Clinical effect of different maintenance doses of caffeine citrate in the treatment of preterm infants requiring assisted ventilation: a pilot multicenter study. / ä¸åŒç»´æŒå‰‚é‡æž¸æ©¼é ¸å’–å•¡å› å¯¹è¾ åŠ©é€šæ°”æ—©äº§å„¿çš„ç–—æ•ˆè¯„ä¼°ï¼šä¸€é¡¹åˆæ­¥å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To explore the optimal maintenance dose of caffeine citrate for preterm infants requiring assisted ventilation and caffeine citrate treatment. METHODS: A retrospective analysis was performed on the medical data of 566 preterm infants (gestational age ≤34 weeks) who were treated and required assisted ventilation and caffeine citrate treatment in the neonatal intensive care unit of 30 tertiary hospitals in Jiangsu Province of China between January 1 and December 31, 2019. The 405 preterm infants receiving high-dose (10 mg/kg per day) caffeine citrate after a loading dose of 20 mg/kg within 24 hours after birth were enrolled as the high-dose group. The 161 preterm infants receiving low-dose (5 mg/kg per day) caffeine citrate were enrolled as the low-dose group. RESULTS: Compared with the low-dose group, the high-dose group had significant reductions in the need for high-concentration oxygen during assisted ventilation (P=0.044), the duration of oxygen inhalation after weaning from noninvasive ventilation (P<0.01), total oxygen inhalation time during hospitalization (P<0.01), the proportion of preterm infants requiring noninvasive ventilation again (P<0.01), the rate of use of pulmonary surfactant and budesonide (P<0.05), and the incidence rates of apnea and bronchopulmonary dysplasia (P<0.01), but the high-dose group had a significantly increased incidence rate of feeding intolerance (P=0.032). There were no significant differences between the two groups in the body weight change, the incidence rates of retinopathy of prematurity, intraventricular hemorrhage or necrotizing enterocolitis, the mortality rate, and the duration of caffeine use (P>0.05). CONCLUSIONS: This pilot multicenter study shows that the high maintenance dose (10 mg/kg per day) is generally beneficial to preterm infants in China and does not increase the incidence rate of common adverse reactions. For the risk of feeding intolerance, further research is needed to eliminate the interference of confounding factors as far as possible.

Early argatroban and antiplatelet combination therapy in acute non-lacunar single subcortical infarct associated with mild intracranial atherosclerosis.

BACKGROUND: Patients with acute non-lacunar single subcortical infarct (SSI) associated with mild intracranial atherosclerosis (ICAS) have a relatively high incidence of early neurological deterioration (END), resulting in unfavorable functional outcomes. Whether the early administration of argatroban and aspirin or clopidogrel within 6-12 h after symptom onset is effective and safe in these patients is unknown. METHODS: A review of the stroke database of Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University and Qingdao Center Hospital, Qingdao University Medical College in China was undertaken from May 2017 to January 2020 to identify all patients with non-lacunar SSI caused by ICAS within 6-12 h of symptom onset based on MRI screening. Patients were divided into two groups, one comprising those who received argatroban and mono antiplatelet therapy with aspirin or clopidogrel on admission (argatroban group), and the other those who received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel during hospitalization (DAPT group). The primary outcome was recovery by 90 days after stroke based on a modified Rankin scale (mRS) score (0 to 1). The secondary outcome was END incidence within 120 h of admission. Safety outcomes were intracranial hemorrhage (ICH) and major extracranial bleeding. The probability of clinical benefit (mRS score 0-1 at 90 days) was estimated using multivariable logistic regression analysis. RESULTS: A total of 304 acute non-lacunar SSI associated with mild ICAS patients were analyzed. At 90 days, 101 (74.2%) patients in the argatroban group and 80 (47.6%) in the DAPT group had an mRS score that improved from 0 to 1 (P < 0.001). The relative risk (95% credible interval) for an mRS score improving from 0 to 1 in the argatroban group was 1.50 (1.05-2.70). END occurred in 10 (7.3%) patients in the argatroban group compared with 37 (22.0%) in the DAPT group (P < 0.001). No patients experienced symptomatic hemorrhagic transformation. CONCLUSIONS: Early combined administration of argatroban and an antiplatelet agent (aspirin or clopidogrel) may be beneficial for patients with non-lacunar SSI associated with mild ICAS identified by MRI screening and may attenuate progressive neurological deficits. TRIAL REGISTRATION: Our study is a retrospectively registered trial.

