant tissue plasminogen activator (rt-PA) treatment in a rat model of thromboembolic middle cerebral artery occlusion (MCAO). Three hours after MCAO, rats were given saline, rt-PA alone or rt-PA combined with TGF-ß1 intravenously. Animals were sacrificed 24h after surgery. HT was calculated as hemorrhagic score. Evans blue dye extravasation was measured for BBB disruption. Basement membrane damage was observed by electron microscopy and quantified by collagen IV and laminin immunostaining. Gelatin zymography was used to measure the activities of matrix metalloproteinase (MMP)-2 and MMP-9. Western blot was performed for the expressions of MMP-2, MMP-9 and plasminogen activator inhibitor type-1 (PAI-1). Rats treated with rt-PA showed elevations in basement membrane damage, BBB disruption and HT. These phenomena were reduced in rats treated by TGF-ß1. We also showed that TGF-ß1 inhibited rt-PA mediated induction of MMP-2 and MMP-9. Meanwhile, TGF-ß1 upregulated PAI-1 expression which was reduced by rt-PA. Taken together, these results suggest that TGF-ß1 can reduce rt-PA induced basement membrane degradation, BBB disruption and HT. One possible mechanism is associated with the elevation of PAI-1. Suppression of MMP-2 and MMP-9 elevated by rt-PA may be another mechanism contributing to the protective effects of TGF-ß1.

Simvastatin exerts antiamnesic effect in Aß25-35 -injected mice.

AIM AND METHODS: Simvastatin (SV) is reported to improve cognition and slow the progression of Alzheimer's disease (AD). This study explored the mechanisms underlying the antiamnesic effect of SV in AD using behavior tests, histological examination, western blot analysis, and electrophysiological recording technique in AD model mice created by intracerebroventricular injection (i.c.v.) of Aß25-35 . RESULTS: Chronic administration of SV (40 mg/kg/day) for 11 days after Aß25-35 -injection ameliorated the impairment of acquisition performance and probe trail test in Morris water maze task and alternation behavior in Y maze task in Aß25-35 -mice. Aß25-35 -induced apoptosis of hippocampal CA1 pyramidal cells and Aß25-35 -impaired high-frequency stimulation (HFS)-dependent long-term potentiation (LTP) induction in hippocampal Schaffer collaterale-CA1 synapse were rescued by SV-treatment. SV prevented Aß25-35 -inhibited protein kinase B (Akt) and extracellular signal-related kinase-2 (ERK2) phosphorylation, which was sensitive to α7 nicotinic acetylcholine receptor (α7nAChR) antagonist MLA. SV-induced neuroprotection was attenuated by MLA or phosphatidylinositol-3-kinase (PI3K) antagonist LY294002. SV-rescued LTP induction was blocked by α7nAChR, PI3K or MAPK/ERK kinase (MEK) antagonist. Finally, the antiamnesia of SV in Aß25-35 -mice was attenuated by blockage of SV-induced neuroprotection or SV-rescued LTP induction. CONCLUSION: The antiamnesia of SV in Aß25-35 -mice depends on its neuroprotection and synaptic plasticity improvement.

Sinomenine reduces iNOS expression via inhibiting the T-bet IFN-γ pathway in experimental autoimmune encephalomyelitis in rats.

Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis (EAE) in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase (anti-iNOS) effect, which is related to the reductions of Th1 cytokine interferon-γ (IFN-γ) and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat interleukin 12 reduced the expression of T-bet and IFN-γ in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibitory effect on iNOS produced by astrocytes cultured with IFN-γ and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet /IFN-γ pathway.

Sinomenine, an antirheumatic alkaloid, ameliorates clinical signs of disease in the Lewis rat model of acute experimental autoimmune encephalolmyelitis.

The therapeutic value of an antirheumatic alkaloid, sinomenine (SIN), was investigated in the acute experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). SIN is a bioactive alkaloid derived from the Chinese medicinal plant, Sinomenium acutum REHDER & E. H. WILSON (Family Menispermaceae). Chinese doctors have utilized this plant to treat rheumatic and arthritic diseases for over one thousand years. Experiments in which EAE-induced Lewis rats exhibit an acute monophasic episode of disease demonstrated that SIN is effective in preventing clinical signs of disease. The therapeutic effect on disease activity was observed at preonset administration times and at various doses tested. Consistent with disease activity in vivo, SIN-treated animals have reduced cellular infiltration within the spinal cord along with decreased TNF-alpha and IFN-gamma expression levels. SIN can significantly inhibit proliferation response of splenocytes induced by MBP(68-82). TNF-alpha and IFN-gamma, secreted by splenocytes induced by MBP(68-82) are inhibited by SIN by dose-dependence manner. The mRNA levels of CC chemokines, RANTES, MIP-1alpha and MCP-1, are inhibited in SIN-treated EAE rats. The data in this proof of concept study support the premise that SIN may be a promising new therapeutic intervention in MS.