Effect of Nonstructural Protein 2 Hypervariable Regions in the Replication of Porcine Reproductive and Respiratory Syndrome Virus in Marc-145 Cells.

BACKGROUND: Highly pathogenic (HP) porcine reproductive and respiratory syndrome virus (PRRSV) causes prolonged high fever, red discoloration of the body, blue ears and a high mortality. Previously, we found that the PRRSV vaccine strain TJM contained a deletion of 120 amino acids (aa 628-747) in nonstructural protein 2 (Nsp2). We aimed to explore the replication features of PRRSV after adding the transiently expressed product of these 120 aa in vitro. METHODS: We constructed seven eukaryotic expression plasmids containing different parts of the 120-aa sequence, transfected them into Marc-145 cells and then inoculated the cells with 103 TCID50 TJM per well. We detected virus replication at mRNA and protein level by real-time RT-PCR and Western blotting, respectively, and determined the virus titer. RESULTS: The transiently expressed 120 aa and one of its truncated polypeptides inhibited PRRSV TJM propagation on Marc-145 cells. The complete 120-aa sequence induced a remarkable decrease in PRRSV replication, causing a reduction in structural protein levels between 36 and 48 h after infection. Additionally, aa 628-727 partly reduced the replication of PRRSV on Marc-145 cells. CONCLUSIONS: The 120 aa from Nsp2, especially aa 628-727, play a negative role in PRRSV TJM proliferation.

Hydrogen sulfide as an effective and specific novel therapy for acute carbon monoxide poisoning.

Hydrogen sulfide (H(2)S) has been recognized as a toxic gas and environment pollutant. So, it is seldom regarded as a therapeutic gas. H(2)S has been recognized recently as a novel gaseous messenger and serves as an important neuromodulator in the central nervous system. Many researches have been focused on the protective role of H(2)S in treatment of several diseases. Like nitric oxide (NO) and carbon monoxide (CO), which are considered as two gaseous transmitters, H(2)S has been regarded as the third one. Recent studies provided evidence that H(2)S exerted antioxidant and anti-apoptotic effects, which protected neurons, cardiomyocytes, pancreatic ß-cells and vascular smooth muscle cells against oxidative stress by scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS). It has been known that multiple factors, including oxidative stress, free radicals and neuronal nitric oxide syntheses as well as abnormal inflammatory responses are involved in the mechanism underlying the brain injury after acute CO poisoning. Studies have shown that free radical scavengers can display neuroprotective properties. Therefore, we hypothesize that H(2)S might be an interesting potential strategy for curing acute CO poisoning.

Lysophosphatidic acid level and the incidence of silent brain infarction in patients with nonvalvular atrial fibrillation.

Lysophosphatidic acid (LPA), which is proposed to play an important role in normal physiological situations such as wound healing, vascular tone, vascular integrity and reproduction, may be involved in the etiology of some diseases such as atherosclerosis, cancer, obesity or myocardial infarction. Abnormal findings, including silent brain infarction (SBI), are frequently observed by magnetic resonance imaging (MRI) in patients with nonvalvular atrial fibrillation (NVAF). However, whether there is a relationship between LPA level and the prevalence of SBI has not been extensively studied. In the present study, the association between them was investigated. 235 patients with NVAF, 116 cases of SBI without NVAF and 120 cases of healthy volunteers (control group), who did not receive any antithrombotic therapy, were enrolled in this study. Plasma LPA levels in the NVAF with SBI group were significantly higher than that in the control group (p < 0.01), NVAF without SBI group (p < 0.01) and SBI without NVAF group (p < 0.01). The LPA levels are lower in the control group than in the NVAF without SBI and SBI without NVAF groups (p < 0.01), however, the latter two groups did not significantly differ from each other for LPA levels (p > 0.05) There were significant differences in the positive rate of platelet activation between each of the groups (p < 0.01). The positive rate of platelet activation was significantly higher in the NVAF with SBI group. We suggest that LPA might be a novel marker for estimation of the status of platelet activation and the risk factor for SBI onset in NVAF patients. We expected that plasma LPA levels could predict the occurrence of SBI in NVAF patients.

Influence of acetylsalicylate on plasma lysophosphatidic acid level in patients with ischemic cerebral vascular diseases.

BACKGROUND AND PURPOSE: Lysophosphatidic acid (LPA) is released from activated platelets. Acetylsalicylate (aspirin) is the most commonly used antiplatelet drug. The purpose of this study is to observe whether treatment with acetylsalicylate decreases the LPA level in patients with ischemic cerebrovascular diseases. METHODS: We performed a study examining LPA level in fresh plasma in cases and controls enrolled in the LPA and Stroke Prevention Study. Level of LPA was assayed by measuring its inorganic phosphorus after separation by chromatography. RESULTS: An elevated LPA level was seen in cases (n = 254) with ischemic cerebrovascular disease (3.11+/- 1.55 micromol/l) compared with 136 healthy controls (1.77 +/- 1.04 micromol/l) (p < 0.001). Administration of aspirin (100 mg q.d.) for 1 month significantly lowered LPA level in patients (n = 142) (2.41 +/- 1.03 mu mol/l) compared with that before taking acetylsalicylate (4.06 +/- 1.03 micromol/l) (p < 0.001). However, the LPA level in patients (n = 36) who stopped acetylsalicylate after taking it for 1 month was re-elevated. Before and after taking acetylsalicylate for 1 month, their LPA levels were 4.23 +/- 1.15 and 1.93 +/- 0.85 micromol/l, respectively. After 1 month withdrawal, level was 3.90 +/- 1.09 micromol/l (p < 0.001 compared that before taking acetylsalicylate). CONCLUSION: Our findings support a close association between increased plasma LPA level and platelet activation. Acetylsalicylate could decrease plasma LPA levels, which may be used as a mechanism for acetylsalicylate in the prevention of ischemic stroke.

NLRP6 Inflammasome Ameliorates Brain Injury after Intracerebral Hemorrhage.

NLRP6 inflammasome, one of the important intracellular innate immune sensors, has been shown to regulate immune responses. However, its roles in the intracerebral hemorrhage (ICH) are completely not clear. In the present study, we investigated the expression profile and biological roles of NLRP6 inflammasome in perihematomal brain tissues of mice subjected to ICH. In this study, we investigated the expression profile of NLRP6 inflammasome in the perihematomal brain tissues and explored the biological role of NLRP6 inflammasome upon acute brain injury in mice subjected to ICH. Increased expression of NLRP6 inflammasome was found in perihematomal brain tissues ranging from 6 h to 3 days, with a peak level at 1 day after ICH. Immunohistochemistry staining also showed that NLRP6 inflammasome was significantly increased in the perihematomal brain tissues at 1 day after ICH. Moreover, immunofluorescence staining showed that NLRP6 inflammasome was mainly colocalized in glial fibrillary acidic protein (GFAP)-positive astrocytes, while with little colocalized expression in NeuN-positive neurons and without expression in CD11b-positive microglia and CD31-positive endothelial cell in the perihematomal brain tissue of mice after ICH. Furthermore, NLRP6-/- ICH mice exhibited significantly higher brain water contents (BMCs), proinflammatory cytokines, NF-κB activity and neurological deficit scores when compared with the wild type (WT) ICH mice. In addition, we found that Toll-like receptor 4 (TLR4)-/- mice, as well as the TAK242 treated mice, had markedly lower expression of NLRP6 inflammasome expression in the perihematomal brain tissue at 1 day after ICH. Our data suggest that the upregulated NLRP6 inflammasome in perihematomal brain tissues attenuates ICH-induced brain injury.

Plasma Phospholipids are Associated with Mild Cognitive Impairment in Type 2 Diabetic Patients.

BACKGROUND: Phospholipids and their metabolisms are closely allied to nosogenesis and aggravation of Type 2 diabetes mellitus and cognitive impairment. The aim of this study is to characterize the plasma levels of phospholipids in type 2 diabetes patients and type 2 diabetes patients with mild cognitive impairment (MCI), and to identify potential biomarkers of type 2 diabetes patients with MCI. METHODS: In this cross-sectional study, a total of 374 type 2 diabetes patients were prospectively enrolled. There were 103 patients with MCI and 271 patients without MCI. Plasma levels of lysophosphatidic acid (LPA) and phospholipids with solubility similar to that of LPA (PSS-LPA) were assayed. RESULTS: Plasma LPA and PSS-LPA levels were significantly higher in patients with MCI than those without MCI (P = 0.007, P ＜ 0.001). A logistic regression analysis indicates that elevated plasma PSSLPA was associated with increased risk of MCI in type 2 diabetic patients, with an OR of 1.87 (1.04- 3.47) after additional adjustment for hyperlipidemia, hypertension, High-sensitivity C-reactive protein, hemoglobin A1c, Intima-media thickness, ankle brachial index, and brachial-ankle pulse wave velocity. In type 2 diabetic patients with MCI, there were negative correlations between plasma LPA, PSS-LPA and the MoCA scores (r =﹣0.322, P < 0.01; r =﹣0.349, P < 0.001). Furthermore, plasma PSS-LPA exhibited a fair diagnostic value for MCI, with an area under the curve of 0.86. CONCLUSION: The level of plasma PSS-LPA may be an important biomarker for diagnosis of MCI.

Biomarkers of Renal Function in Type 2 Diabetic Patients with Cognitive Impairment.

Kidney disease is associated with cognitive impairment in studies of nondiabetic adults. We examined the cross-sectional relation between three measures of renal function and cognitive impairment (CI) in type 2 diabetic patients. A total of 357 patients with type 2 diabetes were prospectively enrolled. There were 108 patients with CI and 249 patients without CI (control). We calculated the urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Serum Cystatin C (Cys C) was measured with an automated particle-enhanced turbidimetric immunoassay. UACR and Cystatin C levels were significantly higher in patients with CI than those without CI (P<0.001), and the eGFR was lower in patients with CI than those without (P=0.003). A logistic regression analysis indicates that kidney impairment biomarkers levels were significantly associated with an increased risk of CI after adjustment for age and gender. The OR of each kidney biomarker (eGFR, UACR, Cystatin C) for CI status was 1.78 (0.89-3.27), 2.36 (1.29-4.42), and 2.77 (1.36-5.97), respectively. Among three kidney biomarkers (eGFR, UACR, Cystatin C), only elevated serum Cystatin C was associated with increased risk of CI in type 2 diabetic patients, with an OR of 1.42 (1.25-4.24) after additional adjustment for duration of diabetes, hypertension, hyperlipidemia, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (Hs-CRP), intima-media thickness (IMT), ankle brachial index (ABI), and brachial-ankle pulse wave velocity (ba-PWV). Furthermore, combination of conventional risk factors and Cystatin C levels exhibited a fair diagnostic value for CI, with an area under the curve (AUC) of 0.91. Among three kidney impairment biomarkers (eGFR, UACR, Cystatin C), only elevated serum Cystatin C was associated with increased risk of CI in type 2 diabetic patients, independent of conventional risk factors. Furthermore, Cystatin C may be a better marker for CI than eGFR and UACR, and exhibited diagnostic value.

Associations between biomarkers of renal function with cerebral microbleeds in hypertensive patients.

BACKGROUND: Cerebral microbleeds (CMBs) have been observed in the elderly and have been regarded as a manifestation of small vessel disease (SVD). Cerebral and glomerular SVD may have a common source of pathogenesis because these organs are closely connected through anatomic and hemodynamic similarities. The purpose of this study was to clarify the associations between kidney biomarker levels and CMBs in hypertensive patients. METHODS: The presence and number of CMBs were assessed on susceptibility-weighted imaging. We calculated the urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Serum cystatin C (CysC) was measured with an automated particle-enhanced turbidimetric immunoassay. RESULTS: UACR and CysC levels were higher in the patients with CMBs than those without, and the eGFR was lower in the patients with CMBs than those without. A logistic regression analysis indicates that eGFR and UACR were independently associated with the prevalence of deep or infratentorial CMBs. The odds ratio (OR) (95% confidence interval (CI)) of eGFR and UACR was 1.95 (1.37-3.27) and 2.25 (1.66-4.46), respectively. CysC was independently associated with CMBs in both deep or infratentorial and lobar locations. The ORs (95% CI) were 2.59 (1.57-6.22) and 1.57 (1.15-4.85), respectively. Furthermore, CysC exhibited fair diagnostic value for CMBs, with an area under the curve of 0.80. CONCLUSIONS: Kidney biomarker levels are associated with the presence of CMB in hypertensive patients without a history of transient ischemic attack (TIA) or stroke, independent of conventional risk factors, and CysC was a better marker for CMBs than eGFR and UACR.

Recombinant rabies virus expressing the H protein of canine distemper virus protects dogs from the lethal distemper challenge.

The rabies virus (RV) vector LBNSE expressing foreign antigens have shown considerable promise as vaccines against viral and bacteria diseases, which is effective and safe. We produced a new RV-based vaccine vehicle expressing 1.824 kb hemagglutinin (H) gene of the canine distemper virus (CDV) by reverse genetics technology. The recombinant virus LBNSE-CDV-H retained growth properties similar to those of vector LBNSE both in BSR and mNA cell culture. The H gene of CDV was expressed and detected by immunostaining. To compare the immunogenicity of LBNSE-CDV-H, dogs were immunized with each of these recombinant viruses by intramuscular (i.m.). The dogs were bled at third weeks after the immunization for the measurement of virus neutralizing antibody (VNA) and then challenged with virulent virus (ZJ 7) at fourth weeks. The parent virus (LBNSE) without expression of any foreign molecules was included for comparison. Dogs inoculated with LBNSE-CDV-H showed no any signs of disease and exhibited seroconversion against both RV and CDV H protein. The LBNSE-CDV-H did not cause disease in dogs and conferred protection from challenge with a lethal wild type CDV strain, demonstrating its potential value for wildlife conservation efforts. Together, these studies suggest that recombinant RV expressing H protein from CDV stimulated high levels of adaptive immune responses (VNA), and protected all dogs challenge infection.

[Genetic variation and pathogenicity analysis of highly pathogenic porcine reproductive and respiratory syndrome virus strain TJ in the course of attenuation].

To develop an attenuated vaccine against the highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRS) virus, the HP-PRRS virus strain TJ was attenuated by serial passages and plaque cloned every 5 to 10 passages in Marc-145 cells. Genetic variation and pathogenicity of HP-PRRSV strain TJ in the course of attenuation were analyzed. The results showed that the strain TJ sustained various sequence changes during the course of attenuation. Fifty-eight amino acids changes and a new continuous 120 amino acids deletion after the discontinuous 30 amino acids deletion (sites 481 and 533-561) occurred in strain TJ passages 140, and the position of 120 amino acids deletion was between 628 to 747 according to VR-2332. Animal test showed that the pathogenicity of strain TJ passages 20 was attenuated obviously, so we presume that genetic variation in nonstructural protein nsp2-nsp5, nsp7 and structural protein GP5 during the attenuation provides the molecular bases for the observed attenuated phenotype.

Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat.

Increasing evidence suggests the beneficial effects of acupuncture on Parkinson's disease (PD). Although clinical evidence for the acupuncture anti-Parkinson's disease effect has been demonstrated, the precise mechanism still remains elusive. It has been suggested a relationship between PD and reactive oxygen species (ROS) can result in neurodegeneration. The aim of this study was to evaluate the status of oxidative stress, as well as the antioxidant enzyme response, and the role of acupuncture stimulation at GB34 (Yanglingquan), LR3 (Taichong), ST36 (Zusanli) and SP10 (Xuehai) acupoints on regulating oxidative stress in the nigrostriatal system in the 6-hydroxydopamine (6-OHDA) lesioned rat. Two weeks after unilateral injection of 6-OHDA into the left medial forebrain bundle (MFB), an apomorphine induced rotational behavior test was performed. The levels of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic, viz., reduced glutathione (GSH), and the levels of malondialdehyde (MDA) in the nigrostriatal system were measured to assess the oxidative stress status. Brain MDA levels significantly increased, while GSH levels were decreased in impaired groups with 6-OHDA injection only, accompanied by a marked reduction in the level of SOD and GSH-Px. The levels of oxidative stress related parameters except CAT, as well as the rotational asymmetry, were reversed by acupuncture stimulation. These results showed that acupuncture treatment displayed antioxidative and/or neuroprotective properties in the 6-OHDA lesioned rat and these protective properties might be mediated, at least in part, by involving regulation of the antioxidant defense system.

[Progress of studies on the mechanism of acupuncture treatment of acute ischemic cerebral stroke].

In the present paper, the authors review the current development of studies on mechanisms of acupuncture treatment of acute ischemic cerebral apoplexy from (1) blood rheology, (2) cerebral microcirculation, 3) metabolism of cerebral tissue, (4) cerebral electrical activity, (5) free radicals and lipid peroxidation reaction, (6) excitatory aminoacid, (7) calcium overload, (8) nitrogen monoxidum, and (9) cerebral apoptosis. Cerebral stroke includes ischemic stroke and hemorrhagic stroke. Ischemic cerebral stroke accounted for about 60%-70% of all the stroke cases. At present, the main remedies for treating acute ischemic cerebral stroke includes thrombolysis, anti-platelet aggregation, improving microcirculation and symptomatic therapy. In stroke, highlighting the efficacy of acupuncture therapy in the treatment of stroke.